TREA

1-indolyalkyl-4-(substituted-pyridinyl)piperazines

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Information

  • Patent Grant
  • 4954502
  • Patent Number
    4,954,502
  • Date Filed
    Friday, April 14, 1989
    35 years ago
  • Date Issued
    Tuesday, September 4, 1990
    33 years ago
Information
Abstract
A series of 1,4-disubstituted piperazine derivatives comprised of indol-3-ylalkyl and substituted pyridin-2-yl substituent groups. These compounds are useful as antidepressant agents.
Description
Claims
  • 1. A compound of Formula I aor the pharmaceutically acceptable acid addition salts thereof, ##STR58## wherein R.sup.1 and R.sup.2 are independently selected from hydrogen and lower alkyl, wherein lower means C.sub.1-4 ;
  • R.sup.3, R.sup.4, R.sup.8 and R.sup.9 are independently selected from hydrogen, lower alkyl, lower alkoxy, carboxamide, halogen, trifluoromethyl and thio-lower alkyl, with the proviso that R.sup.8 and R.sup.9 cannot both be hydrogen at the same time;
  • A is a C.sub.5-7 cycloalkanyl or cycloalkenyl ring, or A is ##STR59## wherein n is an integer from 1 to 3 and R.sup.5 is the same as R.sup.1 ; and
  • R.sup.6 and R.sup.7 are independently selected from hydrogen, methyl or R.sup.6 and R.sup.7 can be taken together as a methylene bridge.
  • 2. The compound of claim 1 wherein A is a C.sub.5-7 cycloalkanyl or cycloalkenyl ring.
  • 3. The compound cf claim 1 wherein A is ##STR60##
  • 4. The compound cf claim 1 wherein R.sup.6 and R.sup.7 are selected from hydrogen or methyl.
  • 5. The compound cf claim 1 wherein R.sup.6 and R.sup.7 are taken together as a methylene bridge.
  • 6. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4(3-methoxy-2-pyridinyl)piperazine.
  • 7. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4(3-trifluoromethyl-2-pyridinyl) -piperazine.
  • 8. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4(3-methoxy-2-pyridinyl)-2-methypiperazine.
  • 9. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-5(3-methoxy-2-pyridinyl)-(1R,4R)-2,5-diazabicyclo[2.2.1] heptane.
  • 10. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4(6-chloro-2-pyridinyl)piperazine.
  • 11. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4(6-methoxy-2-pyridinyl)piperazine.
  • 12. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-5(3-methoxy-2-pyridinyl)-(1S,4S)-b 2,5-diazabicyclo[2.2.1] heptane.
  • 13. The compound of claim 1; 1-[3-(1H-indol-3-yl)propyl]-4(3-methoxy-2-pyridinyl)piperazine.
  • 14. The compound of claim 1; 1-[3-(1H-indol-3-yl)propyl]-4(6-chloro-2-pyridinyl)piperazine.
  • 15. The compound of claim 1; 1-[4-(1H-indol-3-yl)butyl]-4(3-methoxy-2-pyridinyl)piperazine.
  • 16. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4(6-trifluoromethyl-2-pyridinyl)-piperazine.
  • 17. The compound of claim 1; 2-[2-(1H-indol-3-yl)ethyl]-5(6-chloro-2-pyridinyl)-(1S,4S)-2,5diazabicyclo[2.2.1]heptane.
  • 18. The compound of claim 1; 2-[2-(1H-indol-3-yl)ethyl]-5(6-chloro-2-pyridinyl)-(1R,4R)-2,5-diazabicyclo[2.2.1] heptane.
  • 19. The compound of claim 1; 1-[3-(1H-indol-3-yl)propyl]-4(6-trifluoromethyl-2-pyridinyl)-piperazine.
  • 20. The compound of claim 1; 1-[4-(1H-indol-3-yl)butyl]-4(6-chloro-2-pyridinyl)piperazine.
  • 21. The compound of claim 1; 1-[4-(1H-indol-3-yl)butyl]-4(6-trifluoromethyl-2-pyridinyl)-piperazine.
  • 22. The compound of claim 1; 1-[3-(1H-indol-3-yl)propyl]-4(4-trifluoromethyl-2-pyridinyl)-piperazine.
  • 23. The compound of claim 1; 2-[3-(1H-indol-3-yl)propyl]-5(3-methoxy-2-pyridinyl)-(1S,4)-2,5-diazabicyclo[2.2.1] heptane.
  • 24. The compound of claim 1; 2-[3-(1H-indol-3-yl)propyl]-5(3-methoxy-2-pyridinyl)-(1R,4R)- 2,5-diazabicyclo[2.2.1] heptane.
  • 25. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4(6-chloro-2-pyridinyl)-2-methylpiperazine.
  • 26. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4(4-trifluoromethyl-2-pyridinyl)-piperazine.
  • 27. The compound of claim 1; 1-[2-(5-methoxy-1H-indol-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)piperazine.
  • 28. The compound of claim 1; 1-[2-(5-fluoro-1H-indol-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)piperazine.
  • 29. The compound of claim 1; 1-[2-(5-methoxy-1H-indol-3-yl)ethyl]-4-(6-chIoro-2-pyridinyl)piperazine.
  • 30. The compound of claim 1; 1-[2-(5-fluoro-1H-indol-3-yl)ethyl]-4-(6-chloro-2-pyridinyl)piperazine.
  • 31. The compound of claim 1; 1-[2-(1H-indol-3-yl)-ethyl]-4(3-chloro-2-pyridinyl)piperazine.
  • 32. The compound of claim 1; 1-[2-(5-fluoro-1H-indol-3-yl)ethyl]-4-(6-trifluoromethyl-2-pyridinyl)piperazine.
  • 33. The compound of claim 1; 1-[2-(5-methoxy-1H-indol-3-yl)ethyl]-4-(6-trifluoromethyl-2-pyridinyl)piperazine.
  • 34. The compound of claim 1; 3-[4-[4-(6-chloro-2-pyridinyl)1-piperazinyl]-1-cyclohexen-1-yl]-5-methoxyindole.
  • 35. The compound of claim 1; 3-[4-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]-1-cyclohexen-1-yl]-1H-indole
  • 36. The compound of claim 1; 3-[4-[4-(6-chloro-2-pyridinyl)1-piperazinyl]-1-cyclohexen-1-yl]-1H-indole-5-carboxamide.
  • 37. The compound of claim 1; 1-[2-(N-methyl-1H-indol-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)-piperazine.
  • 38. The compound of claim 1; 1-[2-(5,6-dimethoxy-1H-indol-3yl)ethyl]-4-(3-methoxy-2-pyridinyl)piperazine.
  • 39. The compound of claim 1; 1-[3-(N-methyl-1H-indol-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-piperazine.
  • 40. The compound of claim 1; 1-[3-(N-methyl-1H-indol-3-yl)propyl]-4-(6-chloro-2-pyridinyl)-piperazine.
  • 41. The compound of claim 1; 1-[3-(5-fluoro-1H-indol-3-yl)propyl]-4-(6-chloro-2-pyridinyl)piperazine.
  • 42. The compound of claim 1; 1-[3-(5-fluoro-1H-indol-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)piperazine.
  • 43. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4(5-chloro-2-pyridinyl)piperazine.
  • 44. The compound of claim 1; 1-[2-[N-methyl-1H-indol-3-yl)ethyl]-4-(6-chloro-2-pyridinyl)-piperazine.
  • 45. The compound of claim 1; 1-[2-(5-chloro-1H-indol-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)piperazine.
  • 46. The compound of claim 1; 1-[2-(5-chloro-1H-indol-3-yl)ethyl]-4-(6-chloro-2-pyridinyl)piperazine.
  • 47. The compound of claim 1; 1-[2-(5-chloro-1H-indol-3-yl)ethyl]-4-(6-trifluoromethyl-2-methyl-piperazine.
  • 48. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)-2-methyl-piperazine.
  • 49. The compound of claim 1; 4-(6-chloro-2-pyridinyl)-1-[2-(6-methoxy-1H-indol-3-yl)ethyl]-piperazine.
  • 50. The compound of claim 1; 1- methoxy-1H-indol-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)-piperazine.
  • 51. The compound of claim 1; 1-[3-(1H-indol-3-yl)-3-methylpropyl]-4-(6-chloro-2-pyridinyl)piperazine.
  • 52. The compound of claim 1; 1-[3-(1H-indol-3-yl)-3-methylpropyl]-4-(3-methoxy-2-pyridiyl)piperazine.
  • 53. The compound of claim 1; 1-[2-(5,6-dimethoxy-1H-indol3-yl)ethyl]-4-(6-trifluoromethyl-2-pyridinyl)piperazine.
  • 54. The compound of claim 1; 3-[4-[4-(6-chloro-2-pyridinyl)-1piperazinyl]-1-cyclohexen-1-yl]-5-fluoro-1H-indole.
  • 55. The compound of claim 1; 4-(5-chloro-3-methoxy-2-pyridinyl)-1-[3-(1H-indol-3-yl)-propypyl]-piperazine hydrochloride.
  • 56. The compound of claim 1; 4-(6-chloro-2-pyridinyl)-1-[3-(1H-indol-3-yl)propyl]-2-methyl-piperazine.
  • 57. A method for ameliorating of depression in a mammal comprising administration to said mammal of an effective antidepressant amount of a compound claimed in claim 1.
  • 58. A antidepressant pharmaceutical composition in dosage unit form suitable for systemic administration to a mammalian host comprising a pharmaceutical carrier and from about 1 to 500 mg of an active compound selected from the compounds claimed in claim 1.
CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part application of Ser. No. 07/204,845 filed June 10, 1988, now abandoned. This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular the invention is concerned with 1,4-disubstituted piperazine derivatives wherein one substituent is indol-3-yl-alkyl and the other is a substituted pyridin-2-yl moiety. These compounds possess a unique serotonergic profile that should make them useful in treatment of depression. Archer disclosed a large series of CNS-depressant indolylalkylpiperazines in U.S. Pat. No. 3,188,313 which issued June 8, 1965. Among the large number of moieties listed for possible substituent selection on the 4-nitrogen atom of the piperazine ring was pyridyl (unsubstituted). In U.S. Pat. No. 3,562,278, issued Feb. 9, 1971, Archer claimed a series of 1-(indol-3-ylethyl)-4-substituted-piperazines having psychomotor depressant activity. Among the possible 4-substituents listed was pyridyl, again unsubstituted. Of less relevance is U.S. Pat. No. 3,472,855, issued October 1969 to Archer, which discloses extension of the series to benz[g]indolyl moieties as replacements for indolyl. Similarly less relevant is U.S. Pat. No. 4,302,589, issued November 1981 to Fanshawe, et al., which discloses a series of related compounds wherein indoline has replaced the indole moiety. These compounds were disclosed as having antipsychotic properties. None of the aforementioned references disclose or suggest the 1-indolylalkyl-4-(substituted-pyridinyl)-piperazine derivatives and their antidepressant utility of the present invention. In its broadest aspect, the present invention is concerned with piperazinyl derivatives having useful antidepressant properties characterized by a compound of Formula I. ##STR1## In Formula I; R.sup.1 and R.sup.2 are independently selected from hydrogen or lower alkyl. The descriptive term "lower" is used herein to denote an organic radical containing from 1 to 4 carbon atoms. The symbols R.sup.3, R.sup.4, R.sup.8 and R.sup.9 refer to moieties which are independently selected from among hydrogen, lower alkyl, lower alkoxy, carboxamide, halogen, trifluoromethyl, and lower alkylthio; with the proviso that both R.sup.8 and R.sup.9 cannot be hydrogen at the same time. The symbol A represents a cycloalkanyl or cycloalkenyl ring comprised of from 5 to 7 carbon atoms. These bridging rings may be 1,2-; 1,3-; or 1,4-disubstituted bridging cycloalkanes or cycloalkenes. In the cycloalkenyl ring the double bond is adjacent to the point of attachment of the 3-indolyl ring. The symbol A can also be the structural fragment: ##STR2## In this fragment linking the indole piperazine rings, n is an integer from 1 to 3 and R.sup.5 can be either hydrogen or lower alkyl. The carbon atom to which R.sup.5 is attached is adjacent to the piperazine ring. Lastly, R.sup.6 and R.sup.7 are independently selected from hydrogen or methyl, or R.sup.6 and R.sup.7 can be taken together as a methylene bridge. Subclasses of compounds envisioned would be: A is cyclic or linear in structure; the piperazine ring is bridged or unbridged. Preferred classes of compounds are those wherein the indolyl and piperazinyl rings are connected by a 2 or 3 carbon linking chain and wherein R.sup.9 is other than hydrogen and is attached to the 6-position of the 2-pyridinyl ring. Additionally compounds of Formula I also encompass all pharmaceutically acceptable acid addition salts and/or solvates thereof. The present invention is also considered to include stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds of the instant series. Separation of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. It is to be understood that, as used herein, halogen denotes fluorine, chlorine, bromine and iodine; with the term "lower alkyl" referring to both straight and branched chain carbon radicals of from 1 to 4 carbon atoms inclusive. Illustrative of these radicals are carbon chains which can be methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl and 2-methylpropyl. Carboxamide intends a ##STR3## radical. The pharmaceutically acceptable acid addition salts of the invention are those in which the counter-ion does not contribute significantly to the toxicity or pharmacological activity of the salt and, as such, they are the pharmacological equivalents of the bases of Formula I. They are generally preferred for medical usage. In some instances, they have physical properties which makes them more desirable for pharmaceutical formulation such as solubility, lack of hygroscopicity, compressibility with respect to tablet formation and compatibility with other ingredients with which the substance may be used for pharmaceutical purposes. The salts are routinely made by admixture of a Formula I base with the selected acid preferably by contact in solution employing an excess of commonly used inert solvents such as water, ether, benzene, methanol, ethanol, ethyl acetate and acetonitrile. They may also be made by metathesis or treatment with an ion exchange resin under conditions in which the anion of one salt of the substance of the Formula I is replaced by another anion under conditions which allow for separation of the desired species such as by precipitation from solution or extraction into a solvent, or elution from or retention on an ion exchange resin. Pharmaceutically acceptable acids for the purposes of salt formation of the substances of Formula I include sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, cinnamic, mandelic, phosphoric, nitric, mucic, isethionic, palmitic, heptanoic, and others. The compounds of Formula I can be prepared by means of the processes shown in Scheme 1. ##STR4## For the three processes depicted in Scheme 1; R.sup.1 through R.sup.9, and n are as defined hereinabove. Additional symbols appearing in Scheme 1 are f, g, M, X and Y. The symbols f and g are integers from 0 to 5 with the proviso that f+g must be equal to 3, 4 or 5. M represents a metalloid species such as magnesium, lithioaluminum, and the like; which, taken with R.sup.5 are either hydride-type reducing agents such as lithium aluminum hyrides, diborane complexes, etc.; or organometallic alkylating agents such as Grignard reagents, etc. The reagent Y-X represents an organic leaving group reagent wherein X is the leaving group fragment such as tosyl, mesyl, halide, sulfate, phosphate and so forth; and Y is either a proton or a counter ion: e.g. XY can be HBr or tosyl chloride and the like. These reagents, symbolized by R.sup.5 -M and Y-X, as well as other reagent acronyms, are familiar to the practitioner skilled in organic synthesis and their structure and usage would be readily understood. Process #1 in Scheme 1 comprises the following steps: (1) Treatment of an indole carboxylic acid II with R.sup.5 -M, which is either a hyride reducing agent or alkylating agent depending on the selection of R.sup.5 (hydrogen or lower alkyl). This results in generation of the indolylalkanol VI which is a secondary alcohol when R.sup.5 is lower alkyl and a primary alcohol when R.sup.5 is hydrogen (2) Conversion of the alcohol VI to an organic leaving group (also referred to as a nucleofuge in synthetic organic reaction terminology) by use of an appropriate Y-X reagent such as HBr or tosyl chloride to give intermediate V. (3) Displacement of the leaving group anion by the nucleophilic pyridinylpiperazine III to provide the desired product of formula Ia. Process #2 in Scheme 1 comprises a two-step reaction sequence: (1) Condensation of the indolylcarboxylic acid II with the pyridinylpiperazine III, using standard condensation agents such as acid chlorides, acid anhydrides, dicyclohexylcarbodiimide, and the like, to afford the amide intermediate IV. (2) Treatment of the amide IV with R.sup.5 -M to reductively alkylate or reduce to the desired formula Ia product. Process #3 in Scheme 1 comprises the following sequence of steps: (1) The pyridinylpiperazine III is reductively alkylated with a cycloalkanedione mono-ethylene ketal X to give the ketal intermediate IX. (2) Deprotecting the ketal IX to produce the cycloalkanone intermediate VIII. (3) Condensing the cycloalkanone VIII with indole VII to yield the cycloalkenyl product Ib which can be catalytically reduced to the cycloalkanyl product Ic if desired. (1) The indole VII, cycloalkanedione mono-ethylene ketal X, and an acid or base catalyst (e.g. pyrrolidine) are refluxed in alcohol to give the condensation product XII. (2) Intermediate XII is catalytically reduced to the saturated cycloalkane ketal which is deketalized to the cycloalkanone intermediate XI. (3) Cycloalkanone XI is condensed with the pyridinylpiperazine III using conditions as shown to yield product Ic. Reagents, solvents, and reaction conditions for the above described steps of the three processes would be known to one skilled in organic synthesis as all the steps comprise standard organic reactions, the details of which are readily available in the chemical literature. These processes may be adapted to variation in order to produce other compounds embraced by this invention but not specifically disclosed. Variations of the methods to produce the same compounds in somewhat different fashion will also be evident to one skilled in the art. As example of this, VI intermediate compounds wherein n is 1 are conveniently prepared by treating various substituted 3-indoleglyoxylic acid esters with LiAlH.sub.4. To provide greater descriptive detail, representative synthetic examples are provided hereinbelow in the "Description of Specific Embodiments" section. Similarly, preparations of starting intermediate compounds such as II and III, while readily available in the chemical literature, are also described using specific examples in that section of the patent specification. The compounds comprising the present invention inhibit the re-uptake of endogenous serotonin. Selective inhibitors of serotonin uptake are effective for the treatment of mental depression and have been reported to be useful for treating chronic pain (see: R. W. Fuller, "Pharmocologic Modification of Serotonergic Function, Drugs for the Study and Treatment of Psychiatric and Other Disorders", J. Clin. Psychiatry 47:4 (Suppl.) April 1986, pp. 4-8). Compounds of the present invention are also envisioned to be useful in the following disorders: obsessive-compulsive disorder, feeding disorders, anxiety disorders and panic disorders. Additionally, selected compounds of the invention potently inhibit norepinephrine re-uptake and blockade of endogenous norepinephrine re-uptake is also a mechanism through which it is believed that various antidepressant agents exert their therapeutic effect (see: "Antidepressants: Neurochemical, Behavioral, and Clinical Perspectives", edited by S. J. Enna, J. B. Malick and E. Richardson, (1981), Raven Press, New York, pp. 1-12). Determination of endogenous monoaminergic re-uptake inhibition values both for serotonin and norepinephrine was accomplished using test methods described by P. Skolnick, et al.. Br. J. Pharmacology (1985), 86, pp. 637-644; with only minor modifications. In vitro IC.sub.50 (nM) test values were determined for representative compounds of Formula I based on their inhibition of synaptosomal reuptake of tritiated serotonin. Test data IC.sub.50 values lower than 500 nM are considered to reflect activity as an inhibitor of serotonin reuptake. Compounds with Ic.sub.50 values lower than 1OO nM comprise preferred compounds. Another aspect of the instant invention provides a method for treating a mammal afflicted with depression or chronic pain which comprises administering systemically to said mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof. The administration and dosage regimen of compounds of Formula I is considered to be done in the same manner as for the reference compound fluoxetine, cf: Schatzberg, et al., J. Clin. Psychopharmacology 7/6 Suppl. (1987) pp. 445-495, and references therein. Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness, generally the daily dose will be from about 0.05 to about 10 mg/kg, preferably 0.1 to 2 mg/kg, when administered parenterally and from about 1 to about 50 mg/kg, preferably about 5 to 20 mg/kg, when administered orally. In some instances, a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be required. Systemic administration refers to oral, rectal and parenteral (i.e. intramuscular, intravenous and subcutaneous). Generally it will be found that when a compound of the present invention is administered orally, a larger quantity of the active agent is required to produce the same effect as a similar quantity given parenterally. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level that will produce effective antidepressant effects without causing any harmful or untoward side effects. The compounds of the present invention may be administered for antidepressant purposes either as individual therapeutic agents or as mixtures with other therapeutic agents Therapeutically, they are generally given as pharmaceutical compositions comprised of an antidepressant amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions which provide from about 1 to 500 mg of the active ingredient per unit dose are preferred and are conventionally prepared as tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions. The nature of the pharmaceutical composition employed will, of course, depend on the desired route of administration. For example, oral compositions may be in the form of tablets or capsules and may contain conventional excipients such as binding agents (e.g. starch) and we&:ting agents (e.g. sodium lauryl sulfate). Solutions or suspensions of a Formula I compound with conventional pharmaceutical vehicles are employed for parenteral compositions such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection.

US Referenced Citations (4)
Number Name Date Kind
3188313 Archer Jun 1965
3472855 Archer Oct 1969
3562278 Archer Feb 1971
4302589 Fanshawe et al. Nov 1981
Non-Patent Literature Citations (3)
Entry
Trubitsyna et al., Chem. Abst., 93-215274y, (1980).
Golubev et al., Chem. Abst., 95-7218x, (1981).
Lanzilotti et al., Chem. Abst., 92-76222u, (1980).
Continuation in Parts (1)
Number Date Country
Parent 204845 Jun 1988