Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin

• US 9,499,531 B2
• Filed: 06/12/2015
• Issued: 11/22/2016
• Est. Priority Date: 07/15/2004
• Status: Active Grant

• Current Assignee: Albany Molecular Research Incorporated
• Original Assignee: Albany Molecular Research Incorporated
• Inventors: Molino, Bruce F., Liu, Shuang, Guzzo, Peter R., Beck, James P.
• Primary Examiner(s): Ward, Paul V
• Application Number:
  US14/737,897
• Publication Number:
  US 20150274713A1
• Time in Patent Office: 529 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4741 condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
• CPC Class Codes: A61K 31/4743 condensed with ring systems having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 : Tobacco-abuse
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 217/00 : Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 217/08 : with a hetero atom directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 217/12 : with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 217/14 : other than aralkyl radicals
• CPC Class Codes: C07D 217/16 : substituted by oxygen atoms
• CPC Class Codes: C07D 217/20 : with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 407/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

The compounds of the present invention are represented by the chemical structure found in Formula (I):

wherein:

• the carbon atom designated * is in the R or S configuration; and
• X is a fused bicyclic carbocycle or heterocycle selected from the group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, benzoisoxazolyl, indazolyl, indolyl, isoindolyl, indolizinyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, benzotriazolyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, indenyl, indanyl, dihydrobenzocycloheptenyl, tetrahydrobenzocycloheptenyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, indolinyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, 9aH-quinolizinyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 2H-chromenyl, 4H-chromenyl, and a fused bicyclic carbocycle or fused bicyclic heterocycle optionally substituted with substituents (1 to 4 in number) as defined in R¹⁴;
• with R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R¹⁴ defined herein.

Claims

1. A process for preparation of a product compound of Formula (I):

2. The process according to claim 1, wherein treating comprises reacting with an aryl or heteroaryl boronic acid or aryl or heteroaryl boronic acid ester in the presence of a metal catalyst and optionally a base in an inert solvent.

3. The process according to claim 1 further comprising:

cyclizing a third intermediate compound of Formula (VII)

4. The process according to claim 3, wherein cyclizing comprises treating the third intermediate compound of Formula (VII) with a strong acid.

5. The process according to claim 3, further comprising:

treating a fourth intermediate compound of Formula (VI);

6. The process according to claim 5, wherein the reducing agent is selected from the group consisting of sodium borohydride, lithium borohydride, borane, diisobutylaluminum hydride, and lithium aluminum hydride.