US20050090533A1 - Dual NK1/NK3 receptor antagonists - Google Patents

Dual NK1/NK3 receptor antagonists Download PDF

Info

Publication number
US20050090533A1
US20050090533A1 US10/884,707 US88470704A US2005090533A1 US 20050090533 A1 US20050090533 A1 US 20050090533A1 US 88470704 A US88470704 A US 88470704A US 2005090533 A1 US2005090533 A1 US 2005090533A1
Authority
US
United States
Prior art keywords
phenyl
methyl
isobutyramide
alkyl
pyridin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/884,707
Other languages
English (en)
Inventor
Torsten Hoffmann
Andreas Koblet
Jens-Uwe Peters
Patrick Schnider
Andrew Sleight
Heinz Stadler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoffmann La Roche Inc
Original Assignee
Hoffmann La Roche Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=33560750&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20050090533(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Hoffmann La Roche Inc filed Critical Hoffmann La Roche Inc
Assigned to HOFFMANN-LA ROCHE INC. reassignment HOFFMANN-LA ROCHE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: F. HOFFMANN-LA ROCHE AG
Assigned to F. HOFMANN-LA ROCHE AG reassignment F. HOFMANN-LA ROCHE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HOFFMANN, TORSTEN, KOBLET, ANDREAS, PETERS, JENS-UWE, SCHNIDER, PATRICK, SLEIGHT, ANDREW, STADLER, HEINZ
Publication of US20050090533A1 publication Critical patent/US20050090533A1/en
Priority to US12/361,569 priority Critical patent/US7939533B2/en
Priority to US13/076,891 priority patent/US8404708B2/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/547—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • 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
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/08—Bridged systems

Definitions

  • Schizophrenia is one of the major neuropsychiatric disorders, characterized by severe and chronic mental impairment. This devastating disease affects about 1% of the world's population. Symptoms begin in early adulthood and are followed by a period of interpersonal and social dysfunction. Schizophrenia manifests as auditory and visual hallucinations, paranoia, delusions (positive symptoms), blunted affect, depression, anhedonia, poverty of speech, memory and attention deficits as well as social withdrawal (negative symptoms).
  • an appropriate multireceptor affinity profile might be required for efficacy against positive and negative signs and symptoms.
  • an ideal drug against schizophrenia would preferably have a low dosage allowing once-per-day dosage, due to the low adherence of schizophrenic patients.
  • Osanetant (SR 142,801) from Sanofi-Synthelabo was the first identified potent and selective non-peptide antagonist described for the NK3 tachykinin receptor for the potential treatment of schizophrenia, which was reported in the literature ( Current Opinion in Investigational Drugs, 2001, 2(7), 950-956 and Psychiatric Disorders Study 4 , Schizophrenia , June 2003, Decision Resources, Inc., Waltham, Mass.).
  • the proposed drug SR 142,801 has been shown in a phase II trial as active on positive symptoms of schizophrenia, such as altered behavior, delusion, hallucinations, extreme emotions, excited motor activity and incoherent speech, but inactive in the treatment of negative symptoms, which are depression, anhedonia, social isolation or memory and attention deficits.
  • the neurokinin-3 receptor antagonists have been described as useful in pain or inflammation, as well as in schizophrenia, Exp. Opinion. Ther. Patents (2000), 10(6), 939-960 and Current Opinion in Investigational Drugs, 2001, 2(7), 950-956 956 and Psychiatric Disorders Study 4 , Schizophrenia , June 2003, Decision Resources, Inc., Waltham, Mass.).
  • EP 1 192 952 describes a pharmaceutical composition containing a combination of a NK3 receptor antagonist and a CNS penetrant NK1 receptor antagonist for the treatment of depression and anxiety.
  • This advantage may be realized in the administration of an ideal drug against schizophrenia.
  • NK1 receptors have been described as active at the NK1 receptor for the treatment of diseases related to this receptor, such as inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson's disease, anxiety, pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases.
  • CNS central nervous system
  • the neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness, for treatment induced vomiting or for the treatment of psychoimmunologic or psychosomatic disorders, see Neurosci. Res., 1996, 7, 187-214 , Can. J. Phys., 1997, 75, 612-621 , Science, 1998, 281, 1640-1645 , Auton. Pharmacol., 13, 23-93, 1993, WO 95/16679, WO 95/18124 and WO 95/23798 , The New England Journal of Medicine , Vol. 340, No. 3 190-195, 1999, U.S. Pat. No. 5,972,938.
  • the present invention relates to the use of compounds of formula I and pharmaceutically acceptable salts thereof for the treatment of positive and negative symptoms in schizophrenia, novel compounds of formulas I, pharmaceutically active acid-addition salts thereof, all sterioisomeric forms of the compounds of formula I, including each of the individual enantiomers and mixtures thereof, the preparation of the above-mentioned novel compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments.
  • the invention provides a method of treating schizophrenia which comprises administering a compound of formula
  • the compounds of formula I may contain some asymmetric carbon atoms. Accordingly, the present invention includes all stereioisomeric forms of the compounds of formula I, including each of the individual enantiomers and mixtures thereof.
  • the compounds of formula I and their salts are characterized by valuable therapeutic properties. It has surprisingly been found that the compounds of formula I show a high affinity simultaneously to both the NK1 and the NK3 receptors (dual NK1/NK3 receptor antagonists), useful in the treatment of schizophrenia.
  • lower alkyl denotes a straight- or branched-chain alkyl group containing from 1-4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
  • alkyl denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms.
  • lower alkoxy and “alkoxy” denote a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
  • halogen denotes chlorine, iodine, fluorine and bromine.
  • cycloalkyl denotes a saturated carbocyclic group containing 3-6 carbon atoms.
  • aryl means a monovalent cyclic aromatic hydrocarbon group consisting of one or more fused rings in which at least one ring is aromatic in nature.
  • aryl radicals include, but are not limited to, phenyl, naphthyl, biphenyl, indanyl, anthraquinolyl, and the like.
  • the preferred aryl group is phenyl.
  • Heteroaryl means a monovalent aromatic carbocyclic group having one or more rings incorporating one, two, or three heteroatoms within the ring wherein the heteroatoms are chosen from nitrogen, oxygen, or sulfur.
  • heteroaryl radicals include, but are not limited to, imidazolyl, isoxazolyl, thiazolyl, pyrazinyl, thiophenyl, furanyl, pyranyl, pyridinyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzopyranyl, indazolyl, indolyl, isoindolyl, naphtyridinyl, and the like.
  • Preferred heteroaryl groups are isoxazolyl and pyridinyl.
  • “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • pharmaceutically acceptable acid addition salt embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • the invention provides a method of treating schizophrenia which comprises administering a compound of formula wherein
  • the invention provides a method of treating schizophrenia which comprises administering a compound of 1 formula
  • the method employs a compound of formula I-1, wherein R 1 , R 4 and R 5 have the definitions as described in formula I-1 and R 2 and R 3 are both CF 3 .
  • the method employs a compound of formula I-1, wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) e -, which is unsubstituted or substituted by one or more substituents selected from the group consisting of lower alkyl, halogen, —(CR′R′′) d OH, ⁇ O, —NR′R′′, —(CH 2 ) d NR′—C(O)-lower alkyl, —(CH 2 ) d —C(O)-lower alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R′′, —(CH 2 ) d —S(O) 2 -lower alkyl, —(CH 2 ) d -pyrrolidinyl, and —C(O)NR′R′′.
  • the method employs a compound of formula I-1, wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 —, wherein the ring is mono substituted by —CH 2 OH or disubstituted by hydroxy and —CH 2 OH.
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 —, wherein the ring is mono substituted by —CH 2 OH or disubstituted by hydroxy and —CH 2 OH.
  • the method employs a compound of formula I-1, wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 —, wherein the ring is disubstituted by NHC(O)CH 3 and —CH 2 OH.
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 —, wherein the ring is disubstituted by NHC(O)CH 3 and —CH 2 OH.
  • the method employs a compound of formula I-1, wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 —, wherein the ring is disubstituted by ⁇ O and —CH 2 OH.
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 —, wherein the ring is disubstituted by ⁇ O and —CH 2 OH.
  • the method employs a compound of formula I-1 wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 —, wherein the ring is di- or tri-substituted by halogen and —CH 2 OH.
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 —, wherein the ring is di- or tri-substituted by halogen and —CH 2 OH.
  • the method employs a compound of formula I-1, wherein R 4 and R 5 are each independently hydrogen, —(CR′R′′) l —(CR′R′′) l —(CR′R′′) a —OH or —(CR′R′′) l —(CR′R′′) l —(CR′R′′) a -lower alkyl, wherein R′ and R′′ on each carbon atom may be the same or different from each other, or are —C b -alkyl, —C(O)H, —(CH 2 ) d cycloalkyl which is unsubstituted or substituted by hydroxy,
  • the method employs a compound of formula I-1, wherein R 4 and R 5 are each independently hydrogen, —CH(CH 2 OH)CH 2 OH or —(CH 2 ) c OH. Examples of such compounds are
  • the method employs a compound of formula I-1, wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) c —O—(CH 2 ) 2 —, which is unsubstituted or substituted by one or more substituents selected from the group consisting of lower alkyl, halogen, —(CR′R′′) d OH, ⁇ O, —NR′R′′, —(CH 2 ) d NR′—C(O)-lower alkyl, —(CH 2 ) d —C(O)-lower alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R′′, —(CH 2 ) d —S(O) 2 -lower alkyl, —(CH 2 ) d -pyrrolidinyl and —C
  • the method employs a compound of formula I-1, wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 2 —O—(CH 2 ) 2 —, wherein the ring is substituted by —CH 2 OH.
  • the method employs a compound of formula I-1, wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 )C—S(O) f —(CH 2 ) 2 —, which is unsubstituted or substituted by one or more substituents selected from the group consisting of lower alkyl, halogen, —(CR′R′′) d OH, ⁇ O, —NR′R′′, —(CH 2 ) d NR′—C(O)-lower alkyl, —(CH 2 ) d —C(O)-lower alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R′′, —(CH 2 ) d —S(O) 2 -lower alkyl, —(CH 2 ) d -pyrrolidinyl
  • the method employs a compound of formula I-1, wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 2 —S(O) 2 —(CH 2 ) 2 —, wherein the ring is mono-substituted by —CH 2 OH.
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 2 —S(O) 2 —(CH 2 ) 2 —, wherein the ring is mono-substituted by —CH 2 OH.
  • the method employs a compound of formula I-1, wherein R 1 , R 4 and R 5 have the definitions as described above and R 2 and R 3 are other than di-CF 3 .
  • the method employs a compound of formula I-1, wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 — wherein the ring is mono substituted by —CH 2 OH or disubstituted by OH and
  • the invention provides a compound of formula
  • the invention is a compound of formula I-1, wherein R 1 is unsubstituted or substituted phenyl and R 4 and R 5 are each independently hydrogen,
  • the invention is a compound of formula I-1, wherein R 1 is unsubstituted or substituted phenyl, R 4 is hydrogen and R 5 is —(CH 2 ) d -cycloalkyl, unsubstituted or substituted by hydroxy. Examples of these compounds are
  • the invention is a compound of formula I-1, wherein R 1 is unsubstituted or substituted phenyl, R 4 is hydrogen and R 5 is —(CH 2 ) c NR′C(O)-lower alkyl or —(CH 2 ) d S(O) 2 -lower alkyl. Examples of such compounds are
  • the invention is a compound of formula I-1, wherein R 1 is unsubstituted or substituted phenyl and R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 —, which ring is substituted by one or two groups —(CR′R′′) d OH.
  • R 1 is unsubstituted or substituted phenyl and R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 —, which ring is substituted by one or two groups —(CR′R′′) d OH.
  • the invention is a compound of formula I-1, wherein R 1 is unsubstituted or substituted phenyl and R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 —, which ring is substituted by one to three substituents selected from the group consisting of —NR′R′′, —(CH 2 ) d —C(O)-lower alkyl,
  • the invention is a compound of formula I-1, wherein R 1 is unsubstituted or substituted phenyl and R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) h —, which ring is mono- or di-substituted by —(CH 2 ) d OH or —NR′R′′, wherein h is 3 or 5.
  • R 1 is unsubstituted or substituted phenyl and R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) h —, which ring is mono- or di-substituted by —(CH 2 ) d OH or —NR′R′′, wherein h is 3 or 5.
  • R 1 is unsubstituted or substituted phenyl and R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) h —,
  • the invention is a compound of formula I-1, wherein R 1 is unsubstituted or substituted phenyl and R 4 and R 5 form together with the N-atom to which they are attached a ring with
  • the invention is a compound of formula I-1, wherein R 1 is unsubstituted or substituted phenyl and R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 2 , —O—(CH 2 ) 2 —, which is unsubstituted or mono- or -di-substituted by —(CR′R′′) d OH.
  • R 1 is unsubstituted or substituted phenyl and R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 2 , —O—(CH 2 ) 2 —, which is unsubstituted or mono- or -di-substituted by —(CR′R′′) d OH.
  • R 1 is unsubstituted or substituted phenyl
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with
  • the invention is a compound of formula I-1, wherein R 1 is unsubstituted or substituted phenyl and R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) c —S(O) f —(CH 2 ) 2 —, which is unsubstituted or mono-or di-substituted by —(CR′R′′) d OH Examples of such compounds are
  • the invention is a compound of formula I-1, wherein R 1 is unsubstituted or substituted phenyl as described above and R 4 and R 5 form together with the N-atom to which they are attached a ring with —CH 2 CH ⁇ CH—CH 2 —, which is unsubstituted or mono-substituted by, —(CR′R′′) d OH.
  • R 1 is unsubstituted or substituted phenyl as described above and R 4 and R 5 form together with the N-atom to which they are attached a ring with —CH 2 CH ⁇ CH—CH 2 —, which is unsubstituted or mono-substituted by, —(CR′R′′) d OH.
  • R 1 is unsubstituted or substituted phenyl as described above and R 4 and R 5 form together with the N-atom to which they are attached a ring with —CH 2 CH ⁇ CH—CH 2 —, which is unsubstituted or mono
  • the invention is a compound of formula I-1, wherein R 1 is unsubstituted or substituted heteroaryl as described above. Examples of such compounds are
  • R 1 , R 4 and R 5 have the definitions as described above and R 2 and R 3 are both CF 3 .
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) e —, which ring is unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R′′) d OH, ⁇ O, and —NR′R′′, wherein R′ and R′′ may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or substituted by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R′′, —(CH 2 ) d —S(O) 2 -alky
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) e -, wherein the ring is mono or di-substituted by hydroxy, —CH 2 OH or —C(O)H.
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) e -, wherein the ring is mono or di-substituted by hydroxy, —CH 2 OH or —C(O)H.
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) e —, wherein the ring is mono or di-substituted by NH 2 , NHS(O) 2 CH 3 , NCH 3 S(O) 2 CH 3 , N(CH 2 CH 3 )S(O) 2 CH 3 , NHC(O)CH 3 and —CH 2 OH.
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) e —, wherein the ring is mono or di-substituted by NH 2 , NHS(O) 2 CH 3 , NCH 3 S(O) 2 CH 3 , N(CH 2 CH 3 )S(O) 2 CH 3 , NHC(O)CH 3 and —CH 2 OH.
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) e —,
  • a further preferred group of compounds are further those, wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 4 — and wherein the ring is disubstituted by ⁇ O and —CH 2 OH, for example the following compounds:
  • a further preferred group of compounds are those, wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) e —, wherein the ring is substituted by CH 2 S(O) 2 CH 3 , CH 2 SCH 3 or CH 2 S(O)CH 3 . Examples of such compounds are
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) e -, wherein the ring is substituted by S(O) 2 CH 3 , SCH 3 , S(O)CH 3 or S(O) 2 N(CH 3 ) 2 , for example the following compounds:
  • R 4 and R 5 are each independently hydrogen; —(CR′R′′) l —(CR′R′′) l —(CR′R′′) a —OH or —(CR′R′′) l —(CR′R′′) l —(CR′R′′) a -alkyl, wherein R′ and R′′ on each carbon atom may be the same or different from each other; —C b -alkyl; —C(O)H; —(CH 2 ) d cycloalkyl, unsubstituted or substituted by hydroxy; or is —(CH 2 ) c NR′R′′, —(CH 2 ) c NR′C(O)-alkyl, —(CH 2 ) c NR′S(O) 2 -alkyl, —(CH 2 ) d S(O)-alkyl, —(CH 2 ) d S-alkyl, —(CH 2 ) d S
  • R 4 and R 5 are each independently hydrogen, —CH(CH 2 OH)CH 2 OH or —(CH 2 ) c OH, for example,
  • R 4 and R 5 are each independently hydrogen, (CH 2 ) 2 NH 2 , (CH 2 ) 2 NHS(O) 2 CH 3 or (CH 2 ) 2 NHC(O)CH 3 , for example,
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 2 —O—(CH 2 ) 2 —, wherein the ring is unsubstituted or substituted by —CH 2 OH, for example,
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) c —S(O) f —(CH 2 ) v —, which is unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R′′) d OH, ⁇ O, —CHO, and —NR′R′′, wherein R′ and R′′ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R′′,
  • Especially preferred compounds from this group are those wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) 2 —S(O) 2 —(CH 2 ) 2 —, wherein the ring is unsubstituted or substituted by —CH 2 OH or methyl. Examples of such compounds are
  • R 1 , R 4 and R 5 have the definitions as describe above and R 2 and R 3 are other than di-CF 3 . Examples of such compounds are
  • a preferred group of compounds of formula I are compounds wherein R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) c —NR′—(CH 2 ) 2 —, which is unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, CF 3 , —(CR′R′′) d OH, ⁇ O, —CHO, and —NR′R′′, wherein R′ and R′′ are as described above or may form together with the N-atom to which they are attached a ring with —(CH 2 ) e , or by —(CH 2 ) d NR′—C(O)-alkyl, —(CH 2 ) d —C(O)-alkyl, —(CH 2 ) d —C(O)-cycloalkyl, —(CH 2 ) d OC(O)NR′R′′, —(CH
  • R 4 and R 5 form together with the N-atom to which they are attached a ring with —(CH 2 ) c —NR′—(CH 2 ) 2 —, and wherein R′ on the N-atom is hydrogen, lower alkyl, C(O)H, C(O)CH 3 , C(O)-cyclopropyl,
  • Some compounds of formula IC are trans-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(4-hydroxy-cyclohexylamino)-pyridin-3-yl]-N-methyl-isobutyramide,
  • Formula I also encompasses compounds of formula IG I
  • Examples of compounds of formula IG include
  • the invention relates also to compounds of formula I, wherein R 1 is unsubstituted or substituted phenyl as described above and R 4 and R 5 form together with the N-atom to which they are attached a ring with —CH 2 CH ⁇ CH—CH 2 —, which is unsubstituted or mono-substituted by —(CR′R′′) d OH.
  • R 1 is unsubstituted or substituted phenyl as described above and R 4 and R 5 form together with the N-atom to which they are attached a ring with —CH 2 CH ⁇ CH—CH 2 —, which is unsubstituted or mono-substituted by —(CR′R′′) d OH.
  • R 1 is unsubstituted or substituted phenyl as described above and R 4 and R 5 form together with the N-atom to which they are attached a ring with —CH 2 CH ⁇ CH—CH 2 —, which is unsubstituted or mono-sub
  • present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, described in schemes 1 to 14 and in specific examples 1 to 421 and, for example, by a process described below, which process comprises
  • the salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methan-sulphonates, p-toluenesulphonates and the like are examples of such salts.
  • R 1 , R 2 , R 4 and R 5 have the meaning as described above. wherein R 1 , R 2 , R 3 , R 4 and R 5 have the meaning as described above. wherein R 1 , R 2 , R 3 and R 5 have the meaning as described above. wherein R 1 , R 2 and R 3 , have the meaning as described above. wherein R 1 , R 2 and R 3 have the meaning as described above.
  • the —OH group is first transformed into a —OS(O) 2 CH 3 group by reaction with methanesulfonyl chloride and triethylamine in dichloromethane.
  • a thioalkane such as sodium methanethiolate in methanol or DMF
  • the —S-alkyl group can be oxidized to an —S(O)-alkyl group by treatment with Oxone in methanol or MCPBA in dichloromethane.
  • the compounds of formula I containing an —S(O)-alkyl group can be isolated or oxidized further without isolation to compounds containing an —S(O) 2 -alkyl group by treatment with Oxone in methanol or MCPBA in dichloromethane (Examples 331 and 388).
  • the —OH group is transformed into a —SC(O)CH 3 group by reaction with triphenylphosphine, diethyl azodicarboxylate and thioacetic acid in THF.
  • the —SC(O)CH 3 group is oxidized to an —SO 3 H group by reaction with an aqueous solution of hydrogen peroxide in acetic acid.
  • Compounds containing the —SO 3 H are treated consecutively with oxalyl chloride and a catalytic amount of DMF in dichloromethane and an amine to form compounds of formula I wherein R or R 5 contain an —S(O) 2 —NR′R′′ group.
  • the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are dual antagonists of the Neurokinin 1 and 3 receptors.
  • NK 1 receptor The affinity of test compounds for the NK 1 receptor was evaluated at human NK 1 receptors in CHO cells infected with the human NK 1 receptor (using the Semliki virus expression system) and radiolabelled with [ 3 H]substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%) leupeptin (16.8 ⁇ g/ml), MnCl 2 (3 mM) and phosphoramidon (2 ⁇ M).
  • Binding assays consisted of 250 ⁇ l of membrane suspension (approximately 1.5 ⁇ g/well in a 96 well plate), 0.125 ⁇ l of buffer of displacing agent and 125 ⁇ l of [ 3 H]substance P. Displacement curves were determined with at least seven concentrations of the compound.
  • the assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 3 ⁇ 1 ml washes of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in duplicate in at least 2 separate experiments.
  • Recombinant human NK 3 (hNK 3 ) receptor affinity was determined in a 96 well plate assay, using [ 3 H]SR142801 (final concentration 0.3 nM) to radiolabel the hNK 3 receptor in the presence of 10 concentrations of competing compound or buffer. Non specific binding was determined using 10 ⁇ M SB222200. Assay buffer consisted of Tris-HCl (50 mM, pH 7.4), BSA (0.1%), MnCl 2 (4 mM) and phosphoramidon (1 ⁇ M). Membrane preparations of hNK3 receptors (approximately 2.5 ⁇ g/well in a 96 well plate) were used to initiate the incubation for 90 min at room temperature.
  • This assay was terminated by rapid filtration under vacuum through GF/C filters, presoaked for 90 min with PEI (0.3%), with 3 ⁇ 0.5 ml washes of ice-cold Tris buffer (50 mM, pH 7.4) containing 0.1% BSA. The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in duplicate in at least two separate experiments.
  • the present invention also provides pharmaceutical compositions containing compounds of formula I or pharmaceutically usable acid addition salts thereof and a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the pharmaceutical compositions also can be in the form of suppositories or injectable solutions.
  • compositions of the invention in addition to one or more compounds of formula I or a pharmaceutically usable acid addition salt thereof, contain a pharmaceutically acceptable excipient.
  • suitable pharmaceutically inert excipients include pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragées and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used as such excipients e.g. for tablets, dragées and hard gelatine capsules.
  • Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
  • Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
  • Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
  • Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
  • compositions of the invention can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • Compounds of the present invention are dual NK-1/NK-3 antagonists. Therefore, the present invention also provides a method for the treatment of schizophrenia. Such method includes administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable addition salt thereof, to an individual. In particular, such method includes administering a therapeutically effective amount of a compound of formula I-1, or a pharmaceutically acceptable acid addition salt thereof, to an individual.
  • the present invention provides methods for the treatment of schizophrenia which comprise administering to an individual an effective amount of a compound of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, or a pharmaceutically acceptable acid addition salt of any one or more of these compounds.
  • the compounds and compositions of the invention can be administered in a conventional manner, for example, orally, rectally, or parenterally.
  • the pharmaceutical compositions of the invention can be administered orally, for example, in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the pharmaceutical compositions also can be administered rectally, for example, in the form of suppositories or parenterally, for example, in the form of injectable solutions.
  • the dosage at which the compound of the invention is administered can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
  • reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h.
  • the reaction mixture was treated with 220 ml 1 N sodium hydrogencarbonate solution and extracted with three 200-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and triturated with 150 ml diethylether to give 34.6 g (82%) of the title compound as a white solid.
  • the title compound was obtained as a white foam in 52% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide using [6-chloro-4-(2-chloro-4-fluoro-phenyl)-pyridin-3-yl]-methyl-amine instead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.
  • the title compound was obtained as a light yellow foam in 87% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide using [6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine instead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.
  • the title compound was obtained as a light yellow foam in 57% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide using [6-chloro-4-(2,4-dichloro-phenyl)-pyridin-3-yl]-methyl-amine instead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.
  • the title compound was obtained as a light yellow foam in 45% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide using [6-chloro-4-(3,4-dichloro-phenyl)-pyridin-3-yl]-methyl-amine instead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.
  • the title compound was obtained as a light yellow oil in 76% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide using ⁇ 4-[2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-6-chloro-pyridin-3-yl ⁇ -methyl-amine instead of [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine.
  • a solution of 18.2 g (82.8 mmol) (3,5-dichloro-phenyl)-acetic acid methyl ester in 15 ml THF was added to a solution of lithium diisopropylamide in THF (obtained by adding 49.7 ml (99.4 mmol) of a 2 M solution of lithium diispropylamide in THF/heptane/ethylbenzene to 125 ml THF at ⁇ 20° C. After stirring for 45 min. 6.3 ml (99.4 mmol) methyl iodide in 12 ml THF was added at the same temperature over a period of 30 min.
  • the title compound was obtained as a white foam in 84% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide using (R)-1-amino-2-propanol instead of ethanolamine.
  • the title compound was obtained as a light brown foam in 79% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide using (RS)-1-amino-2-propanol instead of ethanolamine.
  • the title compound was obtained as a yellow foam in 55% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide using 1-amino-2-butanol instead of ethanolamine.
  • the title compound was obtained as a white foam in 24% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide using (R)-2-amino-1-propanol instead of ethanolamine.
  • the title compound was obtained as a white foam in 34% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide using 2-amino-1,3-propandiol instead of ethanolamine.
  • the title compound was obtained as a white foam in 30% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide using 2-(methylthio)ethylamine instead of ethanolamine.
  • the title compound was obtained as a white foam in 65% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide using N-acetylethylenediamine instead of ethanolamine.
  • the title compound was obtained as a white foam in 76% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide using (2R,4R)-2-(hydroxymethyl)-4-hydroxypyrrolidine instead of ethanolamine.
  • the title compound was obtained as a light yellow foam in 23% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide using azetidin-3-ol instead of ethanolamine.
  • reaction mixture was stirred at room temperature for 18 h, followed by dilution with 10 ml ethyl acetate and washing with 10 ml saturated sodium carbonate solution. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 130 mg (87%) of the title compound as a white foam.
  • reaction mixture was diluted with 30 ml tert-butyl methyl ether and washed with 20 ml of water and 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was dissolved in 25 ml of a 2 N solution of ammonia in ethanol. The solution was stirred at room temperature for 18 h. The reaction mixture was concentrated and purified by flash chromatography to give 640 mg (60%) of the title compound as a light brown foam.
  • reaction mixture was stirred at room temperature for 18 h, followed by dilution with 10 ml tert-butyl methyl ether and washing with 20 ml water and with 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 86 mg (55%) of the title compound as an off-white foam.
  • reaction mixture was allowed to slowly warm to room temperature during 5 h, followed by dilution with 20 ml ethyl acetate, washing with 10 ml brine and extraction with 20 ml ethyl acetate.
  • the combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 480 mg (64%) of the title compound as a white foam.
  • the title compound was obtained as a white solid in 23% yield after flash chromatography according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N- ⁇ 4-(4-fluoro-phenyl)-6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl ⁇ -N-methyl-isobutyramide using 2-(ethylamino)ethanol instead of 2-(methylamino)ethanol.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
US10/884,707 2003-07-03 2004-07-02 Dual NK1/NK3 receptor antagonists Abandoned US20050090533A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/361,569 US7939533B2 (en) 2003-07-03 2009-01-29 Dual NK1/NK3 receptor antagonists
US13/076,891 US8404708B2 (en) 2003-07-03 2011-03-31 Dual NK1/NK3 receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP03014513 2003-07-03
EP03014513.0 2003-07-03

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/361,569 Continuation US7939533B2 (en) 2003-07-03 2009-01-29 Dual NK1/NK3 receptor antagonists

Publications (1)

Publication Number Publication Date
US20050090533A1 true US20050090533A1 (en) 2005-04-28

Family

ID=33560750

Family Applications (3)

Application Number Title Priority Date Filing Date
US10/884,707 Abandoned US20050090533A1 (en) 2003-07-03 2004-07-02 Dual NK1/NK3 receptor antagonists
US12/361,569 Expired - Fee Related US7939533B2 (en) 2003-07-03 2009-01-29 Dual NK1/NK3 receptor antagonists
US13/076,891 Expired - Fee Related US8404708B2 (en) 2003-07-03 2011-03-31 Dual NK1/NK3 receptor antagonists

Family Applications After (2)

Application Number Title Priority Date Filing Date
US12/361,569 Expired - Fee Related US7939533B2 (en) 2003-07-03 2009-01-29 Dual NK1/NK3 receptor antagonists
US13/076,891 Expired - Fee Related US8404708B2 (en) 2003-07-03 2011-03-31 Dual NK1/NK3 receptor antagonists

Country Status (27)

Country Link
US (3) US20050090533A1 (pt)
EP (1) EP1643998B1 (pt)
JP (1) JP4490421B2 (pt)
KR (1) KR100744859B1 (pt)
CN (1) CN1852712B (pt)
AR (1) AR044974A1 (pt)
AT (1) ATE371451T1 (pt)
AU (1) AU2004253267B2 (pt)
BR (1) BRPI0412291A (pt)
CA (1) CA2530886C (pt)
CO (1) CO5650234A2 (pt)
DE (1) DE602004008631T2 (pt)
DK (1) DK1643998T3 (pt)
ES (1) ES2291891T3 (pt)
HR (1) HRP20070471T3 (pt)
IL (1) IL172614A (pt)
MX (1) MXPA06000192A (pt)
MY (1) MY137156A (pt)
NO (1) NO20056007L (pt)
NZ (1) NZ544244A (pt)
PL (1) PL1643998T3 (pt)
PT (1) PT1643998E (pt)
RU (1) RU2347777C2 (pt)
SI (1) SI1643998T1 (pt)
TW (1) TW200502230A (pt)
WO (1) WO2005002577A1 (pt)
ZA (1) ZA200510453B (pt)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004034619A1 (de) * 2004-07-16 2006-02-23 Grünenthal GmbH Substituierte Aminoverbindungen als 5-HT/NA Uptakehemmer
US20060217393A1 (en) * 2005-03-23 2006-09-28 Christoph Funk NK-1 receptor antagonists
WO2006119390A1 (en) * 2005-05-04 2006-11-09 Vertex Pharmaceuticals Incorporated Pyridines useful as modulators of ion channels
US20080255147A1 (en) * 2005-05-31 2008-10-16 Dean Wilson Heterocycles useful as modulators of ion channels
US7919491B2 (en) 2005-09-09 2011-04-05 Glaxosmithkline Llc Pyridine derivatives and their use in the treatment of psychotic disorders
US20110136798A1 (en) * 2008-08-05 2011-06-09 Clare Louise Anderton Crystalline Forms Of A Pyridine Derivative
US10100030B2 (en) 2013-11-08 2018-10-16 Kissei Pharmaceutical Co., Ltd. Carboxymethyl piperidine derivative

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060030600A1 (en) * 2004-08-06 2006-02-09 Patrick Schnider Dual NK1/NK3 receptor antagonists for the treatment of schizophrenia
DE102004039789A1 (de) 2004-08-16 2006-03-02 Sanofi-Aventis Deutschland Gmbh Arylsubstituierte polycyclische Amine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DK2343304T3 (en) 2005-02-16 2015-06-29 Anacor Pharmaceuticals Inc BIOCIDE BORONOPHTHALIDE COMPOUNDS
KR100902425B1 (ko) * 2005-02-22 2009-06-11 에프. 호프만-라 로슈 아게 Ｎｋ１ 길항제
GB0518472D0 (en) * 2005-09-09 2005-10-19 Glaxo Group Ltd Novel compounds
WO2007039123A2 (en) * 2005-09-22 2007-04-12 Smithkline Beecham Corporation Combination therapy comprising an nk-3 antagonist and an antipsychotic agent
RU2008131324A (ru) 2005-12-30 2010-02-10 Анакор Фармасьютикалз, Инк. (Us) Борсодержащие малые молекулы
MX335993B (es) * 2005-12-30 2016-01-07 Anacor Pharmaceuticals Inc Moleculas pequeñas que contienen boro.
DE602007012847D1 (de) 2006-02-07 2011-04-14 Hoffmann La Roche Benzamid- und heteroarenderivate als cetp-inhibitoren
CA2682506C (en) * 2007-04-20 2016-05-24 F. Hoffmann-La Roche Ag Pyrrolidine derivatives as dual nk1/nk3 receptor antagonists
ATE517100T1 (de) 2007-08-07 2011-08-15 Hoffmann La Roche Pyrrolidinarylether als nk3-rezeptorantagonisten
GB0808747D0 (en) * 2008-05-14 2008-06-18 Glaxo Wellcome Mfg Pte Ltd Novel compounds
EA021411B1 (ru) * 2009-08-27 2015-06-30 Нерр Терапьютикс Лимитед Безводная форма производного пиридина
WO2011054773A1 (en) 2009-11-03 2011-05-12 Glaxosmithkline Llc Novel lactam compounds
US20110144081A1 (en) * 2009-12-15 2011-06-16 Henner Knust Pyrrolidine derivatives
US8487102B2 (en) 2010-04-20 2013-07-16 Hoffmann-La Roche Inc. Pyrrazolopyridine compounds as dual NK1/NK3 receptor antagonists
US8987307B2 (en) 2011-03-03 2015-03-24 Hoffmann-La Roche Inc. 3-amino-pyridines as GPBAR1 agonists
TWI649307B (zh) * 2014-05-07 2019-02-01 日商橘生藥品工業股份有限公司 Cyclohexylpyridine derivative
ES2753539T3 (es) 2015-05-18 2020-04-13 Nerre Therapeutics Ltd Antagonista del receptor NK-1/NK-3 para el tratamiento de los sofocos
MD3483164T2 (ro) 2017-03-20 2020-07-31 Forma Therapeutics Inc Compoziții pirolopirolice ca activatori ai piruvat kinazei (PKR)
SI3765024T1 (sl) 2018-03-14 2024-05-31 KaNDy Therapeutics Limited Nova farmacevtska formulacija, ki vsebuje dvojne antagoniste receptorja NK-1/NK-3
US20200129485A1 (en) 2018-09-19 2020-04-30 Forma Therapeutics, Inc. Treating sickle cell disease with a pyruvate kinase r activating compound
WO2020061255A1 (en) 2018-09-19 2020-03-26 Forma Therapeutics, Inc. Activating pyruvate kinase r
CN118496152A (zh) 2019-11-15 2024-08-16 康堤医疗有限公司 制备nt-814的关键中间体6-氯-4-(4-氟-2-甲基苯基)吡啶-3-胺的新化学方法
EP4431512A1 (en) 2023-03-16 2024-09-18 Bayer Consumer Care AG Novel dual nk-1/nk-3 receptor antagonists

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5972938A (en) * 1997-12-01 1999-10-26 Merck & Co., Inc. Method for treating or preventing psychoimmunological disorders
US20030004157A1 (en) * 2001-04-23 2003-01-02 Susanne Buser Use of NK-1 receptor antagonists against benign prostatic hyperplasia
US20030083345A1 (en) * 2001-07-10 2003-05-01 Torsten Hoffmann Method of treatment and/or prevention of brain, spinal or nerve injury
US6576762B2 (en) * 2000-07-24 2003-06-10 Hoffmann-La Roche Inc. Heteroaromatic substituted amides with antagonistic activity to neurokinin 1 receptors

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL111960A (en) 1993-12-17 1999-12-22 Merck & Co Inc Morpholines and thiomorpholines their preparation and pharmaceutical compositions containing them
DE69434991T2 (de) 1993-12-29 2008-03-06 Merck Sharp & Dohme Ltd., Hoddesdon Substituierte Morpholinderivate und ihre Verwendung als Arzneimittel
TW385308B (en) 1994-03-04 2000-03-21 Merck & Co Inc Prodrugs of morpholine tachykinin receptor antagonists
FR2719311B1 (fr) * 1994-03-18 1998-06-26 Sanofi Sa Composés antagonistes sélectifs du récepteur NK3 humain et leur utilisation comme médicaments et outils de diagnostic.
WO1998024445A1 (en) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Use of nk-1 receptor antagonists for treating schizophrenic disorders
AU767123B2 (en) 1999-02-24 2003-10-30 F. Hoffmann-La Roche Ag Phenyl- and pyridinyl derivatives
EP1035115B1 (en) * 1999-02-24 2004-09-29 F. Hoffmann-La Roche Ag 4-Phenylpyridine derivatives and their use as NK-1 receptor antagonists
SI1103545T1 (en) 1999-11-29 2004-02-29 F. Hoffmann-La Roche Ag 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide
HU230316B1 (hu) * 2000-07-14 2016-01-28 F. Hoffmann-La Roche Ag N-oxidok, mint 4-fenil-piridin-származékok előgyógyszerei, eljárás és előállításukra és az ezeket tartalmazó gyógyszerkészítmények
TWI259180B (en) * 2000-08-08 2006-08-01 Hoffmann La Roche 4-Phenyl-pyridine derivatives
EP1192952A3 (en) 2000-09-28 2003-03-26 Pfizer Products Inc. Combination, for treating depression and anxiety, containing an NK-3 receptor antagonist and a CNS penetrant NK-1 receptor antagonist

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5972938A (en) * 1997-12-01 1999-10-26 Merck & Co., Inc. Method for treating or preventing psychoimmunological disorders
US6576762B2 (en) * 2000-07-24 2003-06-10 Hoffmann-La Roche Inc. Heteroaromatic substituted amides with antagonistic activity to neurokinin 1 receptors
US20030004157A1 (en) * 2001-04-23 2003-01-02 Susanne Buser Use of NK-1 receptor antagonists against benign prostatic hyperplasia
US20030083345A1 (en) * 2001-07-10 2003-05-01 Torsten Hoffmann Method of treatment and/or prevention of brain, spinal or nerve injury

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004034619A1 (de) * 2004-07-16 2006-02-23 Grünenthal GmbH Substituierte Aminoverbindungen als 5-HT/NA Uptakehemmer
US7211579B2 (en) * 2005-03-23 2007-05-01 Hoffmann-La Roche Inc. NK-1 receptor antagonists
US20060217393A1 (en) * 2005-03-23 2006-09-28 Christoph Funk NK-1 receptor antagonists
US7683065B2 (en) 2005-05-04 2010-03-23 Vertex Pharmaceuticals Incorporated Pyridines useful as modulators of ion channels
US20070082889A1 (en) * 2005-05-04 2007-04-12 Dean Wilson Pyridines useful as modulators of ion channels
WO2006119390A1 (en) * 2005-05-04 2006-11-09 Vertex Pharmaceuticals Incorporated Pyridines useful as modulators of ion channels
US20080255147A1 (en) * 2005-05-31 2008-10-16 Dean Wilson Heterocycles useful as modulators of ion channels
US7880008B2 (en) 2005-05-31 2011-02-01 Vertex Pharmaceuticals Incorporated Heterocycles useful as modulators of ion channels
US20110059984A1 (en) * 2005-05-31 2011-03-10 Vertex Pharmaceuticals Incorporated Heterocycles useful as modulators of ion channels
US8329702B2 (en) 2005-05-31 2012-12-11 Vertex Pharmaceuticals Incorporated Heterocycles useful as modulators of ion channels
US7919491B2 (en) 2005-09-09 2011-04-05 Glaxosmithkline Llc Pyridine derivatives and their use in the treatment of psychotic disorders
US8097618B2 (en) 2005-09-09 2012-01-17 Glaxosmithkline Llc Pyridine derivatives and their use in the treatment of psychotic disorders
US20110136798A1 (en) * 2008-08-05 2011-06-09 Clare Louise Anderton Crystalline Forms Of A Pyridine Derivative
US8093242B2 (en) 2008-08-05 2012-01-10 Glaxosmithkline Llc Crystalline forms of a pyridine derivative
US10100030B2 (en) 2013-11-08 2018-10-16 Kissei Pharmaceutical Co., Ltd. Carboxymethyl piperidine derivative

Also Published As

Publication number Publication date
NO20056007L (no) 2006-01-19
AR044974A1 (es) 2005-10-12
IL172614A0 (en) 2006-04-10
KR100744859B1 (ko) 2007-08-01
JP2009500290A (ja) 2009-01-08
US20090137806A1 (en) 2009-05-28
CN1852712A (zh) 2006-10-25
KR20060030893A (ko) 2006-04-11
CA2530886C (en) 2013-05-28
CO5650234A2 (es) 2006-06-30
US20110178055A1 (en) 2011-07-21
JP4490421B2 (ja) 2010-06-23
SI1643998T1 (sl) 2007-12-31
MY137156A (en) 2008-12-31
WO2005002577A1 (en) 2005-01-13
RU2347777C2 (ru) 2009-02-27
PT1643998E (pt) 2007-11-21
BRPI0412291A (pt) 2006-09-19
AU2004253267A1 (en) 2005-01-13
ZA200510453B (en) 2007-01-31
DE602004008631D1 (de) 2007-10-11
RU2006103010A (ru) 2007-08-10
DE602004008631T2 (de) 2008-07-10
CN1852712B (zh) 2010-06-09
DK1643998T3 (da) 2007-12-27
NZ544244A (en) 2008-10-31
TW200502230A (en) 2005-01-16
EP1643998B1 (en) 2007-08-29
MXPA06000192A (es) 2006-04-11
IL172614A (en) 2010-12-30
US7939533B2 (en) 2011-05-10
ATE371451T1 (de) 2007-09-15
EP1643998A1 (en) 2006-04-12
PL1643998T3 (pl) 2008-01-31
US8404708B2 (en) 2013-03-26
HRP20070471T3 (en) 2007-11-30
AU2004253267B2 (en) 2008-12-04
CA2530886A1 (en) 2005-01-13
ES2291891T3 (es) 2008-03-01

Similar Documents

Publication Publication Date Title
US8404708B2 (en) Dual NK1/NK3 receptor antagonists
US9079907B2 (en) Fused heterocyclic compound and use thereof
US20080275021A1 (en) Pyrrolidine derivatives as dual nk1/nk3 receptor antagonists
US10822338B2 (en) Substituted aminoquinazoline compounds as A2A antagonist
JP2018115183A (ja) 中枢神経系疾患の処置のための活性医薬化合物の使用
US20060030600A1 (en) Dual NK1/NK3 receptor antagonists for the treatment of schizophrenia
WO1998046590A1 (en) Thermogenic composition and benzazepine thermogenics
TWI743484B (zh) 用於治療、改善或預防與tau聚集物相關之病症的新穎化合物
CN111004214B (zh) 吡啶酰基哌啶衍生物及其用途
ES2209995T3 (es) Derivados de propilo sustituidos con tienoisoxazolil- y tienopirrazolil-fenoxi, utiles en calidad de antagonistas d4.
TWI491614B (zh) Ｃ－ｍｅｔ蛋白質激酶之胺基吡唑三唑并噻二唑抑制劑
ES2310206T3 (es) Derivados de 1-oxa-3,9-diaza-espiro-5,5-undecan-2-onas y su uso como antagonista del receptor de neurocinina.
US7498438B2 (en) Fused ring NK1 antagonists
US20110136788A1 (en) Therapeutic agent for irritable bowel syndrome
CN114728929A (zh) 吡啶亚甲基哌啶衍生物及其用途
US20200121657A1 (en) SUBSTITUTED METHANOPYRIDO [2, 1-a] ISOINDOLONES AS mAChR MODULATORS FOR TREATING VARIOUS ASSOCIATED PATHOPHYSIOLOGICAL CONDITIONS AND PROCESS FOR PREPARATION THEREOF
US20220002295A1 (en) Heterocyclic compounds and medical use thereof
WO2021046789A1 (zh) 吲唑-甲酰胺衍生物及其用途

Legal Events

Date Code Title Description
AS Assignment

Owner name: HOFFMANN-LA ROCHE INC., NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:F. HOFFMANN-LA ROCHE AG;REEL/FRAME:016150/0096

Effective date: 20040803

AS Assignment

Owner name: F. HOFMANN-LA ROCHE AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HOFFMANN, TORSTEN;KOBLET, ANDREAS;PETERS, JENS-UWE;AND OTHERS;REEL/FRAME:016156/0159

Effective date: 20040802

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION