WO2012020170A1 - Novel 6,7-disubstituted-isoquinoline derivatives and their use - Google Patents
Novel 6,7-disubstituted-isoquinoline derivatives and their use Download PDFInfo
- Publication number
- WO2012020170A1 WO2012020170A1 PCT/FI2011/050707 FI2011050707W WO2012020170A1 WO 2012020170 A1 WO2012020170 A1 WO 2012020170A1 FI 2011050707 W FI2011050707 W FI 2011050707W WO 2012020170 A1 WO2012020170 A1 WO 2012020170A1
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- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- acceptable salt
- methyl
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
Definitions
- the present invention relates to novel 6,7-disubstituted-isoquinoline derivatives and more particularly to novel 6,7-disubstituted-1 -methyl-1 ,2,3,4- tetrahydro- and -3,4-dihydroisoquinoline derivatives and pharmaceutical compositions comprising them.
- the invention also relates to said compounds for use in the treatment of drug addiction and CNS related diseases.
- Endogenous isoquinolines are formed by condensation of biogenic amines - such as phenethylamine - and simple aldehydes, such as formaldehyde or acetaldehyde. They are known to modulate neurotransmission, central metabolism and motor activity.
- An endogenous TIQ derivative salsolinol (1 -methyl-1 ,2,3,4-tetrahydroisoquinoline-6,7-diol) is considered to be a causative factor of Parkinson's disease (PD), while (R)-1 -MeTIQ (1 -methyl-1 ,2,3,4- tetrahydroisoquinoline) was shown to possess an antiparkinsonian activity.
- Salsolinol is formed enzymatically as well as non-enzymatically as a condensation product of acetaldehyde - the primary metabolite of ethanol - with dopamine in the brain of mammals.
- Salsolinol affects the uptake of catecholamines into nerve terminals, the release of stored catecholamines and the activity of monoamine oxidase (MAO), catechol-O-methyl transferase (COMT) and tyrosine hydroxylase. Ethanol induced elevation of salsolinol levels is known to participate in the development of ethanol addiction/alcoholism.
- Salsolinol (SAL) has been postulated to mediate some of the addictive properties of alcohol.
- TIQ and I MeTIQ tetrahydroisoquinolines penetrate to the brain in pharmacologically relevant amounts and induce a variety of effects. Most of the TIQ and I MeTIQ exit the brain (90.4% and 95.3%) and is excreted in urine (76% and 72%) unchanged. The hydroxylated (C4 of the isoquinoline backbone) derivatives of TIQ and I MeTIQ were the most abundant metabolites in the urine (2.7% 8.7%).
- EP 2 090 576 A1 discloses certain 5,8- and 6,7-difluoro substituted isoquinolines as intermediates in the preparation of pyrazolo[1 ,5-a]pyridines for use as metabotropic glutamate receptor modulators.
- the present invention relates to novel compounds of general formula (I)
- R' is H, or
- R' is absent, when the dotted line represent a bond
- Ri and R are each independently selected from the group consisting of H, halo, lower alkyl, trifluoromethyl and trifluoromethoxy;
- R 2 and R 3 are both F, or one of R 2 and R 3 is F and the other is lower alkyl or trifluoromethyl;
- R 5 is selected from the group consisting of halo, lower alkyl, trifluoromethyl and trifluoromethoxy, or when the dotted line represents a bond, and then R 5 may also be H.
- the invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising an effective amount of one or more compounds of formula (I) or stereoisomers or pharmaceutical acceptable salts thereof and a pharma- ceutically acceptable carrier and suitable excipients.
- the invention relates to compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof for use as a medicament.
- the invention also relates to compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof for use in the treatment of drug addiction, alcoholism, anorexia, bulimia, and CNS related diseases.
- halo refers to F, CI, I and Br, preferably F.
- lower alkyl saturated branched or linear hydrocarbons containing 1 - 6 carbon atoms, preferably 1 - 3 carbon atoms, especially methyl or ethyl.
- Examples of preferred compounds of formula (I) are those where the dotted line represents a bond.
- preferred com- pounds are those where R-i, R 2 and R 3 are H.
- Further preferred compounds are those where Ri and R 2 are H and R 3 is F or methyl.
- Preferred specific compounds are
- Typical pharmaceutically acceptable salts are acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, and salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid and the like.
- Pharmaceutically acceptable salts also include alkali metal salts, (e.g. sodium and potassium), alkaline earth metal salts (e.g. calcium or magnesium), aluminium salts, ammonium salts and salts with organic amines such as with methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, morpholine, and the like.
- compositions comprising one or more compounds of the invention may further contain conventional carriers, diluents or excipients and may be administered in a solid dosage form, such as tablets or capsules, or in a liquid form, such as solutions, suspensions, emulsions, elixirs, for oral use, or in the form of sterile injectable solutions for parenteral use.
- a solid dosage form such as tablets or capsules
- a liquid form such as solutions, suspensions, emulsions, elixirs, for oral use, or in the form of sterile injectable solutions for parenteral use.
- Solid dosage forms may additionally include, e.g., binders, such as microcrystalline cellulose, gum tragacanth or gelatine; excipients, such as starch or lactose, disintegrating agent, such as alginic acid or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; and sweeteners and flavoring agents and like.
- binders such as microcrystalline cellulose, gum tragacanth or gelatine
- excipients such as starch or lactose, disintegrating agent, such as alginic acid or corn starch
- lubricants such as magnesium stearate
- glidants such as colloidal silicon dioxide
- sweeteners and flavoring agents and like may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
- compositions are formed in sterile saline or phosphate buffered saline or other
- compositions and dosage forms contain a compound of the invention in an amount effective for the desired purpose.
- the effective amount will typically be determined by a physician, and depend on the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and like.
- Endogenous isoquinolines are compounds which are formed by condensation of biogenic amines and simple aldehydes such as formaldehyde or acetaldehyde.
- the compounds of the invention can be synthesized using well documented reactions and commercially available starting materials.
- These novel I MeTIQ compounds can be used to achieve many desirable pharmacological responses. Fluorination can alter the bond strength, lipophilicity, conformation, electrostatic potential, dipoles, and pKa.
- Substitution, especially fluorination, at the position of metabolic attack - mainly at positions 6, 7 and 4 - is used to alter the route and rate of metabolic degradation. Fluorination may also alter the tissue distribution, pharmacodynamics and toxicology of the compound. It can be generalized that replacing hydrogen with fluorine causes minimal steric effects at the receptor.
- the compounds of the present invention are actively transported over the blood brain barrier by organic cation transporters and are concentrated in the brain. Most of the compounds of the present invention cannot be oxidized to form epoxides thereby making them less prone to cause oxidative stress.
- the compounds of the invention are associated with neuroprotective and neuroregenerative properties instead of neurotoxicity or neuro- degeneration, which is the case with SAL. Further, the novel compounds are better in mimicking desirable effects of SAL and treating alcoholism and Parkinson's disease than e.g. 6-monofluorinated TIQ.
- novel compounds according to the invention are structurally related to I MeTIQ.
- the novel compounds can be used, in addition to the treatment of e.g. Alzheimer's disease and Parkinson's disease, to treat addictions in general - from alcohol to cocaine and heroin.
- Number of positive pharmacological responses can be achieved simultaneously. While decreasing the tendency to relapse and likelihood of developing an addiction, these compounds can act as general mood stabilizers and general neuroprotectants possessing remarkable antiparkinsonian and antiepileptic character.
- the compounds exhibit many pharmacological responses, such as
- MAOs monoamine-oxidases
- ACE acetylcholinesterase
- the compounds according to the present invention may be prepared by processes known per se as follows.
- Step 2 (in the case of R 5 halogen substitution) Sulfonating the aliphatic OH-group to appropriate sulfonyl ester by stirring 1 .0 mol eq. of subst. phenyl-2-amine-1 -ol in DCM with 1 .2 mol eq. of triethylamine (or using pyridine for the solvent) with and adding slowly 1 .1 mol eq. of methylsulfonyl chloride maintaining the temperature at -5°C until conversion was complete. The product was washed several times with brine, dried over anhydrous MgSO and concentrated in vacuo.
- Step 3 (in the case of R 5 halogen substitution) Modified Finkelstein reaction to the sulfonate ester with potassium halide (in this case KF) proceeded by dissolving 1 mol eq. of sulfonyl-intermediate from the step 2 with 6 ml of acetonitrile per gram of substrate, 0.5 mol eq. of 1 -butyl-3-methyl- imidazolium tetrafluoroborate and 5 mol eq. of H 2 O which after 1 .05 mol eq. amount of KF was added and the solution was mixed and sonicated at RT for 180 min or until TLC showed completion.
- the R 5 -halogen substituted compounds were then extracted with DCM and washed several times with brine, dried over anhydrous MgSO and concentrated in vacuo prior proceeding.
- Step 5 Pictet-Spengler reaction - industrial scale (EP 0929527): 1 .0 mol eq. subst. N-tosyl-phenethylamine and 3.0 mol eq. boron trifluoroetherate was refluxed with 21 .0 mol eq. of 1 ,1 -diethoxyethane for 12 h in N 2 atmosphere or until TLC showed completion. The nitrogen is afterwards de-protected; or
- the pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by conventional processes well-known to the person skilled in the art.
- diluents and expedients used in the preparation see, for example, Remington's Pharmaceutical Sciences, 20th Edition, 2000, Marck Publishing Company, Easton, Pennsylvania.
- the pharmacological activity of the compounds of the invention can be verified by methods known in the art.
- the reducing effect on alcohol seeking behavior can be verified using the procedure described by Heidbreder, C.A., et al., Addict Biol. 2007 Mar;12(1 ):35-50.
- the parkinsonism- preventing activity can be shown, for example, as described by Okuda, K., et al. Biol Pharm Bull. 2006 Jul;29(7):1401 -1403.
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Addiction (AREA)
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- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11770473.4A EP2603217B1 (en) | 2010-08-11 | 2011-08-10 | Novel 6,7-disubstituted-isoquinoline derivatives and their use |
CA2808016A CA2808016C (en) | 2010-08-11 | 2011-08-10 | 6,7-disubstituted-isoquinoline derivatives and their use |
ES11770473.4T ES2541401T3 (en) | 2010-08-11 | 2011-08-10 | New isoquinoline derivatives disubstituted in 6.7 and their use |
PL11770473T PL2603217T3 (en) | 2010-08-11 | 2011-08-10 | Novel 6,7-disubstituted-isoquinoline derivatives and their use |
DK11770473.4T DK2603217T3 (en) | 2010-08-11 | 2011-08-10 | HIS UNKNOWN 6,7-DISUBSTITUTED ISOQUINOLINE DERIVATIVES AND THEIR USE |
CN2011800490170A CN103179971A (en) | 2010-08-11 | 2011-08-10 | Novel 6,7-disubstituted-isoquinoline derivatives and their use |
US13/814,987 US8815898B2 (en) | 2010-08-11 | 2011-08-10 | 6,7-disubstituted-sioquinoline derivatives and their use |
RS20150436A RS54081B1 (en) | 2010-08-11 | 2011-08-10 | Novel 6,7-disubstituted-isoquinoline derivatives and their use |
SI201130527T SI2603217T1 (en) | 2010-08-11 | 2011-08-10 | Novel 6,7-disubstituted-isoquinoline derivatives and their use |
RU2013110377A RU2636938C2 (en) | 2010-08-11 | 2011-08-10 | Derivatives of 6,7-double substituted izochinolin and their application in treatment of medicinal dependence and cns diseases |
HRP20150668TT HRP20150668T1 (en) | 2010-08-11 | 2015-06-19 | Novel 6,7-disubstituted-isoquinoline derivatives and their use |
SM201500160T SMT201500160B (en) | 2010-08-11 | 2015-07-03 | New isoquinoline derivatives 6,7-disubstituted and their use |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10397511.6 | 2010-08-11 | ||
EP10397511A EP2420237A1 (en) | 2010-08-11 | 2010-08-11 | Fluorinated derivatives of endogenous isoquinolines for use in the treatment of diseases mediated through endogenous isoquinoline pathways |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012020170A1 true WO2012020170A1 (en) | 2012-02-16 |
Family
ID=43827823
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FI2011/050707 WO2012020170A1 (en) | 2010-08-11 | 2011-08-10 | Novel 6,7-disubstituted-isoquinoline derivatives and their use |
Country Status (16)
Country | Link |
---|---|
US (1) | US8815898B2 (en) |
EP (2) | EP2420237A1 (en) |
CN (1) | CN103179971A (en) |
CA (1) | CA2808016C (en) |
CY (1) | CY1116588T1 (en) |
DK (1) | DK2603217T3 (en) |
ES (1) | ES2541401T3 (en) |
HR (1) | HRP20150668T1 (en) |
HU (1) | HUE026482T2 (en) |
PL (1) | PL2603217T3 (en) |
PT (1) | PT2603217E (en) |
RS (1) | RS54081B1 (en) |
RU (1) | RU2636938C2 (en) |
SI (1) | SI2603217T1 (en) |
SM (1) | SMT201500160B (en) |
WO (1) | WO2012020170A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105585527A (en) * | 2015-12-17 | 2016-05-18 | 浙江工业大学 | 2-(3,4-dihydroisoquinoline)-1(2H)-subunit) acetonitrile compound and application thereof |
WO2022207979A2 (en) | 2021-03-31 | 2022-10-06 | Equinorm Ltd | Novel heterocyclic compounds and their use |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105461626B (en) * | 2015-12-17 | 2018-05-08 | 浙江工业大学 | Aromatic ring or condensed hetero ring connection 3,4- dihydroisoquinoliness conjugated structure compounds and its application |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03148222A (en) * | 1989-11-01 | 1991-06-25 | Tanabe Seiyaku Co Ltd | Preventing and remedy for perkinsonism |
EP0929527A1 (en) | 1996-09-27 | 1999-07-21 | Hoechst Marion Roussel, Inc. | Pictet-spengler reaction for the synthesis of tetrahydroisoquinolines and related heterocyclic compounds |
US6034094A (en) | 1990-12-22 | 2000-03-07 | Boehringer Ingelheim Kg | Pharmaceutically useful 3,4-dihydroisoquinoline |
EP2090576A1 (en) | 2008-02-01 | 2009-08-19 | Merz Pharma GmbH & Co.KGaA | 6-halo-pyrazolo[1,5-a]pyridines, a process for their preparation and their use as metabotropic glutamate receptor (mGluR) modulators |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5491148A (en) | 1991-04-26 | 1996-02-13 | Syntex (U.S.A.) Inc. | Isoquinolinone and dihydroisoquinolinone 5-HT3 receptor antagonists |
US5246943A (en) * | 1992-05-19 | 1993-09-21 | Warner-Lambert Company | Substituted 1,2,3,4-tetahydroisoquinolines with angiotensin II receptor antagonist properties |
BR0015307A (en) * | 1999-11-03 | 2002-07-09 | Albany Molecular Res Inc | Compound, composition, pharmaceutical composition, methods to treat a disorder that is created by or is dependent on the decreased availability of serotonin, norepinephrine or dopamine, and to inhibit the absorption of synaptic norepinephrine, synaptic serotonin and synaptic dopamine in a patient in need of these, and together |
WO2006035280A1 (en) | 2004-09-27 | 2006-04-06 | Ranbaxy Laboratories Limited | 3,4-dihydroisoquinoline compounds as muscrinic receptor antagonists for the treatment of respiratory, urinary and gastrointestinal diseases |
US20060111393A1 (en) * | 2004-11-22 | 2006-05-25 | Molino Bruce F | 4-Phenyl substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin |
-
2010
- 2010-08-11 EP EP10397511A patent/EP2420237A1/en not_active Withdrawn
-
2011
- 2011-08-10 SI SI201130527T patent/SI2603217T1/en unknown
- 2011-08-10 RU RU2013110377A patent/RU2636938C2/en not_active Application Discontinuation
- 2011-08-10 US US13/814,987 patent/US8815898B2/en active Active
- 2011-08-10 PL PL11770473T patent/PL2603217T3/en unknown
- 2011-08-10 EP EP11770473.4A patent/EP2603217B1/en active Active
- 2011-08-10 CN CN2011800490170A patent/CN103179971A/en active Pending
- 2011-08-10 HU HUE11770473A patent/HUE026482T2/en unknown
- 2011-08-10 ES ES11770473.4T patent/ES2541401T3/en active Active
- 2011-08-10 PT PT117704734T patent/PT2603217E/en unknown
- 2011-08-10 DK DK11770473.4T patent/DK2603217T3/en active
- 2011-08-10 WO PCT/FI2011/050707 patent/WO2012020170A1/en active Application Filing
- 2011-08-10 CA CA2808016A patent/CA2808016C/en not_active Expired - Fee Related
- 2011-08-10 RS RS20150436A patent/RS54081B1/en unknown
-
2015
- 2015-06-19 HR HRP20150668TT patent/HRP20150668T1/en unknown
- 2015-07-02 CY CY20151100573T patent/CY1116588T1/en unknown
- 2015-07-03 SM SM201500160T patent/SMT201500160B/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03148222A (en) * | 1989-11-01 | 1991-06-25 | Tanabe Seiyaku Co Ltd | Preventing and remedy for perkinsonism |
US6034094A (en) | 1990-12-22 | 2000-03-07 | Boehringer Ingelheim Kg | Pharmaceutically useful 3,4-dihydroisoquinoline |
EP0929527A1 (en) | 1996-09-27 | 1999-07-21 | Hoechst Marion Roussel, Inc. | Pictet-spengler reaction for the synthesis of tetrahydroisoquinolines and related heterocyclic compounds |
EP2090576A1 (en) | 2008-02-01 | 2009-08-19 | Merz Pharma GmbH & Co.KGaA | 6-halo-pyrazolo[1,5-a]pyridines, a process for their preparation and their use as metabotropic glutamate receptor (mGluR) modulators |
Non-Patent Citations (10)
Title |
---|
"Remington's Pharmaceutical Sciences", MARCK PUBLISHING COMPANY |
ALCOHOL CLIN. EXP. RES., vol. 33, no. 11, November 2009 (2009-11-01), pages 1935 - 44 |
DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 7 November 2011 (2011-11-07), XP002666855, retrieved from STN accession no. 1342184-32-0 Database accession no. 1342184-32-0 * |
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, 2006, pages 241 - 252 |
HEIDBREDER, C.A. ET AL., ADDICT BIOL., vol. 12, no. 1, March 2007 (2007-03-01), pages 35 - 50 |
KATSUHIRO OKUDA ET AL., BIOLOGICAL AND PHARMACEUTICAL BULLETIN, vol. 29, 2006, pages 1401 - 1403 |
KNOEVENAGEL CONDENSATION - TET. LETT., vol. 39, 1998, pages 8013 - 8016 |
OKUDA KATSUHIRO ET AL: "Parkinsonism-preventing activity of 1-methyl-1,2,3,4-tetrahydroisoqui noline derivatives in C57BL mouse in vivo", BIOLOGICAL & PHARMACEUTICAL BULLETIN, vol. 29, no. 7, July 2006 (2006-07-01), pages 1401 - 1403, XP002632499, ISSN: 0918-6158 * |
OKUDA, K. ET AL., BIOL PHARM BULL., vol. 29, no. 7, July 2006 (2006-07-01), pages 1401 - 1403 |
SAITOH T ET AL: "Synthesis and in vitro cytotoxicity of 1,2,3,4-tetrahydroisoquinoline derivatives", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 41, no. 2, 1 February 2006 (2006-02-01), pages 241 - 252, XP024993836, ISSN: 0223-5234, [retrieved on 20060201], DOI: DOI:10.1016/J.EJMECH.2005.11.003 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105585527A (en) * | 2015-12-17 | 2016-05-18 | 浙江工业大学 | 2-(3,4-dihydroisoquinoline)-1(2H)-subunit) acetonitrile compound and application thereof |
CN105585527B (en) * | 2015-12-17 | 2018-06-26 | 浙江工业大学 | 2- (3,4- dihydro-isoquinolines -1 (2H)-subunit) cyanide compounds and its application |
WO2022207979A2 (en) | 2021-03-31 | 2022-10-06 | Equinorm Ltd | Novel heterocyclic compounds and their use |
Also Published As
Publication number | Publication date |
---|---|
DK2603217T3 (en) | 2015-07-13 |
CY1116588T1 (en) | 2017-03-15 |
PT2603217E (en) | 2015-08-26 |
CA2808016C (en) | 2018-10-30 |
HRP20150668T1 (en) | 2015-09-11 |
RS54081B1 (en) | 2015-10-30 |
HUE026482T2 (en) | 2016-06-28 |
US20130137719A1 (en) | 2013-05-30 |
RU2013110377A (en) | 2014-09-20 |
EP2603217B1 (en) | 2015-04-08 |
PL2603217T3 (en) | 2015-09-30 |
CA2808016A1 (en) | 2012-02-16 |
SMT201500160B (en) | 2015-09-07 |
SI2603217T1 (en) | 2015-08-31 |
EP2603217A1 (en) | 2013-06-19 |
ES2541401T3 (en) | 2015-07-20 |
RU2636938C2 (en) | 2017-11-29 |
CN103179971A (en) | 2013-06-26 |
US8815898B2 (en) | 2014-08-26 |
EP2420237A1 (en) | 2012-02-22 |
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