Classifications

• • 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
  • C07D495/12—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 three hetero rings
  • C07D495/14—Ortho-condensed systems
• • 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
  • A61P25/24—Antidepressants

Definitions

• the invention relates to new 3-substituted 3, 4, 5, 7-tetrahydro-pyrrolo [3 ', 4': 4, 5] thieno [2, 3-d] pyrimidine derivatives, their preparation and their use in the preparation of active pharmaceutical ingredients f en.
• SSRIs serotonin reuptake inhibitors
• the antidepressant effect only occurs after a treatment of at least 3 weeks , in addition, about 30% of the patients are resistant to therapy.
• the blockade of presynaptic serotonin autoreceptors increases the release of the serotonin by canceling the negative coupling and thus the current transmitter concentration in the synaptic cleft. This increase in transmitter concentration is considered the antidepressant principle.
• This mechanism of action differs from the previously known antidepressants, which simultaneously activate the 5 presynaptic and somatodendritic autoreceptors and therefore lead to a delayed onset of action only after desensitization of these autoreceptors.
• the direct auto-receptor blockade circumvents this effect.
• the presynaptic serotonin autoreceptor is the 5-HT- B subtype (Fink et al., Arch. Pharmacol. 352 (1995), p. 451). Its selective blockage by S-HTi B / D 'antagonists increases the release of serotonin in the brain: GW Price et al., Behavioral Brain Research 73 (1996), 5 pp. 79-82; PH Hutson et al., Neuropharmacology Vol. 34, No. 4 (1995), pp. 383-392.
• the selective 5-HT- B antagonist GR 127 935 surprisingly reduces the release of serotonin in the cortex after systemic administration.
• One explanation could be the stimulation of somatodendritic 5-HT ⁇ A receptors in the raphe region by the released serotonin, which inhibits the rate of fire of serotonergic neurons and thus the release of serotonin (M. Skingle et al., Neuropharmacology Vol. 34 No. 4 (1995), pp. 377-382, pp. 393-402).
• 5 A strategy to circumvent the auto-inhibitory effects in serotonergic regions of origin follows the blockade of the presynaptic 5-HT 1B receptors. This hypothesis is supported by the observation that the influence of paroxetine on the serotonin release in the dorsal raphe nucleus of the rat by the
• the second strategy involves blocking both types of auto-receptors, namely the 5-HT 1A receptors to increase neuronal firing and the 5-HT 1 B receptors to increase terminal serotonin release (Starkey and Skingle, Neuropharmacology 33. (3-4) (1994), 393).
• 5-HT IB / D "antagonists alone or coupled with a 5-HT- A receptor antagonistic component should therefore increase the release of serotonin in the brain and could therefore include advantages in the therapy of depression and related mental illnesses.
• R 1 is a hydrogen atom, a C 1 -C 4 -alkyl group, an acetyl group, a phenylalkyl C 1 -C 4 radical, the aromatic optionally being replaced by halogen, C 1 -C 4 -alkyl, trifluoromethyl, hydroxy, C 1 -C 4 4 -alkoxy, amino, cyano or nitro groups is substituted or a carboxylic acid C ! -C 3 -alkyl ester residue means
• R 2 is a halogen or CC 4 alkyl, trifluoroethyl, trifluoromethoxy, hydroxy, Ci-CValkoxy, amino, monomethylamino, prostitute hylamino, cyano or nitro groups which are mono- or disubstituted phenyl, pyridyl, optionally by halogen atoms, CC 4 alkyl -, Pyrimidinyl or pyrazinyl group, optionally with a benzene nucleus, optionally by halogen atoms, Ci-CValkyl, hydroxy, tri. fluoromethyl, Ci-C ⁇ -alkoxy, amino, cyano or nitro groups can be mono- or disubstituted and optionally 1 stick Can contain substance atom, or with a 5- or 6-membered
• Ring which can contain 1-2 oxygen atoms, can be fused
• A represents NH or an oxygen atom
• Z represents a nitrogen atom, carbon atom or CH, where the bond between Y and Z can also be a double bond,
• n represents the number 2, 3 or 4,
• R 1 is hydrogen, ethyl, carboxylic acid ethyl ester
• R 2 o-methoxyphenyl, 1-naphthyl, 2-methoxy-1-naphthyl, 2-methyl-1-naphthyl
• Z is a nitrogen atom
• n is the number 2 and 3.
• the compounds of formula I according to the invention can be prepared by using a compound of formula II
• R 1 has the meaning given above
• R 3 represents a cyano group or a C 3 -3 -alkyl-carboxylic acid ester group
• R 4
• C 3 alkyl means with a primary A in the formula III
• R 2 has the meaning given above, and the compound thus obtained is optionally converted into the acid addition salt of a physiologically acceptable acid.
• reaction is conveniently carried out in an inert organic solvent, especially a lower alcohol, e.g. Methanol or ethanol, or a cyclic saturated ether, especially tetrahydrofuran or dioxane.
• a lower alcohol e.g. Methanol or ethanol
• a cyclic saturated ether especially tetrahydrofuran or dioxane.
• the implementation usually takes place at temperatures of
• R 1 has the meaning given above
• R 3 is a cyano group or a C 3 -3 -alkyl-carboxylic acid ester group and R 4 is C 3 -3 -alkyl, with a primary amino alcohol of the formula IV
• halogenating agent e.g.
• the compounds of the formula I according to the invention can either be recrystallized by recrystallization from the customary organic solvents, preferably from a lower alcohol, such as ethanol, or purified by column chromatography.
• the free 3-substituted 3, 4, 5,7-tetrahydro-pyrrolo [3 ', 4': 4,5] thieno [2, 3-d] pyrimidine derivatives of the formula I can in the usual way in the acid addition salts of a solution with the stoichiometric amount of the corresponding acid.
• Pharmaceutically acceptable acids are, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
• the invention also relates to a therapeutic agent, characterized in that it contains a compound of the formula I or its pharmacologically acceptable acid addition salt as active ingredient in addition to conventional carriers and diluents, and the use of the new compounds in combating diseases.
• the compounds according to the invention can be administered in the usual way orally or parenterally, intravenously or intramuscularly.
• the dosage depends on the age, condition and weight of the patient and on the type of application.
• the daily dose of active substance is between approximately 1 and 100 mg / kg body weight when administered orally and between 0.1 and 10 mg / kg body weight when administered parenterally.
• the new compounds can be used in common galenical application forms, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
• the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et. Al : Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1978).
• the administration forms obtained in this way normally contain the active ingredient in an amount of 1 to 99% by weight.
• the compounds of the invention have a high affinity for the serotonin receptors 5-HT ⁇ B , 5-HT ⁇ D and 5-HT ⁇ A.
• the affinity for these receptors is approximately the same, at least of the same order of magnitude.
• some of the compounds according to the invention have good serotonin reuptake inhibition - a principle which is implemented in most antidepressants.
• These compounds are suitable as medicaments for the treatment of disease states in which the serotonin concentration is reduced and in which one wishes to block the activity of the presynaptic receptors 5-HT ⁇ B , 5-HT ⁇ A , 5-HTI D as part of a therapy without to strongly influence other receptors. Depression, for example, is such an illness.
• the compounds of the present invention can also be used for
• central nervous disorders such as seasonal mood disorders and dysthymia
• This also includes anxiety such as generalized anxiety, panic attacks, sociophobia, obsessive-compulsive disorders and post-traumatic stress symptoms, memory disorders including dementia, amnesias and age-related memory loss as well as psychogenic eating disorders such as anorexia nervosa and bulimia nervosa.
• the compounds of the invention may also be useful for the treatment of endocrine disorders such as hyperprolactinemia, as well as for the treatment of vascular spasms (particularly the brain vessels), hypertension and gastrointestinal disorders associated with motility and secretion disorders. Another area of application is sexual disorders.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Neurology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pain & Pain Management (AREA)
• Psychiatry (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=7838438

Family Applications (1)

Country Status (25)

Families Citing this family (10)

Family Cites Families (3)

• 1997
  • 1997-08-08 DE DE19734444A patent/DE19734444A1/de not_active Withdrawn
• 1998
  • 1998-07-23 US US09/485,188 patent/US6355647B1/en not_active Expired - Lifetime
  • 1998-07-23 AU AU90683/98A patent/AU749539B2/en not_active Ceased
  • 1998-07-23 NZ NZ502657A patent/NZ502657A/en unknown
  • 1998-07-23 KR KR1020007001252A patent/KR20010022658A/ko not_active Application Discontinuation
  • 1998-07-23 CN CN98808009A patent/CN1267303A/zh active Pending
  • 1998-07-23 JP JP2000506214A patent/JP2001512734A/ja active Pending
  • 1998-07-23 PL PL98340726A patent/PL340726A1/xx not_active Application Discontinuation
  • 1998-07-23 IL IL13416198A patent/IL134161A0/xx unknown
  • 1998-07-23 SK SK105-2000A patent/SK1052000A3/sk unknown
  • 1998-07-23 HU HU0101311A patent/HUP0101311A3/hu unknown
  • 1998-07-23 TR TR2000/00371T patent/TR200000371T2/xx unknown
  • 1998-07-23 CZ CZ2000462A patent/CZ290678B6/cs not_active IP Right Cessation
  • 1998-07-23 ID IDW20000239A patent/ID24222A/id unknown
  • 1998-07-23 WO PCT/EP1998/004633 patent/WO1999007711A1/de not_active Application Discontinuation
  • 1998-07-23 BR BR9811091-8A patent/BR9811091A/pt not_active IP Right Cessation
  • 1998-07-23 CA CA002300391A patent/CA2300391A1/en not_active Abandoned
  • 1998-07-23 EP EP98942610A patent/EP1003752A1/de not_active Withdrawn
  • 1998-08-06 HR HR19734444.5A patent/HRP980435A2/hr not_active Application Discontinuation
  • 1998-08-07 AR ARP980103914A patent/AR016594A1/es not_active Application Discontinuation
  • 1998-08-07 TW TW087113048A patent/TW513435B/zh active
  • 1998-08-07 ZA ZA9807114A patent/ZA987114B/xx unknown
  • 1998-08-10 CO CO98045546A patent/CO4960665A1/es unknown
• 2000
  • 2000-02-07 NO NO20000605A patent/NO20000605L/no not_active Application Discontinuation
  • 2000-02-10 BG BG104151A patent/BG104151A/bg unknown

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events