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WO2008086353A1 - Dérivés contenant du propargyle de tétrahydro-benzthiazoles et procédés de fabrication et d'utilisation de ceux-ci - Google Patents

Dérivés contenant du propargyle de tétrahydro-benzthiazoles et procédés de fabrication et d'utilisation de ceux-ci Download PDF

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Publication number
WO2008086353A1
WO2008086353A1 PCT/US2008/050512 US2008050512W WO2008086353A1 WO 2008086353 A1 WO2008086353 A1 WO 2008086353A1 US 2008050512 W US2008050512 W US 2008050512W WO 2008086353 A1 WO2008086353 A1 WO 2008086353A1
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group
propargyl
compounds
carbon atoms
methyl
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PCT/US2008/050512
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English (en)
Inventor
Vincent R. Zurawski, Jr.
Moussa B.H. Youdim
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems

Definitions

  • the invention relates to derivatives of tetrahydro-benzthiazoles that comprise at least one propargyl group, to methods of using such compounds, to methods of using such compounds and to intermediates useful to produce such compounds.
  • Neurological disorders refers to disease and conditions of the brain and nervous systems. Such disease and conditions include degenerative diseases, functional diseases, and psychiatric disorders as well as head and nerve injuries, pain and other debilatating or functionally limiting conditions. Examples of degenerative diseases include Alzheimer's disease, Parkinson's disease and Multiple Sclerosis. Examples of psychiatric disorders include schizophrenia, depression, bipolar disorder. Examples of other diseases include Tourette's syndrome and Bell's palsy.
  • Pramipexole which is marketed under the tradename Mirapex®, is used in the treatment of Parkinson's disease. Pramipexole is a tetrahydro-benzthiazole described in U.S. Patent Number 4,886,812, which is incorporated herein by reference.
  • the irreversible monoamine oxidase B inhibitor, rasagiline is characterized by its neuroprotective and neurorescue activity in both neuronal cell cultures and in vivo animal models, including those of Parkinson's disease (Youdim MB, et al. Neuropharmacological, neuroprotective and amyloid precursor processing properties of selective MAO-B inhibitor antiparkinsonian drug, rasagiline. Drugs Today (Bare). 2005 Jun; 41(6):369- 91.; Mandel S, et al. Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives. Brain Res Rev. 2005 Apr; 48(2):379-87).
  • the neuroprotective activity of rasagiline and other propargylamine-containing drugs may be in part the result of their ability to induce the mRNAs of GDNF and BDNF and induce release of GDNF and (Maruyama et al., N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-S Y5Y cells through activation of NF-kappaB transcription factor. Neurochem Int. 2004 May; 44(6):393-400; and Bar Am, et al., 2005 supra).
  • GDNF glial cell line-derived neurotrophic factor
  • the present invention relates to compounds have the general formula:
  • R 1 represents a propargyl group, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the above mentioned phenyl nuclei may be substituted by 1 or 2 halogen atoms,
  • R 2 represents a propargyl group, a hydrogen atom or an alkyl group with 1 to 4 carbon atoms,
  • R 3 represents a propargyl group, a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 1 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms, and
  • R 4 represents a propargyl group, a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms or
  • R 3 and R 4 together with the nitrogen atom between them represent a pyrrolidino, piperidino, hexamethyleneimino or morpholino group; wherein at least one of at least one Of R 1 , R 2 , R 3 and R 4 is a propargyl group.
  • the present invention further relates to pharmaceutical compositions that comprise such compounds.
  • the present invention further relates to methods of treating neurological disorders comprising the step of administering such compounds in a therapeutically effective amount.
  • the present invention further relates to methods of making such compounds.
  • the present invention further relates to intermediates useful in methods of making such compounds.
  • Propargyl is alkyl functional group with the structure HC ⁇ C-CH2- . This functional group is linked to an amine group of a tetrahydro-benzthiazole. The resulting compound is useful in the treatment of neurological disorders, particularly Parkinson's disease.
  • R 1 represents a propargyl group, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the above mentioned phenyl nuclei may be substituted by 1 or 2 halogen atoms,
  • R 2 represents a propargyl group, a hydrogen atom or an alkyl group with 1 to 4 carbon atoms,
  • R 3 represents a propargyl group, a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 1 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms, and
  • R 4 represents a propargyl group, a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms or
  • R 3 and R 4 together with the nitrogen atom between them represent a pyrrolidino, piperidino, hexamethyleneimino or niorpholino group; wherein at least one of at least one of R 1 , R 2 , R 3 and R 4 is a propargyl group, and pharmaceutically acceptable salts thereof.
  • the compound has a single propargyl group.
  • the functional group with the formula NR 3 R4 is attached to carbon at position 5 or 6, preferably position 5 (i.e. two from the S).
  • the compound has a single propargyl group and the functional group with the formula NR3R4 is attached to carbon at position 5 or 6, preferably position 5 (i.e. two from the S).
  • R 1 is H, R 2 is H, R 3 is a propargyl group, and R4 is propyl. In some preferred embodiments, R 1 is H, R 2 is H , R 3 is a propargyl group, and R 4 is H. In some preferred embodiments, R 1 is H, R 2 is H, R 3 is a propargyl group, and R 4 is methyl. In some preferred embodiments, R 1 is propargyl, R 2 is H, R 3 is H, and R 4 is H. In some preferred embodiments, R 1 is propargyl, R 2 is methyl, R 3 is H, and R 4 is H.
  • R 1 is propargyl, R 2 is H, R 3 is a propyl group, and R 4 is H.
  • R 1 is propargyl, R 2 is methyl, R 3 is a propyl group, and R 4 is H.
  • R 1 is propargyl, R 2 is H, R 3 is a propyl group, and R 4 is methyl.
  • R 1 is propargyl, R 2 is methyl, R 3 is a propyl group, and R 4 is methyl.
  • the functional group with the formula NR 3 R 4 is attached to carbon at position 5 or 6, and R 1 is H, R 2 is H, R 3 is a propargyl group, and R 4 is propyl. In some preferred embodiments, the functional group with the formula NR 3 R 4 is attached to carbon at position 5 or 6, and R 1 is H, R 2 is H , R 3 is a propargyl group, and R 4 is H. In some preferred embodiments, the functional group with the formula NR 3 R 4 is attached to carbon at position 5 or 6, and R 1 is H, R 2 is H, R 3 is a propargyl group, and R 4 is methyl.
  • the functional group with the formula NR 3 R 4 is attached to carbon at position 5 or 6, and R 1 is propargyl, R 2 is H, R 3 is H, and R 4 is H. In some preferred embodiments, the functional group with the formula NR 3 R 4 is attached to carbon at position 5 or 6, and R 1 is propargyl, R 2 is methyl, R 3 is H, and R 4 is H. In some preferred embodiments, the functional group with the formula NR 3 R 4 is attached to carbon at position 5 or 6, and R 1 is propargyl, R 2 is H, R 3 is a propyl group, and R 4 is H.
  • the functional group with the formula NR 3 R 4 is attached to carbon at position 5 or 6, and R 1 is propargyl, R 2 is methyl, R 3 is a propyl group, and R 4 is H. In some preferred embodiments, the functional group with the formula NR 3 R 4 is attached to carbon at position 5 or 6, and R 1 is propargyl, R 2 is H, R 3 is a propyl group, and R 4 is methyl. In some preferred embodiments, the functional group with the formula NR 3 R 4 is attached to carbon at position 5 or 6, and R 1 is propargyl, R 2 is methyl, R 3 is a propyl group, and R 4 is methyl.
  • the compounds has the structure:
  • the compounds has the structure:
  • the compounds has the structure:
  • the compounds has the structure:
  • the compounds has the structure:
  • the compounds has the structure:
  • the compounds has the structure:
  • the compounds has the structure:
  • the compounds has the structure:
  • the synthesis of the compounds may be performed, for example, by first producing tetrahydro-benzthiazoles that do not contain propargyl groups by the synthesis schemes set forth in U.S. Patent Number 4,886,812. Following synthesis of such compounds, propargyl groups may be added at one or more of positions R 1 , R 2 , R 3 and R 4 .
  • the compounds of this invention contain asymmetric carbon atoms and thus give rise to optical isomers and diastereoisomers.
  • the present invention includes such optical isomers and diastereoisomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
  • an enantiomer substantially free of the corresponding enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding enantiomer.
  • substantially free means that the compound is made up of a significantly greater proportion of one enantiomer. In preferred embodiments, the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
  • HPLC high performance liquid chromatography
  • the compounds useful in the present invention also include pharmaceutically acceptable salts of the compounds of formula (I).
  • pharmaceutically acceptable salt it is meant any compound formed by the addition of a pharmaceutically acceptable base and a compound of formula (I) to form the corresponding salt.
  • pharmaceutically acceptable it is meant a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
  • Pharmaceutically acceptable salts include, but are not limited to, those derived from such organic and inorganic acids such as, but not limited to, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids.
  • organic and inorganic acids such as, but not limited to, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methane
  • the present invention relates to methods of treating neurological disorders comprising the step of administering such compounds in a therapeutically effective amount.
  • the compounds of this invention are of interest for the treatment of neurological disorders including degenerative disorders such as Parkinson's disease, Alzheimer's disease and Multiple scleroris as well as disorders such as Tourette's syndrome.
  • the compounds of this invention are also of interest for the treatment of mental disorders, including psychotic disorders such as schizophrenia including paranoid type, disorganized type, catatonic type, and undifferentiated type, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, and psychotic disorder not otherwise specified; L-DOP A-induced psychosis; psychosis associated with Alzheimer's dementia; psychosis associated with Parkinson's disease; psychosis associated with Lewy body disease; bipolar disorders such as bipolar I disorder, bipolar II disorder, and cyclothymic disorder; depressive disorders such as major depressive disorder, dysthymic disorder, substance-induced mood disorder, and depressive disorder not otherwise specified; mood episodes such as major depressive episode, manic episode, mixed episode, and hypomanic episode; anxiety disorders such as panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, substance-
  • mood disorders such as depressive disorders or bipolar disorders often accompany psychotic disorders such as schizophrenia.
  • psychotic disorders such as schizophrenia.
  • a more complete description of the aforementioned mental disorders can be found in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Washington, DC, American Psychiatric Association (1994).
  • the compounds of the present invention are also of interest for the treatment of epilepsy; migraines; sexual dysfunction; sleep disorders; eating disorders, and obesity.
  • the compounds of the present invention can also be used to treat central nervous system deficiencies associated, for example, with trauma, stroke, and spinal cord injuries.
  • the compounds of the present invention can therefore be used to improve or inhibit further degradation of central nervous system activity during or following the malady or trauma in question. Included in these improvements are maintenance or improvement in motor and motility skills, control, coordination and strength.
  • the present invention provides methods of treating each of the maladies listed above in a mammal, preferably in a human, the methods comprising providing a therapeutically effective amount of a compound of this invention to the mammal in need thereof.
  • treating it is meant partially or completely alleviating, inhibiting, preventing, ameliorating and/or relieving the disorder.
  • treating includes partially or completely alleviating, inhibiting or relieving the condition in question.
  • mammals as used herein refers to warm blooded vertebrate animals, such as humans.
  • composition means either directly administering a compound or composition of the present invention, or administering a derivative or analog which will form an equivalent amount of the active compound or substance within the body.
  • the present invention further relates to pharmaceutical compositions that comprise such compounds.
  • Pharmaceutical compositions are useful for treating or controlling disease states or conditions of the central nervous system comprising at least one compound of the invention, mixtures thereof, and or pharmaceutical salts thereof, and a pharmaceutically acceptable carrier therefore.
  • Such compositions are prepared in accordance with acceptable pharmaceutical procedures, such as described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985).
  • Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
  • the compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.
  • the pharmaceutical carrier may be solid or liquid.
  • Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsif ⁇ ers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
  • oils e.g. fractionated coconut oil and arachis oil
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
  • the compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository.
  • the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
  • the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
  • Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
  • a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, pref ⁇ lled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0.02 ⁇ g/kg - 750 ⁇ g/kg. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached; precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated.
  • a further aspect of the invention relates to methods of making the compounds of the invention.
  • Examples 1-16 set forth synthesis schemes for specific embodiment of the invention.
  • the present invention further relates to novel intermediates which are useful to produce compounds of the invention.
  • Examples 1-16 disclose novel intermediates useful to produce other compounds of the invention.
  • Pramipexole hydrochloride (4.94 g, 20 mmole), sodium acetate (1.64 g, 20 mmol), and propargyl aldehyde (1.08 g, 20 mmole) in ethanol (100 mL) is treated with sodium triacetoxyborohydride (6.3 g, 30 mmol) and stirred for 18 hours.
  • the reaction mixture is quenched with hydrochloric acid and the ethanol is evaporated.
  • the residue is taken in water (100 mL) and the pH of the solution is adjusted to pH 11 or higher by the addition of sodium hydroxide solution.
  • the product is extracted with dichloromethane (150 mL). The organic layer was washed with water, dried (Na 2 SO 4 ), and concentrated to get the product.
  • the compound was purified by column chromatography.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés contenant du propargyle de tétrahydro-benzthiazoles. La composition pharmaceutique comprenant un ou plusieurs dérivés contenant du propargyle de tétrahydro-benzthiazoles est également décrite. Le procédé d'utilisation de dérivés contenant du propargyle de tétrahydro-benzthiazoles dans le traitement d'individus qui ont des troubles neurologiques est décrit.
PCT/US2008/050512 2007-01-08 2008-01-08 Dérivés contenant du propargyle de tétrahydro-benzthiazoles et procédés de fabrication et d'utilisation de ceux-ci Ceased WO2008086353A1 (fr)

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US87947007P 2007-01-08 2007-01-08
US60/879,470 2007-01-08

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WO2008086353A1 true WO2008086353A1 (fr) 2008-07-17

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009056811A3 (fr) * 2007-10-31 2009-10-15 Motac Neuroscience Limited Médicaments

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4886812A (en) * 1984-12-22 1989-12-12 Dr. Karl Thomae Gmbh Tetrahydro-benzthiazoles, the preparation thereof and their use as intermediate products or as pharmaceuticals
US20050197365A1 (en) * 2004-02-27 2005-09-08 Jeffrey Sterling Diamino thiazoloindan derivatives and their use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4886812A (en) * 1984-12-22 1989-12-12 Dr. Karl Thomae Gmbh Tetrahydro-benzthiazoles, the preparation thereof and their use as intermediate products or as pharmaceuticals
US20050197365A1 (en) * 2004-02-27 2005-09-08 Jeffrey Sterling Diamino thiazoloindan derivatives and their use

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009056811A3 (fr) * 2007-10-31 2009-10-15 Motac Neuroscience Limited Médicaments

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