WO2008086353A1

WO2008086353A1 - Propargyl-containing derivatives of tetrahydro-benzthiazoles and methods of making and using the same

Info

Publication number: WO2008086353A1
Application number: PCT/US2008/050512
Authority: WO
Inventors: Vincent R. Zurawski, Jr.; Moussa B.H. Youdim
Original assignee: Individual
Current assignee: Individual
Priority date: 2007-01-08
Filing date: 2008-01-08
Publication date: 2008-07-17
Anticipated expiration: 2009-07-08

Abstract

Propargyl-containing derivatives of tetrahydro-benzthiazoles are disclosed. Pharmaceutical composition comprising one or more propargyl-containing derivatives of tetrahydro-benzthiazoles are also disclosed. Method of using propargyl-containing derivatives of tetrahydro-benzthiazoles in the treatment of individuals who have neurological disorders are disclosed.

Description

PROPARGYL-CONT AINING DERIVATIVES OF TETRAHYDRO-BENZTHIAZOLES AND METHODS OF MAKING AND USING THE SAME

FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

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 (Azilect®/Agilect®), 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). Structure activity studies indicate that the neuroprotective activity resides in the propargylamine moiety (Youdim MB, et al. The anti-Parkinson drug rasagiline and its cholinesterase inhibitor derivatives exert neuroprotection unrelated to MAO inhibition in cell culture and in vivo. Ann N Y Acad Sci. 2001 Jun; 939:450- 8.; Youdim MB and JJ Buccafusco. Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol Sci. 2005 Jan; 26(l):27-35). Similarly, the anti-Alzheimer cholinesterase inhibitor, ladostigil (Weinstock M, et ctl.. TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer's disease. J Neural Transm Suppl. 2000; (60): 157-69), also possessing the propargylamine moiety, is characterized by its neuroprotective activity, a feature missing in other cholinesterase inhibitor anti-Alzheimer drugs in the clinic. Additional extensive studies have indicated that free propargylamine itself shares these same pharmacological activities with similar potency; these observations led to the development of propargylamine-iron chelators such as the M30 series and HLA-20 (Youdim, et al., 2001 supra; Bar- Am O, et al. Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. FASEB J. 2005 Nov; 19(13): 1899-901. Epub 2005 Sep 7; Gal S, et al. Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. J Neurochem. 2005 Oct; 95(l):79-88; and Zecca L, et al. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004 Nov; 5(11):863-73). These studies have demonstrated that a propargylamine moiety can be introduced into compounds possessing primary, secondary or tertiary amines. The Youdim laboratory has also made similar types of derivative compounds with amantadine, memantine and adenosine A2 antagonist.

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).

Their remains a need for compounds with improved activities for treating neurological disorders such as Parkinson's disease. SUMMARY OF THE INVENTION

The present invention relates to compounds have the general formula:

wherein: R₁ 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,

R₂ represents a propargyl group, a hydrogen atom or an alkyl group with 1 to 4 carbon atoms,

R₃ 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

R₄ 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

R₃ and R₄ together with the nitrogen atom between them represent a pyrrolidino, piperidino, hexamethyleneimino or morpholino group; wherein at least one of at least one Of R₁, R₂, R₃ and R₄ 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.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

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.

The compounds having the formula:

R₃ and R₄ together with the nitrogen atom between them represent a pyrrolidino, piperidino, hexamethyleneimino or niorpholino group; wherein at least one of at least one of R₁, R₂, R₃ and R₄ is a propargyl group, and pharmaceutically acceptable salts thereof. In some preferred embodiments, the compound has a single propargyl group. In some preferred embodiments, 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). In some preferred embodiments, 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).

In some preferred embodiments, R₁ is H, R₂ is H, R₃ is a propargyl group, and R4 is propyl. In some preferred embodiments, R₁ is H, R₂ is H , R₃ is a propargyl group, and R₄ is H. In some preferred embodiments, R₁ is H, R₂ is H, R₃ is a propargyl group, and R₄ is methyl. In some preferred embodiments, R₁ is propargyl, R₂ is H, R₃ is H, and R₄ is H. In some preferred embodiments, R₁ is propargyl, R₂ is methyl, R₃ is H, and R₄ is H. In some preferred embodiments, R₁ is propargyl, R₂ is H, R₃ is a propyl group, and R₄ is H. In some preferred embodiments, R₁ is propargyl, R₂ is methyl, R₃ is a propyl group, and R₄ is H. R₁ is propargyl, R₂ is H, R₃ is a propyl group, and R₄ is methyl. In some preferred embodiments, R₁ is propargyl, R₂ is methyl, R₃ is a propyl group, and R₄ is methyl.

In some preferred embodiments, the functional group with the formula NR₃R₄ is attached to carbon at position 5 or 6, and R₁ is H, R₂ is H, R₃ is a propargyl group, and R₄ is propyl. In some preferred embodiments, the functional group with the formula NR₃R₄ is attached to carbon at position 5 or 6, and R₁ is H, R₂ is H , R₃ is a propargyl group, and R₄ is H. In some preferred embodiments, the functional group with the formula NR₃R₄ is attached to carbon at position 5 or 6, and R₁ is H, R₂ is H, R₃ is a propargyl group, and R₄ is methyl. In some preferred embodiments, the functional group with the formula NR₃R₄ is attached to carbon at position 5 or 6, and R₁ is propargyl, R₂ is H, R₃ is H, and R₄ is H. In some preferred embodiments, the functional group with the formula NR₃R₄ is attached to carbon at position 5 or 6, and R₁ is propargyl, R₂ is methyl, R₃ is H, and R₄ is H. In some preferred embodiments, the functional group with the formula NR₃R₄ is attached to carbon at position 5 or 6, and R₁ is propargyl, R₂ is H, R₃ is a propyl group, and R₄ is H. In some preferred embodiments, the functional group with the formula NR₃R₄ is attached to carbon at position 5 or 6, and R₁ is propargyl, R₂ is methyl, R₃ is a propyl group, and R₄ is H. In some preferred embodiments, the functional group with the formula NR₃R₄ is attached to carbon at position 5 or 6, and R₁ is propargyl, R₂ is H, R₃ is a propyl group, and R₄ is methyl. In some preferred embodiments, the functional group with the formula NR₃R₄ is attached to carbon at position 5 or 6, and R₁ is propargyl, R₂ is methyl, R₃ is a propyl group, and R₄ is methyl.

In some preferred embodiments, the compounds has the structure:

In some preferred embodiments, the compounds has the structure:

In some preferred embodiments, the compounds has the structure:

In some preferred embodiments, the compounds has the structure:

In some preferred embodiments, the compounds has the structure:

In some preferred embodiments, the compounds has the structure:

In some preferred embodiments, the compounds has the structure:

In some preferr embodiments, the compounds has the structure:

In some preferred embodiments, 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 R₁, R₂, R₃ and R₄.

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.

Where an enantiomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer. Thus, 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," as used herein, 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).

The compounds useful in the present invention also include pharmaceutically acceptable salts of the compounds of formula (I). By "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. By the term "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, including mono- and bi- 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.

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-induced anxiety disorder, and anxiety disorder not otherwise specified; adjustment disorders such as adjustment disorders with anxiety and/or depressed mood; intellectual deficit disorders such as dementia and memory deficit; eating disorders (e.g., hyperphagia, bulimia or anorexia nervosa) and combinations of these mental disorders that may be present in a mammal. For example, mood disorders such as depressive disorders or bipolar disorders often accompany 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.

Thus 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. By "treating", as used herein, it is meant partially or completely alleviating, inhibiting, preventing, ameliorating and/or relieving the disorder. For example, "treating" as used herein 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. "Provide", as used herein, 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. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, 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, emulsifϊers, 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) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration 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. For administration by intranasal or intrabronchial inhalation or insufflation, 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.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, 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, prefϊlled 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 μg/kg - 750 μg/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.

EXAMPLES

Example 1: Preparation of 6-[N-propyl-N-prop-2-ynyl]-4,5,6,7-tetrahydro-benzothiazole- 2,6-diamine (1)

(Pramipexole) (propargyl aldehyde)

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 (Na₂SO₄), and concentrated to get the product. The compound was purified by column chromatography.

Example 2: Preparation of 6-N-prop-2-ynyl-4,5,6,7-tetrahydro-benzothiazole-2,6- diamine (2)

4,5,6,7-Tetrahydro-benzothiazole-2,6-diamine (α, 5.1 g, 30 mmol) and propargyl aldehyde (1.62 g, 30 mmole) in ethanol (100 mL) is treated with sodium triacetoxyborohydride (8.4g, 40 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 (Na₂SO₄), and concentrated to get the product. The compound was purified by column chromatography.

Example 3: Preparation of 6-[N-methyl-N-prop-2-ynyI]-4,5,6,7-tetrahydro- benzothiazoIe-2,6-diamine (3)

2 3

Compound 2 (6.21 g, 30 mmol) and formaldehyde (37 %) is taken in ethanol (200 mL). Sodium triacetoxyborohydride (8.4 g, 40 mmol) is added and the reaction mixture is 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 a pH 1 1 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 (Na₂SO₄), and concentrated to get the product. The compound was purified by column chromatography.

Example 4: Preparation of of 6-[N-propyl-N-prop-2-ynyl]-4,5,6,7-tetrahydro- benzothiazole-2,6-diamine (1)

Example 5: Preparation of 6-[N-methyl-N-prop-2-ynyl]-4,5,6,7-tetrahydro- benzothiazole-2,6-diamine (3)

Example 6: Preparation of 6-N-prop-2-ynyl-4,5,6,7-tetrahydro-benzothiazole-2,6- diamine (2)

Example 7: Preparation of 2-N-prop-2-ynyl-4,5,6,7-tetrahydro-benzothiazole-2,6- diamine (4)

Example 8: Preparation of 2-[N-methyl-N-prop-2-ynyl]-4,5,6,7-tetrahydro- benzothiazole-2,6-diamine (5)

5

Example 9: Preparation of 6-N-propyI-2-N-prop-2-ynyl-4,5,6,7-tetrahydro- bcnzothiazolc-2,6-diaminc (6)

Example 10: Preparation of 2-[N-methyl-N-prop-2-ynyl]-6-N-propyl-4,5,6,7-tetrahydro- benzothiazole-2,6-diamine (7)

Example 11: Preparation of 2-[N-methyI-N-prop-2-ynyl]-4,5,6,7-tetrahydro- benzothiazole-2,6-diamine (5a)

5a Example 12: Preparation of 2-N-Prop-2-ynyI-4,5,6,7-tetrahydro-benzothiazole-2,6- diamine (4a)

4a

Example 13: Preparation of 2-[N-methyl-N-prop-2-ynyl]-6-N-propyl-4,5,6,7-tetrahydro- benzothiazole-2,6-diamine (7a)

Example 14: Preparation of 6-N-propyl-2-N-prop-2-ynyl-4,5,6,7-tetrahydro- bcnzothiazole-2,6-diamine (6a)

Example 15: Preparation of 6-[N-methyl-N-propyl]-2-N-prop-2-ynyl-4,5,6,7-tetrahydro- benzothiazole-2,6-diamine (8)

Example 16: Preparation of 6-[N-methyl-N-propyl]-2-[N-methyl-N-prop-2-ynyl]-4,5,6,7- tetrahydro-benzothiazoIe-2,6-diamine (9)

Claims

1. A compound having the formula:

wherein:

R₁ 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,

R₃ and R₄ together with the nitrogen atom between them represent a pyrrolidino, piperidino, hexamethyleneimino or morpholino group; wherein at least one of at least one OfR₁, R₂, R₃ and R₄ is a propargyl group, and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 having a single propargyl group.

3. A compound according to claim 2 having the formula: NR₃R₄ attached to carbon that is two from the S.

4. A compound according to claim 1 having the formula: NR₃R₄ attached to carbon that is two from the S.

5. A compound according to claim 1 selected from the group consisting of: compounds in which R₁ is H, R₂ is H, R₃ is a propargyl group, and R₄ is propyl; compounds in which R₁ is H, R₂ is H , R₃ is a propargyl group, and R₄ is H; compounds in which R₁ is H, R₂ is H, R₃ is a propargyl group, and R₄ is methyl; compounds in which R₁ is propargyl, R₂ is H, R₃ is H, and R₄ is H; compounds in which R₁ is propargyl, R₂ is methyl, R₃ is H, and R₄ is H; compounds in which R₁ is propargyl, R₂ is H, R₃ is a propyl group, and R₄ is H; compounds in which R₁ is propargyl, R₂ is methyl, R₃ is a propyl group, and R₄ is

H; compounds in which R₁ is propargyl, R₂ is H, R₃ is a propyl group, and R₄ is methyl; and compounds in which R₁ is propargyl, R₂ is methyl, R₃ is a propyl group, and R₄ is methyl.

6. A compound according to claim 5 selected from the group consisting of compounds having the formula:

and pharmaceutically acceptable salts thereof.

7. A pharmaceutical composition comprising one or more compounds of any of claims 1-6 and a pharmaceutically acceptable carrier or diluent.

8. A pharmaceutical composition comprising one compound of any of claims 1-6 and a pharmaceutically acceptable carrier or diluent.

9. The pharmaceutical composition of any of claims 7 or 8 wherein the compound or compounds are present in a therapeutically effective amount to treat an individual with a neurological disorder.

10. The pharmaceutical composition of claim 9 wherein the individual has Parkinson's disease.

11. A method of treating an individual who has a neurological disorder comprising the step of administering to said individual one or more compounds of any of claims 1-6 in a therapeutically effective amount.

12. The method of claim 11 comprising the step of administering to said individual one compound in a therapeutically effective amount.

13. The method of and of claim 1 1 or wherein the individual has Parkinson's disease.