SK8242003A3 - Excitatory amino acid receptor antagonists - Google Patents

Abstract

The present invention provides novel pharmaceutically acceptable salts of the compounds of Formula (I) and Formula (Ia), as well as methods for using the pharmaceutically acceptable salts, and also provides processes for making compounds of Formula (I) and Formula (Ia), or the pharmaceutically acceptable salts thereof. Compounds of formula (I) and formula (Ia) are useful for the treatment of neurological disorders, especially migraine.

Description

Technical field

The invention relates to excitatory amino acid receptor antagonists.

BACKGROUND OF THE INVENTION

In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between the neurotransmitter that releases the transmitting neuron and the receptor on the surface of the receiving neuron, whereupon the receptor induces excitation in the receiving neuron. Thus, L-glutamate, which is the most widespread neurotransmitter in the CNS, mediates the major nerve pathways in mammals and is therefore referred to as the excitatory amino acid ”(abbreviation ΈΑΑ”). Receptors that respond to glutamate are called excitatory amino acid receptors (ΈΑΑ receptors), see Watkins and Evans, Ann. Rev. Pharmacol. Toxicol., 21,165 (1981); Monaghan, Bridges and Cotman, Ann. Rev. Pharmacol. Toxicol. 29, 365 (1989); Watkins, Krogsgaard - Larsen and Honore, Trans. Pharm. Sci., 11, 25 (1990). Excitatory amino acids are of great physiological importance because they play a role in a number of physiological processes such as long-term potentiation (learning and memory), development of synaptic plasticity, motor control, respiration, cardiovascular regulation and sensory perception.

Excitatory amino acid receptors are divided into two general types. Receptors that are directly associated with the opening of cation channels in the cell membrane of neurons are called ionotropic ”. This type of receptor is further subdivided into at least three subtypes, which are defined by the depolarizing effect on selective agonists, which are N-methyl-Daspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). ) and kainic acid (KA). Molecular biological studies have confirmed that AMPA receptors consist of subunits (GluR 1 - GluR ₄ ) that are

32138 / B arranged to form functional ion channels. Five kainate receptors have been identified that divide into high affinity receptors (KA1 and KA2) and low affinity receptors (consisting of the GluRs, GluR6 and / or GIUR7 subunits), see Bleakman et al., Molecular Pharmacology, 49, no. 4, 581 (1996). The second general type of receptors are metabotropic excitatory amino acid receptors coupled to a G protein or second mediator. This latter type is linked to several second mediator systems, resulting in increased phosphoinositide hydrolysis, activation of phospholipase D, increased or decreased cAMP formation, and changes in ion channel function, see Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993).

Both types of excitatory amino acid receptors appear not only as mediators of normal synaptic signal transduction along excitatory pathways, but are also involved in the modification of synaptic junctions in development and lifetime, see Schoepp, Bockaert and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990) and McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).

Excessive or undesirable stimulation of excitatory amino acid receptors results in neuronal cell damage or loss of function due to a mechanism known as excitotoxicity. It has been suggested that this process causes neuronal degeneration in a number of neurological disorders and diseases. The context of this mechanism with neuronal degeneration allows physicians to alleviate these degenerative neurological processes, which is a very important requirement in therapy. For example, excitotoxicity to the excitatory amino acid receptor is believed to be the cause of the pathophysiology of a variety of neurological diseases, including the etiology of cerebral deficits following bypass surgery in cardiosurgery and transplantation, stroke, cerebral ischemia, spinal cord injury due to trauma or inflammation, cardiac arrest and hypoglycemic neuronal damage. In addition, chronic neurodegenerative conditions and diseases, including Alzheimer's disease, Huntington's chorea, congenital ataxia, AIDS dementia, amyotrophic lateral sclerosis, idiopathic and

32138 / B drug-induced Parkinson's disease as well as visual impairment and retinopathy. Other neurological disorders in which excitotoxicity and / or glutamate dysfunction are somehow involved are muscle cramps including tremor, drug tolerance and withdrawal symptoms, brain swelling, convulsive disorders including epilepsy, depression, anxiety and anxiety associated with diseases such as post-traumatic stress syndrome, retardation (dyskinesia), postpsychotic depression, schizophrenia, bipolar disease, mania and drug intoxication or drug addiction (see generally US Patent 5,446,051 and 5,670,516). Excitatory amino acid receptor antagonists may also be useful as analgesics and for the treatment or prevention of various forms of headache, including histamine cephalgia, headache of the type associated with pressure and chronic daily headache. In addition, the European patent application, published as WO 98/45 720, states that excitotoxicity to excitatory amino acid receptors is involved in the etiology of acute and chronic pain conditions including severe pain, interacting pain, neuropathic pain and post-traumatic pain.

It is also known that the trigeminal ganglia and their associated neural pathways are associated with headache and face pain, and especially migraine. Moskowitz (Cephalalgia, 12, 5-7 (1992)) suggested that unknown causes stimulate trigeminal ganglia, which in turn innervate the vasculature in the head tissue, thereby giving an impulse to the release of vasoactive neuropeptides of the zaxone innervating vasculature. These neuropeptides initiate a number of sequential events, leading to neurogenic meningitis and, consequently, pain. This neurogenic inflammation is blocked by sumatriptan at a dose similar to that required for the treatment of acute migraine in humans. However, such doses of sumatriptan are associated with contraindications due to the sumatriptan contribution to the control of vasocontraction properties (see Maclntyre, PD et al., British Journal of Clinical Pharmacology, 34, 541-546 (1992); Chester, AH et al., Cardiovascular Research, 24, 932-937 (1990); Conner, HE et al., European Journal of Pharmacology, 161, 91-94 (1990)). It has been reported that all five members of the kainate subtype of ionotropic glutamate receptors are expressed on trigeminal neurons

32138 / B ganglia, and in particular high levels of GluR ₅ and KA2 were observed (Sahara et al., The Joumal of Neuroscience, 17, 17, 6611, (1997)). As such, migraine represents yet another neurological disorder that may be related to the glutamate receptor excitotoxicity.

The use of a neuroprotective drug, such as an excitatory amino acid receptor antagonist, is believed to be useful in the treatment or prevention of all of the aforementioned diseases (disorders) and / or in trying to reduce the extent of the neurological consequences associated with these diseases. For example, studies have shown that AMPA receptor antagonists are neuroprotective in focal and global ischemia models. A competing AMPA receptor antagonist, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo [f] quinoxaline) has been reported to be effective in preventing general and local ischemic injury (Sheardown et al., Science, 247, 571 (1990)) Buchan et al., Neuroreport, 2, 473 (1991), LePeillet et al., Brain Resarch, 571, 115 (1992)). The non-competitive AMPA receptor antagonists GKYI 52466 have been shown to be potent neuroprotectants in overall global ischemia in rat models, LePeillet et al., Brain Research, 571, 115 (1992). EP A 590 789 A1 and US Patents 5,446,051 and 5,670,516 disclose that certain decahydroisoquinoline derivatives are AMPA receptor antagonists and are themselves useful in the treatment of a variety of disorders and conditions, including pain and migraine headache. WO 98/45 270 discloses that certain decahydroisoquinoline derivatives are selective iGluR ₅ receptor antagonists and are useful for the treatment of various types of pain, including severe, chronic, interacting and neuropathic pain.

According to the invention, the Applicants have now discovered novel compounds which are selective antagonists of the iGluR ₅ receptor subtype and thus could be useful in the treatment of a number of neurological disorders or neurodegenerative diseases as mentioned above. Such selective antagonists could solve the long felt need to allow treatment of neurological disorders without the side effects. Such treatment of neurological disorders and neurodegenerative diseases is discussed herein.

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SUMMARY OF THE INVENTION

The invention provides a compound of formula I:

OH

Formula I or a pharmaceutically acceptable salt or prodrug thereof.

In a preferred embodiment, the invention provides a compound of formula Ia:

OR ²

Formula la where

R ¹ and R ² each independently represent hydrogen, (C 1 -C 20) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₁ -C ₆ ) alkenyl,

C 6) aryl, (C CeJalkyKCs CK-cycloalkyl, (Ci-6) alkyl-N, _N-Cl-C6 dialkylamine, (C- | _-C6) alkyl-pyrrolidine, (Cl-6) alkyl-piperidine or _(Cl-C6) 32138 / B-alkyl morpholine, with the proviso that at least one of R ¹ and R ² is other than hydrogen, or a pharmaceutically acceptable salt thereof.

In a particularly preferred embodiment, the invention provides a D - (-) mandelic acid salt of Formula I or Formula Ia, wherein Formula I and Formula Ia are as defined above.

In another embodiment, the invention provides a method for treating or preventing neurological disorders or neurodegenerative conditions, comprising administering to a patient in need thereof an effective amount of a compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt of any of these compounds. Examples of these neurological disorders or neurodegenerative conditions are, for example: cerebral deficiencies occurring after surgical insertion of the heart by-pass in transplantation; stroke; cerebral ischemia; spinal cord lesions resulting from trauma or inflammation; perinatal hypoxia; cardiac arrest; hypoglycaemic nerve damage; Alzheimer disease; Huntington's chorea; congenital ataxia; dementia due to AIDS; amyotrophic lateral sclerosis; idiopathic or drug-induced Parkinson's disease; eye damage and retinopathy; muscle spasticity including tremor; drug tolerance and abstinence; brain swelling; convulsive disorders including epilepsy; depression; anxiety and anxiety disorders such as post-traumatic stress syndrome; tardive dyskinesia; psychoses associated with depression, schizophrenia, bipolar disorder, mania and drug intoxication or drug addiction; headache including histamine cephalgia, pressure pain and chronic daily headaches; migraine; acute and chronic pain conditions including severe pain, interacting pain, neuropathic pain and post-traumatic pain.

In particular, the invention provides a method of treating or preventing migraine comprising administering to a patient in need thereof an effective amount of a compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof.

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More specifically, the invention provides a method of treating or preventing migraine comprising administering to a patient in need thereof an effective amount of a salt of D - (-) - mandelic acid of Formula I or Formula Ia.

The invention also provides a process for the preparation of a compound of formula Ia, wherein a compound having the structure (2) is treated together:

(2) wherein R ² is as defined herein, Pg is a suitable nitrogen protecting group, and LgO is a suitable leaving group, in a suitable solvent a suitable base, followed by the addition of a compound having the structure (3):

(3) wherein R ¹ is as defined herein, followed by oxidation to a compound having the structure (5):

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followed by halogenation and removal of the nitrogen protecting group.

In addition, the invention provides pharmaceutical compositions comprising compounds of Formula I and Formula Ia, including pharmaceutically acceptable salts, and hydrates thereof, for use in the treatment of neurological disorders or neurodegenerative conditions, comprising as an active ingredient a compound of Formula I or Formula Ia in combination with a pharmaceutically acceptable carrier. solvent or excipient. The invention also includes novel intermediates, methods of synthesizing compounds of Formula I and Formula Ia.

More specifically, the invention provides pharmaceutical compositions useful for the treatment or prevention of migraine which contain as active ingredient a salt of D - (-) - mandelic acid of formula I or formula Ia in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.

The invention also provides the use of a compound of formula I or formula Ia for the manufacture of a pharmaceutical composition for the treatment or prevention of neurological disorders or neurodegenerative conditions.

More specifically, the invention provides the use of a compound of Formula I or Formula Ia for the manufacture of a pharmaceutical composition for treating or preventing migraine.

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DETAILED DESCRIPTION OF THE INVENTION

The invention provides compounds that are effective as selective antagonists of the µGluR 6 receptors and their pharmaceutically acceptable salts, prodrugs and compositions based on these compounds.

In addition, the invention provides a method of treating neurological disorders or neurodegenerative conditions. In particular, the invention also provides a method of treating migraine, which may be illustrated by a particular mechanism of action consisting in inhibiting neurogenic dural protein extravasation. Treatment of migraine with compounds and compositions is based on the use of iGluR ₅ receptor antagonists that are selective over other excitatory amino acid receptors, thus inhibiting the neurogenic extravasation that is the cause of migraine without causing side effects or drug effects. are designed to optimize the 5-HT 1 -mediated vasocontractive activity of sumatriptan.

It will be appreciated that the compounds of the invention can be prepared from known starting materials in the form of prodrugs that can be formulated with a mixture (formulation). The term prodrug, as used herein, means a compound of Formula I or a compound of Formula Ia that is structurally modified such that the prodrug is converted in vivo, for example, by hydrolytic, oxidative, reducing or enzymatic cleavage to the parent compound (e.g., carboxylic acid ( Dicarboxylic acids) as defined in formula I. Such prodrugs may be, for example, metabolic labile esters or diesters of derivatives of the original active substances, provided that the active substances have a carboxyl group. Of course, the invention also encompasses all such prodrugs, such as metabolic labile esters or diesters of the compounds of formula I. In all cases, the use of the compounds described herein as prodrugs is included in an embodiment of the invention, which is often preferred, and therefore prodrugs of all compounds are included in the prodrugs. the term when an active substance is mentioned herein. Preferred prodrugs are diesters of derivatives of formula I.

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Conventional procedures for selecting and preparing suitable prodrugs are well known to those skilled in the art.

Hereinafter, examples of prodrugs of formula I to be understood as being part of the invention are given below, and these prodrugs are specified by the following formula la:

Formula la where

R ¹ and R ² each independently represent hydrogen, (C ₁ -C ₂₀ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C 1 -C ₆ ) alkylaryl, (C ₁ -C ₆ alkyl-C ₅ -C ₁₆ ) cycloalkyl, (C ₁ -C ₆ alkyl-NN-C 1-6 alkyl); Cedialkylamine, (C 1 -C 6 alkyl-pyrrolidine, (C 1 -C ₆ ) alkyl-piperidine or (C 1 -C ₆ ) alkyl-morpholine, with the proviso that at least one of R ¹ and R ² is other than hydrogen, or a pharmaceutically acceptable salt any of the defined compounds.

It should be noted that selective antagonists of the iGluR ₅ receptor antagonists of the invention may exist as pharmaceutically acceptable salts and such salts as such are also encompassed by the invention. The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds, provided that they are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts are those prepared by reacting the compounds of the invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition salts with base addition salts.

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It is clear to one skilled in the art, after reading the information in this patent, that almost all of the compounds used in the invention are capable of forming salts, and that these salts are generally used in pharmaceutical compositions, often because they are easier to crystallize and purify than the free bases. . In any event, the use of the pharmaceutically active agents described herein as salts is within the scope of this invention as described herein, and often is preferably the pharmaceutically acceptable salts of all compounds included within the scope of the meanings when referring to the base itself.

Acids that are commonly used to form addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and organic acids such as p-toluenesulfonic acid, mandelic acid, 1,5-naphthalenedisulfonic acid, methanesulfonic acid. acid, oxalic acid, bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of these pharmaceutically acceptable salts are sulfate, bisulfate, bisulfate, sulfite, hydrogen sulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, hydrochloride, dihydrate, m.p. heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexine-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, ahydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, counter-silate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed from mineral acids such as hydrochloric acid and hydrobromic acid, and those formed from organic acids such as D - (-) - mandelic acid, 1,5-naphthalenedisulfonic acid, maleic acid, and methanesulfonic acid. acid.

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Base addition salts are those derived from inorganic bases such as ammonium hydroxide or alkali or alkaline earth metal hydroxides, carbonates and bicarbonates and the like. Thus, such bases useful in the preparation of the salts of the invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like. Potassium and sodium salts are most preferred. It is to be distinguished that a certain counterion, which forms part of a salt of the present invention, is not usually critical in that the salt is, as a whole, pharmacologically acceptable and that the counterion does not impart undesirable properties to the salt, for the whole. It is further understood that salts may exist in the form of hydrates.

As used herein, the term "stereoisomer" refers to a compound made of the same atoms bonded by the same bonds but having a different three-dimensional structure, which structures are not interchangeable. Three-dimensional structures are called configurations.

As used herein, the term "enantiomer" means two stereoisomers whose molecules are relative to each other as non-overlapping mirror images. The term chiral center refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" means stereoisomers that are not enantiomers. In addition, two diastereomers having different configurations at only one chiral center are referred to herein as epimers. The terms "racemate", "racemic mixture" or "racemic modification" mean a mixture of equal proportions of enantiomers.

The term enantiomeric enrichment, as used herein, means increasing the amount of one enantiomer relative to the other. The conventional way of expressing this enantiomeric enrichment that is achieved is based on a quantity that expresses the enantiomeric excess and is commonly referred to as "ee" by enantiometric excess. This quantity is expressed as a percentage and is calculated from the following equation:

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E ¹ -E ² ee = ---------- x 100

E ¹ + E ² wherein E ¹ is the amount of the first enantiomer and E ² is the amount of the second enantiomer. Thus, if the original ratio of the two enantiomers present in the enantiomeric mixture is 50:50, the enantiomeric enrichment to give a final ratio of 50:30, or "ee of the first enantiomer" is equal to 25%. However, if the final ratio is to be 90: 10, then the "ee of the first enantiomer" is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred, and an ee of greater than 99% is particularly preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using established techniques and procedures such as gas and high performance liquid chromatography on a chiral packed column. The choice of a suitable chiral column, eluent and the necessary conditions to achieve separation of enantiomeric pairs is within the skill of one of ordinary skill in the art. In addition, enantiomeric compounds of Formula I or Formula Ia can be separated by standard methods known in the art, such as those described in J. Jacques et al., Enantiomers, Racemates, and Resolutions, John Wiley and Sons, Inc. , 1981.

The compounds of the invention have one or more chiral centers and can exist in different stereoisomeric configurations. As a result of the existence of these chiral centers, the compounds of the invention occur as racemates, mixtures of enantiomers and as individual enantiomers, and furthermore also as diastereomers and mixtures of diastereomers. All such racemates, enantiomers and diastereomers are within the scope of the invention.

The terms "R" and "S" are used herein as used in organic chemistry to refer to the specific configuration of chiral centers. The term "R" (rectus) means that the configuration of the chiral centers is such that if we look at the molecule against the lowest group along its axis to the chiral center and follow the groups in the clockwise direction, they have the order of precedence ( first above and then

32138 / B below). The term "S" (sinister) means that the configuration of the chiral center has, in the described view of the molecule, the order of the attached groups from the higher group to the next lower in the counterclockwise direction. The priority rule for the groups used herein is based on atomic numbers (the order from highest to lowest means order with decreasing atomic number). A partial list of groups sorted by priority, including a discussion of their stereochemistry, can be found in Nomenclature of Organic Compounds: Principles and Practice, (J. H. Fletcher et al., Eds. 1974) on pages 103-120.

Specific stereoisomers and enantiomers containing compounds of Formula I and Formula Ia can be prepared by known procedures, which can be performed by one of ordinary skill in the art, such as those described by Eliel and Wilen, Stereochemistry of Organic Compounds, John Wiley and Sons , Inc., 1994, Chapter 7, entitled Separation of Stereoisomers. Resolution. Racemization ”, and further see Collet and Wilen, Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. For example, specific stereoisomers and enantiomers may be prepared by stereospecific syntheses using enantiomerically and geometrically pure or enantiomerically or geometrically enriched starting materials. . In addition, specific stereoisomers and enantiomers can be separated and obtained by techniques such as chiral stationary phase chromatography, enzymatic resolution or fractional recrystallization of an addition salt formed using reagents used for this purpose.

As used herein, the term "Pg" means a suitable nitrogen protecting group. Examples of suitable nitrogen protecting groups, as used herein, are those intended to protect or block a nitrogen group against unwanted reactions in the synthesis steps. The choice of a suitable nitrogen protecting group to be used in the synthesis design will depend on the conditions used in the subsequent reaction steps where the protection is used and can be made by one of ordinary skill in the art. Generally, the groups listed in Greene are used to protect nitrogen:

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Protective Groups in Organic Synthesis ”(John Wiley & Sons, New York, 1981). Suitable nitrogen protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-chlorobenzyl 4-nitrobenzoyl and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate-forming groups are groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, pmethoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenyl) -1-methylethoxycarbonyl, α, α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylcarbonyloxy, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred nitrogen protecting groups are formyl, acetyl, methoxycarbonyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boe) and benzyloxycarbonyl (Cbz).

As used herein, the term "(C 1 -C ₄ ) alkyl" means a linear or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl and the like.

As used herein, the term "(C 1 -C 6) alkyl" means a linear or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl and the like.

As used herein, the term "(C 1 -C ₁₀ ) alkyl" means a linear or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms.

32138 / B atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2- dimethyl 3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.

As used herein the term _"(Ci-C2) alkyl" means a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, among others, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, nnonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n- pentadecyl, nhexadecyl, n-heptadecyl, n-nonadecyl, n-eicosyl and the like. It is to be understood that the terms _"(C-C4) alkyl," (C Cejalkyl "and" (Ci-C-io) alkyl "are included within the definition of" (C _R C ₂₎ alkyl.

As used herein, the terms Me, "Et", "Pr" "iPr", "Bu" and "t-Bu" mean methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.

As used herein, the term "(C 1 -C ₄ ) alkoxy" means an oxygen atom bearing a linear or branched, monovalent saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to, methyloxy, ethyloxy, n-propoxy, isopropoxy, n-butoxy and the like.

As used herein, the term "(C 1 -C ₆ ) alkoxy" means an oxygen atom bearing a linear or branched, monovalent saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to, methyloxy, ethyloxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy, n-hexyloxy and the like.

As used herein, the term (C 1 -C 6 alkyl-C ₁ -C ₆ alkoxy) means a linear or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms having a (C 1 -C ₆ ) alkoxy group attached to the aliphatic chain.

As used herein, the terms "halogen", "halide" or "Hal" mean chlorine, bromine, iodine or fluorine unless otherwise indicated.

As used herein, the term "(C ₂ -C 6) alkenyl" means a linear or branched, monovalent, unsaturated aliphatic chain of 2 to 6 carbon atoms. Typical (C ₂ -C ₆ ) alkenyl groups are, among others, ethenyl (also known as vinyl), 1-methyletenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 232138 / B methyl-2- propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl and the like.

As used herein, the term "aryl" means a monovalent carbocyclic group containing one or more fused or unfused phenyl rings and includes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl and the like. The term substituted aryl means an aryl group substituted with one or two substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, (C 1 -C 6) alkyl (C 3 -C 10) cycloalkyl, (C 1 -C 6 alkylaryl, (C 1 -C 6) alkoxycarbonyl, protected carboxyl, carboxymethyl, hydroxymethyl, amino, aminomethyl or trifluoromethyl.

As used herein, the term "(C 1 -C 6) alkylaryl" means a linear or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms having an aryl group attached to the aliphatic chain. The term "C 1 -C 6 alkylaryl" includes, but is not limited to, the following substituents:

and so on.

As used herein, the term "aryl (C 1 -C 6) alkyl" means an aryl group having a linear or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms, which is attached to the aryl group. The term "aryl (C 1 -C ₆ ) alkyl" includes, but is not limited to, the following substituents:

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and so on.

As used herein, the term "(C ₃ -C 10) cycloalkyl" means a saturated hydrocarbon structure composed of one or more fused or non-fused rings containing 3 to 10 carbon atoms. Typical C ₃ -C ₁₀ cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantanyl and the like.

As used herein, the term "C 1 -C 6 alkyl (C ₃ -C 10) cycloalkyl" means a linear or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms having a (C ₃ -C 10) cycloalkyl attached to the aliphatic chain. The term "C 1 -C ₆ alkyl (C ₃ -C 10) cycloalkyl" includes, but is not limited to, the following substituents:

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and so on.

As used herein, the term "(C 1 -C 6) alkoxycarbonyl" means a carbonyl group having a (C 1 -C 6) alkyl group attached to the carbonyl carbon via an oxygen atom. Examples of this group include, but are not limited to, t-butoxycarbonyl, methoxycarbonyl, and the like.

As used herein, the term heterocycle ”means a five- or six-membered ring containing one to four heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. The remaining ring atoms are, as one skilled in the art knows, carbon atoms. The rings may be saturated or unsaturated. Examples of heterocyclic groups include, but are not limited to, thiophenyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thiazolidinyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridiazinyl, pyridiazinyl, pyridiazinyl, pyridiazinyl, pyridiazinyl, triazolyl tetrahydropyrimidyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, pyrimidinyl, imidazolidinyl, morpholinyl, pyranyl, thiomorpholinyl and the like. The term "substituted heterocycle" means a heterocyclic group substituted with one or two substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, oxo, (C 1 -C ₆ ) alkyl, (C 1 -C ₄ ) alkoxy, C 1 -C 6 alkyl (C ₃ 32138 / B)

C 10) cycloalkyl, (C 1 -C ₆ ) alkylaryl, (C 1 -C ₆ ) alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl, amino, aminomethyl or trifluoromethyl.

As used herein, the term "N, NC 1 -C 6 dialkylamine" means a nitrogen atom substituted by two linear or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms. The term "N, N-C 1 -C 6 dialkylamine" includes -N (CH 3) 2, -N (CH ₂ CH ₃ ) 2,

N (CH ₂ CH ₂ CH ₃ ) ₂ , -N (CH ₂ CH ₂ CH ₂ CH ₃ ) ₂ and the like.

As used herein, the term C 1 -C 6 alkyl-N. N-C 1 -C 6 dialkylamine "means a linear or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms having an N, N-C 1 -C 6 -cenyialkylamine attached to the aliphatic chain. The term C 1 -C 6 alkyl-N, N-C 1 -C 8 -alkylamine includes the following substituents:

and so on.

As used herein, the term "(C 1 -C ₆ ) alkyl-pyrrolidine" means a linear or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms having a pyrrolidine attached to the aliphatic chain. This term includes ”(C1-C6) alkylpyrrolidine”:

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and so on.

As used herein, the term "(C 1 -C ₆ ) alkylpiperidine" means a linear or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms having a piperidine attached to the aliphatic chain. The term "(C 1 -C 6) alkylpiperidine" includes the following substituents:

and so on.

As used herein, the term (C 1 -C 6 alkyl-morpholine) means a linear or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms having morpholine attached to the aliphatic chain. Within the scope of this term "C 1 -C ₆ alkyl-morpholine" include the following substituents:

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and so on.

“” Indicates a binding that points forward from the page area.

........ iiillllll

"Means a link that points backward beyond the page area.

As used herein, the term "iGluR 5" means subtype 5 of the kainate ionotropic glutamate receptor, the largest class of excitatory amino acid receptors.

As used herein, migraine is a disorder of the nervous system characterized by repeated headache attacks (not caused by brain structure, or abnormalities such as tumor or stroke), digestive problems, and possibly neurological symptoms such as visual distortion. Typical migraine headaches usually last for at least one day and are usually accompanied by vomiting, anorexia and photophobia.

Migraine is a chronic "disease or acute" event. The term chronic, as used herein, means a condition that slowly develops and persists for a long time. Chronic conditions themselves, if diagnosed, are treated, and treatment continues throughout the course of the disease. In contrast, the term acute ”means a sudden deterioration or attack that is short-lived followed by periodic remission. Thus, the treatment of migraine includes both the treatment of an acute episode and so on

32138 / B chronic conditions. In an acute event, the compound of the invention is administered at the onset of symptoms and is discontinued when the symptoms have disappeared. As described above, the chronic condition is treated throughout the course of the disease.

As used herein, the term "patient" means a mammal such as a mouse, gerbil, guinea pig, rat, dog or human. However, it should be understood that the preferred patient is a human.

As used herein, the term "selective iGluR ₅ receptor antagonist" is intended to include excitatory amino acid receptor antagonists that selectively bind to the kainate receptor of the iGluR ₅ subtype, wherein selectivity is expressed over the iGluR ₂ AMPA receptor subtype. Preferably, the antagonist is a selective iGluR ₅ receptor antagonist for use in the present invention the binding affinity at least 10 fold greater for iGluR than for iGluR _2, more preferably at least 100 fold greater. Selective antagonists iGluRs ₅ receptor can be readily purchased or prepared, which can handle are skilled by the methods outlined here. For example, WO 98/45 270 provides examples of selective iGluR ₅ receptor antagonists and discloses methods of synthesis.

As used herein, the terms "treating" or "treat" means reducing the symptoms of the disease, eliminating their causes on a temporary or permanent basis, and preventing, slowing or reversing the development or severity of the symptoms of said disease. The methods of the invention include both therapeutic and prophylactic administration.

As used herein, the term "effective amount" means the amount or dose of a compound, when administered singly or in multiple doses to a patient, which provides the desired effect to a patient having a diagnosis in need of such treatment or is treated. An effective amount can be readily determined by diagnosis and can be determined by one of ordinary skill in the art using known techniques and observing results obtained under analogous circumstances. In determining the effective amount or dose of a compound to be administered, a number of factors need to be considered, including but not limited to: the mammal species, its size, age, general health, degree of severity of the disease or severity of treatment. migraine, the reaction given

32138 / B of the patient, the particular compound to be administered, the route of administration, the bioavailability of the preparation to be administered, the treatment regimen chosen, the use of concomitant administration of other drugs and other critical circumstances.

A typical daily dose contains from about 0.01 mg / kg to about 100 mg / kg of each compound used in the method of treatment. Preferably, the daily dose will be about 0.05 mg / kg to about 50 mg / kg, more preferably about 0.1 mg / kg to about 25 mg / kg.

The preferred route is oral administration of the compounds used according to the invention, when administered alone or in a combination comprising a compound capable of acting as a selective iGluR ₅ receptor antagonists. Oral administration, however, is not the only route, not the only preferred route. Other preferred routes of administration include the transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, or intrarectal routes. When the selective iGluRs receptor antagonist is administered in combination containing the compounds, one of the compounds may be administered by one route, for example, orally, and the other transdermally, percutaneously, intravenously, intramuscularly, intranasally, pulmonally, buccally or intrarectally, as appropriate. The mode of administration may vary, limited by the physical properties of the compounds and by the requirements for the convenience of administering the drugs to the patient and to the person taking care of the patient.

The compounds of the invention can be administered as pharmaceutical compositions, and therefore pharmaceutical compositions through which they are incorporated into the body of a compound of Formula I or Formula Ia are important embodiments of the invention. These compositions may also take any physical form that is pharmaceutically acceptable, but orally administered pharmaceutical compositions are most preferred. The pharmaceutical compositions comprise as an active ingredient an effective amount of a compound of Formula I or Formula Ia, including pharmaceutically acceptable salts, prodrugs and hydrates thereof, wherein the effective amount is meant to be the daily dose of the compound to be administered. Each dosage unit may contain a daily dose of the compound, or a proportion of the daily dose, such as half or a third. The amount of each compound to be contained in each dosage unit depends on how particular it is

The 32138 / B compound selected for therapy is involved, and from other factors such as the indication for which the drug is being administered. The pharmaceutical compositions of the invention may be formulated so as to provide rapid, sustained or sustained release of the active ingredient after administration to a patient using known techniques.

The compositions are preferably formulated in unit dosage forms, each dosage containing from about 1 to about 500 mg of each compound alone or in unit dosage form, more preferably from about 5 to about 300 mg (e.g. 25 mg). The term "unit dosage form" refers to a physically discrete unit suitable as a single dose to a patient, each unit containing a preselected amount of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical carrier, diluent or excipient.

Inert ingredients for pharmaceutical compositions are conventional. Conventional pharmaceutical methods may be used. All conventional types of formulations can be used including tablets, chewing gums, capsules, solutions, parenteral solutions, intranasal sprays or powders, lozenges, suppositories, transdermal patches and suspensions. Generally, the compositions comprise from about 0.5% to about 50% of the compounds in total, depending on the desired doses and the type of composition to be used. However, an effective amount of a compound is best defined to be that amount of the compound that represents the desired dose for a patient in need of such treatment. The activity of the compounds used in the invention is independent of the composition of the composition, and the compositions are therefore selected purely according to the requirements of pleasant use and cost.

Capsules are prepared by mixing the compound with a suitable diluent and filling the appropriate amounts of the mixture into capsules. Common solvents are, inter alia, inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, cereal flours and the like edible powders.

Tablets are prepared by direct compression, wet granulation or dry granulation. Their formulations usually contain, in addition to the active compound

32138 / B solvents, binders, lubricants and disintegrants. Typical solvents are, for example, various types of starch, lactose, mannitol, kaolin, phosphate or calcium sulfate, inorganic salts such as sodium chloride, powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin sugars such as lactose, fructose, glucose and the like. Also suitable are natural and synthetic gums, including gum arabic, alginates, methylcellulose, polyvinylpyrrolidone and the like. Polyethylene glycol, ethylcellulose and waxes also serve as binders.

Tablets are often coated with sugar, which adds flavor and closes the tablet. The compounds can also be formulated as chewable tablets, which is accomplished by using a large amount of a pleasant tasting agent such as mannitol in the formulation, as is currently used in the art. Also, fast-dissolving tablet formulations are often used nowadays, allowing the patient to deliver the correct dose and to get rid of the difficulties experienced by some patients with swallowing solid drugs.

In tablet formulations, a lubricant is often required to prevent scratching of the tablets and their adherence to the mucosa during ingestion. Lubricants are selected from solid sliding materials such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

Disintegrants to accelerate tablet disintegration are substances which, when wetted, bud, disrupt the tablet and release the active compound. These include starches, clays, celluloses, alginates and gums. Furthermore, in particular cereal and potato starches, methylcellulose, agar, bentonite, wood cellulose, natural sponge powder, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose and, for example, sodium lauryl sulfate.

Often enteric formulations are used to protect the active ingredients from the strongly acidic contents of the stomach. These formulations are produced by coating the solid forms with a polymerization film which is insoluble in acidic medium and dissolved in a basic medium. Examples of films suitable for this purpose are cellulose acetate, cellulose phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and hydroxypropyl acetate succinate methylcellulose.

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Conventional bases may be used to administer the compound as a suppository. Traditionally, cocoa butter can be modified by adding waxes to slightly increase the melting point. Water-soluble suppository bases, especially polyethylene glycols, are also widespread.

Transdermal patches have become popular. They usually contain a resin composition in which the active ingredients dissolve and which is kept in contact with the skin through a film covering the composition. There are already many patents in this field. Other, more complicated patches and the like products and compositions which are also used, in particular have a membrane having a large number of punctured sites with many pores through which the active substance is conveyed by osmotic pressure.

The following table provides an illustrative overview of formulations suitable for use with the compounds of the invention. It is intended to illustrate the invention only, and not to be construed as limiting the invention in any way.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

Composition of the composition

Hard gelatin capsules are prepared using the following ingredients.

component Quantity (mg / capsule) Active ingredient 250 Starch, dried 200 Magnesium stearate 10 Pretty 460 mg

The above ingredients are mixed and filled into a hard gelatin capsule after

460 mg amounts.

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Composition of the composition

A tablet is prepared using the following ingredients.

component Quantity (mg / tablet) Active ingredient 250 Cellulose, microcrystalline 400 Silica, fumed 10 Stearic acid 5 Pretty 665 mg

The ingredients are mixed and compressed into tablets, each weighing 665 mg.

The following table provides an illustrative series of formulations suitable for use as a base comprising the active compound to be used in the invention. The following data is provided in the description by way of example only, for illustration and is not to be construed as limiting the invention in any way.

Composition of the composition

The aerosol solution is prepared containing the following components (parts by weight).

component number Active ingredient 0.25 ethanol 29.75 Propellant 22 (chlorodifluoromethane) 70.00 Pretty 100.00

The active compound is mixed with ethanol and a portion of Propellant 22 ”, cooled to -30 ° C, is added, and the mixture is transferred to a filling machine.

The required amount is then fed into a steel vessel and diluted

32138 / B with the remainder of the Propellant 22. The valve unit is then connected to the vessel.

Composition of the composition

Tablets, each containing 60 mg of active ingredient, are prepared as follows:

component Quantity (mg) Active ingredient 60.0 starch 45.0 Microcrystalline cellulose 35.0 polyvinylpyrrolidone 4.0 Carboxymethyl starch Na 4.5 Magnesium stearate 0.5 talc 1.0 Pretty 150

The active ingredient, starch and cellulose are passed through a sieve no. 45 mesh U.S. (18 mesh / cm) and mix gently. The polyvinylpyrrolidone solution is mixed with the resulting powder and then passed through a 14 mesh U.S. sieve. (6 mesh / cm). The granules so obtained are dried at 50 ° C and then passed through a sieve no. 18 mesh U.S. (7 mesh / cm). Sodium starch sodium, magnesium stearate and talc, which are passed through sieve no. 60 mesh U.S. (24 mesh / cm) are then added to the granules which are then compressed on a tablet machine to give tablets each weighing 150 mg.

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Composition of the product

Capsules, each containing 80 mg of the drug, are prepared as follows:

component Quantity (mg) Active ingredient 80 starch 59 Microcrystalline cellulose 59 Magnesium 2 Pretty 200

The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a sieve no. 45 mesh U. S. (18 mesh / cm) and filled into a hard gelatin capsule in 200 mg amounts.

Composition of the composition

Suppositories, each containing 225 mg of active ingredient, can be prepared as follows:

component Quantity (mg) Active ingredient 225 Saturated fatty acid glycerides 2 000 Pretty 2 225

The active ingredient is passed through a sieve no. 60 mesh U.S. (24 mesh / cm) and suspended in saturated fatty acid glycerides, which are melted using the minimum heat required. The mixture is then poured into a suppository mold with a nominal size of 2 g and cooled.

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Composition of the product

A suspension is prepared containing 50 mg of active ingredient in a dose of 5 ml:

component number Active ingredient 50 mg Sodium carboxymethylcellulose 50 mg syrup 1.25 ml Benzoic acid solution 0,10 ml flavor as needed Color as needed Clean water to total: 5 ml

The active substance is passed through a sieve no. 45 mesh U.S. (18 mesh / cm) and mixed with carboxymethylcellulose sodium and syrup to form a fine paste. The benzoic acid solution, flavor and color are then separately mixed with a portion of the added water and the solution is added to the paste with stirring. Then add water to obtain the prescribed volume.

Composition of the product

The composition of the intravenous formulation may be as follows:

component number Active ingredient 100 mg mannitol 100 mg 5N sodium hydroxide 200 ml Purified water to the whole 5 ml

The data should be understood to mean that one of ordinary skill in the art will be able, after reading the procedures described above, to apply them to a method of treating neurological disorders or neurodegenerative conditions, particularly migraines,

32138 / B, wherein an effective amount of a compound of Formula I or Formula Ia is administered to a patient.

The compounds of Formula I and Formula Ia can be prepared, for example, by the following procedures as outlined in Scheme I. The schemes are not intended to limit the scope of the invention in any way. All substituents, unless otherwise indicated, are defined in advance. The reagents and starting materials are readily available to one of ordinary skill in the art. For example, certain necessary starting materials may be prepared by one skilled in the art by following the procedures set forth in US 5,356,902 (issued on October 18, 1994) and 5,446,051 (granted on August 29, 1995).

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Scheme I

Formula 1

Formula la

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In Scheme I, Step A, 6- (hydroxymethyl) -2- (methoxycarbonyl) decahydroisoquinoline-3-carboxylate of a compound of formula (I) (wherein Pg is a suitable nitrogen protecting group as defined above, with methoxycarbonyl being preferred) of standard conditions to react with a compound of formula Lg-Hal, wherein Lg is a suitable leaving group and Hal represents chlorine, bromine or iodine to give a compound having structure (2). For example, a solution of compound (I) in a suitable organic solvent such as dichloromethane cooled to 0 ° C is treated with an excess of a suitable organic base such as triethylamine followed by 1 to 2 equivalents of the compound of formula Lg-Hal.

Examples of Lg-Hal are m-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride and the like. (In addition, it is clear to one skilled in the art that a halogen atom such as chlorine, bromine or iodine can also be used as a suitable leaving group instead of LgO.) The reaction mixture is warmed to room temperature for about 5 to 20 hours. Compound (2) is then isolated by standard methods. For example, the reaction mixture is washed with water, the organic layer is separated and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude compound (2). Column chromatography on silica gel then affords the product as a 10-50% solution in ethyl acetate / hexane as a purified compound (2) using a suitable eluent.

In Scheme I, Step B, compound (2) is treated under standard conditions with a pyrrolidine having the structure (3) to give a compound having the structure (4). For example, compound (2) is mixed with about 1 - 1.5 equivalents of 4-hydroxy-L-proline ethyl ester (R ₃ is ethyl) and 1 - 1.5 equivalents of potassium carbonate, heated under reflux in a suitable solvent such as acetonitrile for about 60-70 hours. The reaction mixture was cooled to room temperature and the solvents were removed in vacuo. Compound (4) is then isolated by standard methods such as extraction. For example, the reaction mixture is partitioned between water, an organic solvent such as diethyl ether, and the like

The 32138 / B aqueous layer was extracted 2-6 times with diethyl ether. Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to give compound (4). Compound (4) is then purified by silica gel chromatography using a suitable eluent such as 10-50% ethyl acetate / hexanes or methanol / chloroform.

Alternatively, in Step B, a pyrrolidine having structure (3) can be combined with a suitable resin filter cake and the resulting mixture is treated with a compound having structure (2) to give a compound having structure (4). For example, Amberlite IRA 67 resin is treated with water, then stirred and filtered, and the filter cake thus obtained is washed with a suitable solvent such as acetone when the water content of the flushing liquid is less than about 5% by weight. 4-Hydroxy-L-proline, ethyl ester hydrochloride and acetone are then applied to the filter and the mixture is stirred at room temperature for about 1-2 hours. The mixture is then filtered and the filter cake is washed again with acetone. Then, a filtered solution of hydroxyproline ethyl ester can be used directly. The Amberlite IRA 67 slurry was stirred in water and the mixture was filtered. The filter cake is washed with a suitable solvent such as acetone until the wash liquor is below 5% by weight. This second filter cake can also be treated with a solution of hydroxyproline ethyl ester from the above solution of compound (2) and the mixture is heated under reflux. After about 24 hours, the reaction mixture was cooled and filtered. The filter cake was then washed with dichloromethane (about 300 mL) and the combined filtrates were concentrated in vacuo. The residue can then be concentrated several times and freed from dichloromethane to give compound (4) as an oil which is used directly in the next step.

In Scheme I, Step C, compound (4) is oxidized under standard conditions to yield a compound having structure (5). For example, a phosphorus pentoxide solution is treated with a dichloromethane solution and the reaction mixture is cooled to about -10 ° C. Dimethylsulfoxide is then added with stirring, and a solution of compound (4) dissolved in dichloromethane is then added to the reaction mixture. The reaction mixture is then warmed to about 20-22 ° C for 4-5 hours, stirred for 8-20 hours, cooled to about 0 ° C, then treated.

32138 / B triethylamine in a ratio to maintain the reaction temperature below about 5 ° C. The reaction mixture was allowed to warm to room temperature, stirred for about one hour, and then added to the solution of 0.1 M HCl in a ratio to keep the reaction temperature below about 10 ° C. Compound (5) is then isolated by standard methods. For example, an additional portion of dichloromethane is added and the reaction mixture is separated again. The aqueous layer was then extracted 2-6 times with dichloromethane and the organics were combined, washed with 1M NaHCO ₃ , dried with magnesium sulfate, then concentrated in vacuo to give compound (5). The crude product can then be purified by silica gel chromatography using a suitable eluent such as 10-50% ethyl acetate in toluene or methanol / dichloromethane.

In Scheme I, in Step D, compound (5) is fluorinated to give a compound having structure (6). For example, a solution of compound (5) in ethanol is dissolved in a suitable organic solvent such as 1,2-dichloroethane, Deoxofluoro ([bis- (2-methoxyethyl) amino] thio trifluoride) is added and the mixture is stirred at room temperature. at room temperature for about 20-25 hours. The reaction mixture is then further treated with concentrated NaHCO ₃ solution and stirred for about 15 minutes. The layers were then separated and the aqueous layer was extracted 2-6 times with toluene. The layers were separated and the organic layers combined, filtered, dried over Na ₂ SO 4 and then concentrated in vacuo to give the compound having structure (6). The crude material can then be purified by silica gel chromatography using a suitable eluent such as (50:50) toluene / heptane or 10-50% ethyl acetate in toluene.

In Scheme I, Step E, the compound having structure (6) is deprotected under standard protecting group conditions by a method known to one of skill in the art to provide a compound of Formula Ia. For example, when Pg is a methoxycarbonyl protecting group, compound (6) is dissolved in a suitable organic solvent such as dichloromethane while working under a nitrogen atmosphere and treated with trimethylsilyl iodide. The reaction mixture was allowed to warm to room temperature and stirred for 10-20 hours. The reaction mixture was quenched by addition of saturated

32138 / B aqueous NaHCO3 solution. The aqueous layer was then extracted 2-5 times with dichloromethane. The combined organics were washed with 1N sodium thiosulfate solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give the compound of formula Ia. The crude product can be purified by chromatography on silica gel with a suitable eluent such as methanol / dichloromethane to give the purified compound of formula Ia.

In Scheme I, Step F, a compound of Formula Ia can optionally be hydrolyzed to a compound of Formula I under conditions well known in the art. For example, the compound of formula Ia can be dissolved in a suitable organic solvent such as methanol and treated with a stoichiometric excess of a suitable base. Examples of suitable bases are, inter alia, an aqueous solution of lithium, sodium, potassium and the like, with lithium hydroxide being preferred. The reaction mixture is then allowed to stir for about 10-20 hours and then neutralized to pH 6 with 1N HCl, then concentrated in vacuo. This material is then purified by techniques known in the art, such as chromatography using a suitable eluent.

In Scheme I, step G, optionally, the compound (6) can be simultaneously deprotected and hydrolyzed to give a compound of formula I. For example, the solution of compound (6) is diluted with 6.0 N HCl and heated to reflux. for about 15-20 hours. The reaction mixture is then allowed to cool to room temperature and concentrated in vacuo to give the compound of formula I. The compound of formula I can then be purified by techniques well known in the art, such as ion exchange cationic chromatography using as eluent methanol / water followed by treatment with a 2N solution of ammonia in methanol or ethanol to purify the compound of formula I.

In addition, one skilled in the art knows that the compound of formula I can be esterified under standard conditions to give a compound of formula Ia. For example, the compound of formula I may be dissolved in a suitable organic solvent such as ethanol and treated with a suitable acid. Examples of suitable acids are hydrogen chloride gas, aqueous sulfuric acid, p

32138 / B toluenesulfone and the like, with hydrogen chloride gas being preferred. The reaction mixture is heated to reflux for a suitable time. The reaction mixture can be concentrated, for example in vacuo, to give the crude compound of formula Ia. This crude product can then be purified by techniques well known in the art, such as cation exchange chromatography using methanol / water as eluent followed by 2N ammonia in ethanol to purify the compound of formula Ia.

The compounds of formula I and formula Ia according to the invention can be chemically synthesized from known intermediates such as 6-hydroxymethyl-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate. This intermediate, in turn, can be chemically synthesized from 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid, the synthesis described in US 4,902,695; Nos. 5,446,051 and 5,356,902 (the entire contents of which are incorporated herein by reference).

Methods for the synthesis of the 6- (hydroxymethyl) -2- (methoxycarbonyl) decahydroisoquinoline-3-carboxylate intermediate useful for the synthesis of the compounds of the invention are shown in Schemes IIa and IIb below.

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Scheme 11a

Scheme llb

Scheme llb

AUN

(Ii)

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In Scheme 11a, Step A, 6-oxo-decahydroisoquinoline-3-carboxylic acid is treated with methyltriphenylphosphonium bromide to give 6-methylidine-decahydroisoquinoline-3-carboxylic acid (i-a). For example, a slurry of 1 equivalent of 6-oxo-2-methoxycarbonyldecahydroisoquinoline-3-carboxylic acid and about 1.4 equivalents of methyltriphenylphosphonium bromide in THF and DMF is mechanically stirred under a nitrogen atmosphere and cooled to -10 ° C. A solution of potassium tert-butoxide (2.4 equivalents in THF) was then added dropwise over 10 minutes. The slurry was then allowed to warm to room temperature and stirred at room temperature for 2.5 hours (complete by TLC). The reaction mixture was then partitioned between water and EtOAc and the layers were separated. The organic phase is extracted 2 times with water, the aqueous portions are combined and the resulting mixture is washed 2-6 times with dichloromethane. An aqueous solution was then prepared by acid addition of 6M HCl solution, extracted 2-6 times with dichloromethane. The last three organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to give the compound having structure (i-a).

In Scheme 11a, in Step B, the intermediate 6-methylidinodecahydroisoquinoline-3-carboxylic acid (compound (ia)) is esterified by reaction with a compound of formula R ₂ Br (where R ₂ is defined herein) to give 6-methylidine - decahydroisoquinoline-3-carboxylate intermediate (ii). For example, 6-methylidine-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with triethylamine and bromoethane. The reaction mixture was heated to 50 ° C for about 3 hours, cooled and partitioned between 50:50 ethyl acetate-heptane and 1N HCl solution. The organic phase is isolated and washed 3 times with water, saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the compound of structure (ii). This crude material was dissolved in 10% ethyl acetate / heptane and applied to a silica gel layer (10 g in 10% ethyl acetate / heptane). This layer was washed with 10% ethyl acetate / heptane, then with 15% ethyl acetate / heptane and then with 25% ethyl acetate / heptane. The washings were combined and concentrated in vacuo to give a solid

32138 / B yields a purified compound having structure (ii).

In Scheme 11a, in step C, the 6-methylidine decahydroisoquinoline-3-carboxylate intermediate (compound (ii)) is subjected to hydroboration followed by oxidation to give the 6-hydroxymethyl decahydroisoquinoline-3-carboxylate intermediate compound (1). For example, this is accomplished by dissolving ethyl 6-methylidine-2-methoxycarbonyldecahydroisoquinoline-3-carboxylate in THF and cooling to about -15 ° C under a nitrogen atmosphere. A 1M solution of BH ₃ in THF is then added dropwise over 5-7 minutes, which is pre-cooled and the reaction mixture is stirred at -10-12 ° C for about 2 hours. The reaction mixture is then slowly treated with a suitable base such as lithium or sodium hydroxide and 30% H2O2 is slowly added over 15 minutes. The reaction mixture is then allowed to warm to room temperature and then partitioned between ethyl acetate and 50% saturated. sodium chloride solution. The aqueous layer was extracted with ethyl acetate, and the combined organics were washed with sodium bisulfite, brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield intermediate (1).

Alternatively, the intermediate 6-hydroxymethyl-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate (compound (1)) can be prepared by the synthesis described in Scheme 11b. In Scheme 11b, Step A, 6-oxo-decahydroisoquinoline-3-carboxylic acid is esterified by reaction with a compound of formula R 2 -Br (where R 2 is defined herein) to give the intermediate 6-oxo-decahydroisoquinoline-3-carboxylate ( compound (ib)). For example, 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with triethylamine and bromoethane. It was then heated to 50 ° C for about 3 hours, cooled and partitioned between 50:50 ethyl acetate-heptane and 1N HCl solution. The organic phase is isolated and washed 3 times with water, saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the compound having structure (i-b). This crude material was dissolved in 10% ethyl acetate / heptane and loaded onto a silica gel pad (10 g in 10% ethyl acetate / heptane). This layer was washed with 10% ethyl acetate / heptane, 15

32138 / B% ethyl acetate / heptane and 25% ethyl acetate / heptane. These eluents were combined and concentrated in vacuo to give the purified compound having structure (i-b).

In Scheme 11b in Step B, 6-oxo-decahydroisoquinoline-3-carboxylate, an intermediate, referred to as compound (i-b), is treated with methyltriphenylphosphonium bromide to give 6-methylidine-decahydroisoquinoline-3-carboxylate compound (ii). For example, a slurry of 1 equivalent of 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate (compound (ib)) and about 1.4 equivalents of methyltriphenylphosphonium bromide in THF and DMF is mechanically stirred under nitrogen and cooled to 5 ° C. A solution of potassium tert-butoxide (2.4 eq. THF) was then added dropwise over 10 minutes. The mixture was allowed to warm to room temperature and stirred for 2.5 hours (by TLC, after which time the reaction was complete). The reaction mixture was partitioned between water and EtOAc and the layers were separated. The organic phase is extracted 2 times with water and the aqueous extracts are combined. The combined fractions thus obtained form a mixture which is washed 2-6 times with dichloromethane. Aqueous solution was prepared by adding 6M HCl solution and extracted 2-6 times with dichloromethane. The last three organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to give the compound of structure (ii).

In Scheme IIb, Step C, using procedures as described in Scheme Ha, Step C, above, the intermediate 6-methylidinedecahydroisoquinoline-3-carboxylate (compound (ii)) is subjected to hydroboration followed by oxidation, thereby to give the 6-hydroxymethyldecahydroisoquinoline-3-carboxylate intermediate compound (1).

The following Preparations and Examples illustrate the compounds and methods of the invention. The reagents and starting compounds can be readily obtained by one skilled in the art. These examples are intended to be illustrative only and therefore do not limit the scope of the invention in any sense.

As used herein, the following meanings have the meanings indicated: "i.v." means intravenously; "after. means orally; "I.p." means intraperitoneally; "Eq" or "equiv." Means equivalents; "G" means grams;

32138 / B ”mg” means milligrams; Ί ”means liters; "Ml" means milliliters; “ΜΙ” means microliters; "Mol" means moles; "Mmol" means millimoles; psi means pounds per square inch ”; “MmHg” means milliliters of mercury; “Min” means minutes; h ”or hour” means hours; “° C” means degrees Celsius; "TLC" means thin layer chromatography; "HPLC" means high performance liquid chromatography; Rf is the retention factor; ”Rt” means retention time; “Δ” means field under tetramethylsilane in ppm; THF ”means tetrahydrofuran; "DMF" means Ν, Ν-dimethylformamide; DMSO ”means dimethylsulfoxide; aq 'means aqueous; EtOAC 'means ethyl acetate; iPrOAc ”means isopropyl acetate; MeOH means methanol; MTBE ”means tert-butyl methyl ether; RT ”means room temperature; Ki "means the dissociation constant of the enzyme-antagonist complex and serves as an index of ligand binding strength and" ID ₅₀ "and" ID ₁₀₀ "refer to doses of the therapeutically active compound to be administered to cause a 50% and 100% decrease in physiological response.

Examples of methods for preparing the active compounds according to the invention

Preparation 1

Preparation of [3S, 4aR, 6S, 8aR] -6-Methylidine-2- (methoxycarbonyl) 1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid

32138 / B

A slurry of methyltriphenylphosphonium bromide (12.4 g, 34.6 mmol) in THF (25 mL) was cooled to -10 to -12 ° C under a nitrogen atmosphere and treated with sodium hexamethyldisilazide (35 mL and 1M solution in THF), which is added by syringe over 6 to 8 minutes with concomitant stirring. The reaction mixture is then stirred for 20 minutes at -10 to -12 ° C and then cannula is added over 3-4 minutes to [3S, 4aR, 6S, 8aR] -6-oxo-2- (methoxycarbonyl) 1,2, 3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (10.0 g, 26.6 mmol) (which was previously treated with sodium hexamethyldisilazide (27 mL of a 1M solution in THF) at 0-3 ° C and stirring for 10 minutes), dissolved in DMF (20 mL) and cooled to 0-3 ° C under a nitrogen atmosphere. THF (3 mL) was then added to the flask containing the Wittig reagent, which was also added to the reaction mixture. The reaction mixture was then allowed to stir at 0-3 ° C for 5 minutes, then allowed to warm to room temperature and stirred for an additional 3 hours. Ethyl acetate (100 mL) and water (50 mL) were then added with stirring, and the layers were separated. Extract the organic layer with water (50 mL) and wash the combined aqueous portions with methylene chloride (5 x 75 mL). The combined aqueous fractions were then treated with 6M HCl (15 mL) and extracted with methylene chloride (3 x 50 mL). The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (6.59 g, 98%) as a yellow oil.

Alternative synthesis of [3S, 4aR, 6S, 8aR] -6-methylidine-2- (methoxycarbonyl) 1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid

[3S, 4aR, 6S, 8aR] -6-oxo-2- (methoxycarbonyl) 1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid slurry (50.0 g, 0.133 mol, 1.0 equiv) and methyltriphenylphosphonium bromide (66.4 g, 0.186 mol, 1.4 equiv) in THF (150 mL) and DMF (25 mL) were mechanically stirred under a nitrogen atmosphere and cooled to 5 ° C. A solution of potassium tert-butoxide (187 mL of a 1.7 M solution in THF, 0.319 mol, 2.4 equiv) was then added dropwise over 10 minutes. The mild exothermic reaction of this addition,

32138 / B leads to an increase in the temperature of the reaction mixture to 6 ° C. The resulting slurry was then allowed to warm to room temperature and stirred at this temperature for 2.5 hours (after which time was complete by TLC). The reaction mixture was then partitioned between water (250 mL) and EtOAc (250 mL) and the layers were separated. The organic phase was extracted with water (2 x 100 mL) and the aqueous portions were combined and washed with dichloromethane (5 x 300 mL). The aqueous solution was then acidified by addition of 6M HCl solution (50 mL) and extracted with dichloromethane (3 x 150 mL). The last three organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to give the title compound as a yellow film (36.17 g). The estimated concentration of the active ingredient in the proton NMR product was 89% by weight (the remainder being solvents), so the corrected yield was 32.2 g (95.6%).

Preparation 2

Preparation of [3S, 4aR, 6S, 8aR] -ethyl 6-methylidine-2- (methoxycarbonyl) 1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[5S-αR.eS.SaRj-ε-methylidine-2-methoxycarbonyl-1S-2-α] -Se-S. adehydrohydroisoquinoline-3-carboxylic acid (6.59 g, 26.0 mmol, prepared according to Preparation 1) was dissolved in acetonitrile (26 mL) and treated with triethylamine (7.25 mL, 52 mmol) and bromomethane (5.82 mL, 78 mmol). The reaction mixture is heated at 50 ° C for about 3 hours, cooled and partitioned between 50:50

32138 / B ethyl acetate / heptane (100 mL) and 1N HCl solution (75 mL). The organic phase was isolated and washed with water (3 x 30 mL), saturated sodium bicarbonate (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude title compound as an amber colored oil. This crude product was dissolved in 10% ethyl acetate / heptane (15 mL) and loaded onto a silica gel layer (10 g in 10% ethyl acetate / heptane). The layer was then washed with 10% ethyl acetate / heptane (10 mL), 15% ethyl acetate / heptane (15 mL), and 25% ethyl acetate / heptane (90 mL). The eluent fractions with the eluted compound were combined and concentrated in vacuo to give the purified title compound (6.84 g, 91%) as a colorless oil.

Preparation 3 [3S, 4aR, 6S, 8aR] -ethyl 6- (hydroxymethyl) -2- (methoxycarbonyl) 1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[3S, 4aR, 6S, 8aR] -ethyl-6-methylidine-2- (methoxycarbonyl) -1,6,6-a-S, -Sa-decahydroisoquinoline-S-carboxylate (2.0 g, 7.11 mmol) prepared as in Preparation Example 2, was dissolved in THF (10 mL) and heptane (2 mL) and cooled to about -15 ° C under a nitrogen atmosphere with stirring. Then, a 1M solution of BH 3 .THF in THF (3.91 mL, 3.91 mmol) was added dropwise over 5-7 minutes, and the reaction mixture was stirred for about 2-4 hours at -10 to -14 ° C. The reaction mixture was treated with ethanol (1.25 mL) for 2 minutes and then allowed to warm to 20 ° C. The reaction mixture was then slowly treated with 1M

32138 / B LiOH solution (3.91 mL), followed by slow addition of 30% H ₂ O ₂ (1.2 mL, added at such a rate that the reaction mixture temperature remained below 30 ° C). The reaction mixture was then allowed to stir at room temperature for 30-45 minutes, then partitioned between ethyl acetate (12 mL) and 10% sodium bisulfite solution (14 mL). The organic layer was washed with 10% sodium bisulfite (16 mL), brine (8 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (2.01 g) as a colorless oil.

Example 1

3S, 4aR, 6S, 8aR Ethyl-6 - (((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) 1,2,3,4,4a, 5,6,7,8,8a -decahydroisoquinoline-3-carboxylate · D - (-) - mandelic acid

EtO

OEt • D - (-) - Mandelic acid

A. Preparation

The chiral

32138 / B

[3S, 4aR, 6S, 8aR] -ethyl 6- (hydroxymethyl) -2- (methoxycarbonyl) 1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate solution ( 37.5 g, 0.125 mol) and triethylamine (35.0 mL, 0.25 mol) in EtOAc (94 mL) were added dropwise to a solution of p-nitrobenzenesulfonyl chloride (28.6 g, 0.125 mol) in EtOAc (94 mL). ) while maintaining the temperature at 0 to 2 ° C (addition time: 30 minutes). The reaction mixture was allowed to warm to room temperature, stirred for about 2.5 hours, then quenched by the addition of water (100 mL), 1M HCl (100 mL) and brine (20 mL). The layers were separated and the organic phase was washed with 1M NaHCO ₃ solution (150 mL), brine (150 mL) and dried over MgSO ₄ . Concentration in vacuo afforded the title compound as an oil (58.9 g, 97%).

¹ H NMR (CDCl ₃ ): 88.41 (2H, d), 8.05 (2H, d), 4.38 (t, 1H), 4.17 (m, 2H), 3.97 (m, 2H), 3.69 (s, 3H), 3.39 (m, 2H), 2.12 (m, 1H), 1.85 (m, 3H), 1.55 (m, 5H), 25 (m, 5 H).

B. Preparation

The chiral

Amberlite IRA 67 resin (334.7 g) was treated with water (about 680 mL) while mixing the resin. The mixture is filtered and the filter cake is washed with acetone until the water content of the wash solution is less than 5% by weight. The filter cake was then treated with hydroxyproline ethyl ester HCl (72.7 g, 0.372 mol) and acetone (700 mL) and stirred at room temperature for about 1-2 hours. The mixture was then filtered and the filter cake was washed with acetone (300 mL). this

32138 / B hydroxyproline ethyl ester filter solution was used directly. A slurry of Amberlite IRA 67 (465 g) in water (about 900 mL) was stirred and then filtered. Wash the filter cake with acetone until the water content of the wash solution is less than 5% by weight. This filter cake was then treated with a solution of the hydroxyproline ethyl ester from the above experiment and a solution of the compound of Step A (100 g, 0.206 mol) in EtOAc (about 150 mL) and the resulting mixture was heated to reflux. After about 24 hours, the reaction mixture was cooled and filtered. The filter cake was washed with dichloromethane (about 300 mL), the combined filtrates were concentrated in vacuo and the residue was concentrated several times by distilling off the dichloromethane to give the title compound as an oil which was used directly in the next step.

C. Preparation

The chiral

Dichloromethane (about 230 mL) was treated with phosphorus pentoxide (117.2 g, 0.825 mol) and cooled to about -10 ° C. To this mixture was added dimethyl sulfoxide (96.8 g, 1.24 mol) at such a rate that the temperature of the reaction mixture was maintained at about 10 ° C. The reaction mixture was stirred at about -10 ° C and treated with a solution of the compound of Step B above in dichloromethane (about 230 mL) at such a rate that the temperature of the reaction mixture remained below about -10 ° C. The reaction mixture is heated to about 20-22 ° C for several hours (4-5) and stirred overnight, then cooled to about 0 ° C and treated with triethylamine.

32138 / B (83.5 g, 0.825 mol) was added at a rate such that the temperature of the reaction mixture was below 5 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was added to a 0.1 M HCl solution (about 460 mL was precooled to about 0-5 ° C) at a rate such that the temperature of the reaction mixture was below 10 ° C. Another portion of dichloromethane (about 460 mL) was added, the mixture was stirred briefly, and the layers were separated. The aqueous was extracted with dichloromethane (ca. 460 mL) and the combined organic extracts were washed with 1M NaHCO3 (ca. 460 mL). The layers were separated and the organic layer was dried with magnesium sulfate and concentrated in vacuo. This crude product was purified by silica gel chromatography (Silica Gel 60) and washed with 35% EtOAc in toluene to give the title compound as an oil (36.9 g, 41% of 504 476).

¹ H NMR (CDCl ₃ ) δ: 4.39 (t, 1H), 4.18 (m, 4H), 3.72 (m, 1H), 3.70 (s, 3H), 3.40 ( m, 3H), 3.00 (d, 1H), 2.40-2.69 (m, 4H), 2.08 (m, 1H), 1.45-1.95 (m, 9H), 1 30 (m, 6H); 1.10 (m, 1H).

D. Preparation

The chiral

A solution of the compound from Step C above (8.98 g, 0.0205 mol) and ethanol (0.227 mL, 0.0039 mol) in 1,2-dichloroethane (43 mL) was treated with deoxofluoro ([bis- (2-methoxyethyl) amino] thiotrifluoride, 6.5 ml, 0.0353 mol) and the reaction mixture was stirred at RT

32138 / B at room temperature for about 21 hours. The reaction mixture was then treated with a saturated solution of NaHCO ₃ in water (60 mL) and stirred for 15 minutes. Separate the layers and extract the aqueous with toluene (about 45 mL). After separation of the layers, toluene was separated and the 1,2-dichloroethane solutions were combined and dried with Na ₂ SO ₄ . The drying agent is then filtered off and the filter cake is washed with toluene (about 30 ml). The filtrate was concentrated in vacuo and the residue was dissolved in 50:50 toluene: heptane (ca. 17 mL). The solution is then loaded onto a column packed with Silica Gel 60 ”(43 g in 50:50 toluene / heptane). Wash the column with 50:50 toluene: heptane (about 230 mL), toluene (about 430 mL), 10% EtOAc in toluene (about 240 mL), and 20% EtOAc in toluene (about 86 mL). The eluent fractions containing the pure compound were combined and concentrated in vacuo to give the title compound as a syrup (5.79 g, 61%).

¹ H NMR (CDCl ₃ ): 84.35 (m, 1H), 4.20 (m, 4H), 3.70 (s, 3H), 3.40 (m, 4H), 2.78 (m, 1H), 2.40-2.65 (m, 3H), 2.30 (m, 1H), 2.15 (m, 1H), 1.70-1.95 (m, 4H), 1.45 1.65 (m, 4H), 1.30 (m, 6H), 1.10 (m, 2H).

E. Preparation of 3S, 4aR, 6S, 8aR-Ethyl-6 - (((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5,6, 7,8,8a-decahydroisoquinoline-3-carboxylate (in free base form)

The chiral

32138 / B

Preparation of 3S, 4aR, 6S, 8aR-Ethyl-6 - (((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5,6,7, 8,8a-decahydroisoquinoline-3-carboxylate D (-) - mandelic acid salt

The chiral

A solution of the compound from Step D above (9.7 g, 0.021 mol) in dichloromethane (about 70 mL) and toluene (about 30 mL) was cooled to 0-5 ° C and treated with iodotrimethylsilane (12.7 g, 0.063 mol), which is added dropwise. The reaction mixture was then allowed to warm to room temperature and stirred for about 16 hours, then concentrated in vacuo, concentrated several times from MTBE (methyl t-butyl ether) and then dissolved in MTBE (about 70 mL) and toluene (about 30 mL). ) and washed with saturated NaHCO ₃ (about 100 mL), 1N sodium thiosulfate (about 100 mL) and water (about 100 mL). The organic layer was concentrated in vacuo and the residue was concentrated several times from MTBE, then dissolved in toluene (about 22 mL) and then treated with a solution of D - (-) - mandelic acid (2.75 g, 0.181 mol) in MTBE (about 33 mL). The mixture is then stirred at room temperature for about 2 hours, then cooled to about -15 ° C and stirred for about 2 hours. The D - (-) - mandelic acid salt was collected by filtration, washed with cold MTBE (about 73 mL at -15 ° C) and dried to a crystalline solid (8.25 g, 71%).

¹ H NMR (DMSO-d 6) δ: 7.16-7.38 (m, 5H), 4.72 (s, 1H), 4.12 (m, 4H), 3.65 (m, 1H), 3.51 (m, 1 H), 3.33 (m, 1 H), 2.25-2.91 (m, 8 H), 1.85 (m, 2 H), 1.70 (m, 2 H), 1 34-1.86 (m, 5H), 1.15-1.38 (m, 7H), 0.81 (m, 1H).

32138 / B

Example 2

Preparation of 3S, 4aR, 6S, 8aR-Ethyl-6 - (((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) decahydroisoquinoline-S-carboxylate · 1,5-naphthalene disulfonic acid

1,5-Naphthalenedisulfonic acid, tetrahydrate

A solution of 1,5-naphthalenedisulfonic acid tetrahydrate (1.1 g, 3.05 mmol) in refluxing ethanol (about 5 mL) was treated with a solution of 3S, 4aR, 6S, 8aRetyl-6 - (((2S) -2) (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) 1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (free base of the diester compound of Example 1, step Above (1.2 g, 3.0 mmol) in ethanol (about 5 mL) and the mixture was heated under reflux until crystals began to form (about 5 minutes). The reaction mixture was then cooled and allowed to stand at room temperature for about 3 days. The product was collected by filtration, washed with ethanol (3 x 5 mL) and dried (2.0 g, 96%). The product can be recrystallized from water or methanol.

Example 3

Preparation of 3S, 4aR, 6S, 8aR-6 - (((2S) -2- (hydroxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) dihydrochloride) -1,2,3,4,4a, 5,6,7, 8,8adekahydroizochinolín-3-carboxylic acid

32138 / B

H

OH

HCl

Preparation of 3S, 4aR, 6S, 8aR-6 - (((2S) -2- (carboxylic acid) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5,6,7,8 , 8α-Decahydroisoquinoline-3-carboxylic acid (free base)

F

H

A mixture of the compound of Example 1, Step D above (16.3 g, 0.0353 mol) and 6M HCl (170 mL) was heated to reflux and the distillate of the reaction mixture (about 15 mL) was separated over 3 hours. The reaction mixture was cooled and washed with dichloromethane (2 x 50 mL), then treated with activated carbon (about 8 g) and then stirred at 60 ° C for 30 minutes. The mixture was then cooled and filtered through a Hyflo bed. The filter cake was washed with water (about 50 mL) and the aqueous filtrates were combined and concentrated in vacuo to a solid (14.2 g). This solid (8.61 g, 61%) was concentrated from 2-propanol, then treated with 2-propanol (about 43 mL) and heated at 50 ° C for 1 hour. The mixture was then cooled to about 0 ° C and stirred for 30 minutes. The solid was collected by filtration, washed with cold 2-propanol (20 mL), and dried to give a solid.

32138 / B white powder (7.5 g) which is the dihydrochloride of the title compound. This powder (2.5 g, 33.3% of the amount obtained) was treated with 1N NaOH solution (11.9 mL) and the resulting solution was then concentrated in vacuo. The residue was concentrated from EtOH, then the concentrated residue was treated with 50:50 EtOH: EtOAc. The mixture was then warmed to about 35 ° C, cooled to room temperature and stirred for 1 hour. It is then filtered. The filter cake was washed with 50:50 EtOH: EtOAc (5 mL) and the combined filtrates were concentrated to a foam. The resulting foam was concentrated from EtOAc and then treated with EtOAc (10 mL) and stirred. The free base of the title compound was collected by filtration and dried to a powder (1.96 g, corrected for drug concentration). Yield calculated on the free base: 1.96 g divided by 0.333 divided by 0.61 = 9.65 g or 79%.

¹ H NMR (D ₂ O + DCI): 4.55 (t, 1H), 4.07 (m, 1H), 3.83 (m, 1H), 3.65 (m, 1H), 3.25 (m, 1H), 2.95 (m, 4H), 2.59 (m, 1H), 1.89 (m, 3H), 1.77 (m, 1H), 1.65 (m, 1H) 1.46 (m, 3H), 1.35 (d, 1H), 1.20 (m, 1H), 0.84 (m, 1H).

Example 4

To confirm that the iGluR ₅ receptor subtype mediates neurogenic protein extravasation, functional dependencies on migraine, the affinity of binding of test compounds to the iGluR ₅ receptor were first measured. This was done in standard ways. For example, the activity of compounds as antagonists of the iGluR ₅ receptor can be determined by detecting binding of radiolabeled ligand to the cloned and expressed human iGluR ₅ receptor (Korczak et al., 1994, Recept. Channels, 3, 41-49) and recorded electrophysically cell tension by currents in just isolated rat dorsal ganglion neurons (Bleakman et al., 1996, Mol. Pharmacol., 49, 581-585). The selectivity of the compounds for the iGluR ₅ receptor subtype can be determined by comparing the antagonist activity for the iGluR 5 receptor with the antagonist activity against other AMPA and kainate receptors. Methods useful for such comparisons are: assaying receptor ligand binding and recording the results of whole cell electrophysiological strain measurements to determine functional activity on human GIuRt, GIuR ₂ , GIuR _3, and

32138 / B

GluR ₄ receptors (Fletcher et al., 1995, Recept. Channels, 3, 21-31); see also Receptor-ligand binding studies and whole-cell voltage clamp electrophysiological recordings of functional activity at human GluR ₆ receptors (Hoo et al., Recept. Channels, 2, 327-388); electrophysiological recordings of whole cell stress expressing functional activity at AMPA receptors on just isolated brain Purkinje neurons (see Bleakman et al., 1996, Mol. Pharmacol, 49, 581-585) and assays on other tissues expressing AMPA receptors (see Fletcher and Lodge, 1996, Pharmacol. Ther., 70, 65-89).

A. Affinity of antagonist binding to iGluR ₅ receptor

HEK ₂ 93 cell lines stably transfected with human iGluR receptors are used for the assay. Replacement of 3 [H] AMPA with an increased antagonist concentration is measured in cells expressing iGluR 1, iGluR ₂ , iGluR _3, and iGluR ₄ , while exchanged 3 [H] kainates (KA) are assayed on cells expressing iGluR ₅ , iGluR ₆ , iGluRy and KA2. For compounds of Formula I or Formula Ia, the activity of antagonist binding activity (Ki) is estimated, for example in μΜ. As an indicator of selectivity used the ratio of binding affinity to iGluR ₂ AMPA receptor subtype to the binding affinity for iGluR ₅ kainate receptor subtype (Ki for iGluRs ₂ / K for iGluR _5), which are also determined. The compounds provided by the invention exhibit greater binding affinity for iGluRs (lower Ki values) than for iGluR ₂ , preferably at least 10 times greater for iGluRs than for iGluR _2, and even more preferably at least 100 times greater.

Example 5

The following animal model can be used to determine the ability of compounds of Formula I or Formula Ia to inhibit protein extravasation and is an exemplary functional assay of the neuronal mechanism of migraine.

32138 / B

Animal model of dural protein extravasation

A. Harlan Spraque-Dawley rats (225 - 325 g) or guinea pigs from Charles River Laboratories (225 - 325 g) are anesthetized with sodium pentobarbital administered intraperitoneally (65 mg / kg or 45 mg / kg) and placed in stereotaxic frame (David, Kopf Instruments) with knife set at -3.5 mm for rat or -4.0 mm for guinea pig. After a mid-sagittal section, two pairs of bilateral holes are formed and drilled through the skull (6 mm posterior, 2.0 and 4.0 mm lateral in rats; 4 mm posterior and 3.2 and 5.2 mm lateral in guinea pigs, all coordinates measured from bregma). Thereafter, paired stainless steel stimulation electrodes, which are electrically insulated in addition to the tip (Rhodes Medical Systems, Inc.), are immersed in the holes in both hemispheres to a depth of 9 mm (rats) or 10.5 mm (guinea pigs).

B. The femoral vein is exposed and intravenously (i.v.) injected with the test compound at a dose volume of 1 ml / kg, or alternatively, the test compound is administered orally (p.o.) using a gastric dosing probe at a volume of 2.0 ml / kg. About 7 minutes after i.v. the 50 mg / kg dose of Evans Blue, a fluorescent dye, is also injected intravenously. Evans blue forms complexes with proteins in the blood and is used as a marker for protein extravasation. Exactly 10 minutes after injection of the test compound, the left trigeminal ganglion is stimulated for 3 minutes with a 1.0 mA current (5 Hz, 4 ms duration) using a Model 273 potentiostat / galvanostat (EG&G Princeton Applied Research).

C. 15 minutes after stimulation, animals were sacrificed by replacing the blood with 20 ml saline. The top of the skull is removed to allow removal of the dural membranes. The membrane samples are then removed from both hemispheres, washed with water, and microscope slides are removed. After drying, the tissues

32138 / B are coated with 70% glycerin in water.

D. A fluorescent microscope (Zeiss) equipped with an input monochromator and a spectrophotometer is used to determine the amount of Evans Blue in each sample according to A. An excitation wavelength of approximately 535 nm is used and the emission intensity at 600 nm is measured. The microscope is equipped with a servomotor-driven washer and is also connected to a personal computer. This allows the computer to control pad movement and perform fluorescence measurements at 25 points (500 mm apart) for each hard diaper sample. The mean and standard deviation of the individual measurements are calculated by the computer.

E. Extravasation induced by electrical stimulation of the trigeminal ganglion has an ipsilateral effect (i.e., it occurs only on the side of the diabetic on which the trigeminal ganglion is stimulated). This allows the second (unstimulated) diaper half to be used as a control. The ratio (extravasation ratio) of the magnitude of extravasation in the diabetic side from the stimulated side to the magnitude of extravasation in the diabetic side from the unstimulated side is calculated. Control animals treated with saline only showed an extravasation ratio of about 2.0 in rats and about 1.8 in guinea pigs.

In contrast, compounds that completely prevent extravasation from the stimulated side in the hard cerebral diaper have an extravasation ratio of about 1.0.

F. Dose-response curves for each compound of Formula I and Formula Ia indicate 50% (ID ₅₀ ) or 100% (m ₁₀₀ ) that can be estimated. 3S, 4aR, 6S, 8aR-Ethyl-6 - (((2S) -2- (ethoxycarbonyl) 4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5,6, 7,8,8a-decahydroisoquinoline-3-carboxylate dihydrochloride, has an ID ₁₀ value of about 0.01 ng / kg when administered orally to rats.

32138 / B

Claims (2)

A pharmaceutically acceptable salt of a compound of the formula: and / or a prodrug thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of a D - (-) - mandelic acid salt or a 1,5-naphthalenedisulfonic acid salt. The pharmaceutically acceptable salt of claim 1, wherein the salt is a D - (-) - mandelic acid salt. The pharmaceutically acceptable salt of claim 1, wherein the salt is the 1,5-naphthalenedisulfonic acid salt. A compound which is 3S, 4aR, 6S, 8aR-6 - (((2S) -2- (carboxylic acid) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5 , 6,7,8,8-decahydroisoquinoline-3-carboxylic acid · D - (-) - mandelic acid. 5. A compound which is 3S, 4aR, 6S, 8aR 6 - (((2S) -2- (carboxylic acid) 4,4-difluoropyrrolidinyl) methyl) -1,2,3,4 _L 4, 5.6; 7,8,8a-decahydroisoquinoline-3-carboxylic acid 1,5-naphthalene disulfonic acid. 32138 / B 6. A pharmaceutically acceptable salt of a compound of the formula: where R ¹ and R ² each independently is hydrogen, (C ₁ -C ₂₎ alkyl, (C _{2 -C)} alkenyl, (C _C6) alkylaryl, _(Cl-C6) alkyl (C3-C, o) cycloalkyl, (CrCeJalkyl-NN-C -C dialkylamino, (C, -C6) alkyl-pyrrolidine, _(Cl-C6) alkyl-piperidine, or _(Ci-C6) alkyl- morpholine, with the proviso that at least one of R ¹ and R ² is other than hydrogen, wherein the pharmaceutically acceptable salt is selected from the group consisting of D - (-) - mandelic acid salt or 1,5-naphthalenedisulfonic acid salt. The pharmaceutically acceptable salt of claim 6, wherein R ¹ and R ² are each independently (C 1 -C ₂₀ ) alkyl. The pharmaceutically acceptable salt of claim 7, wherein R ¹ and R ² are each independently (C 1 -C ₆ ) alkyl. The pharmaceutically acceptable salt of claim 8, wherein the salt is a D - (-) - mandelic acid salt. The pharmaceutically acceptable salt of claim 8, wherein the salt is a 1,5-naphthalenedisulfonic acid salt. 32138 / B A compound which is 3S, 4aR, 6S, 8aR ethyl 6 - (((2S) -2- (ethoxycarbonyl) 4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5,6, 7,8,8a-decahydroisoquinoline-3-carboxylate D - (-) - mandelic acid. A compound which is 3S, 4aR, 6S, 8aR-ethyl-6 - (((2S) -2 (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) -1,2,3,4,4a, 5 , 6,7,8,8-decahydroisoquinoline-3-carboxylate · 1,5-naphthalene disulfone. A method of treating a neurological disorder or neurodegenerative disease, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable salt of claim 1. The method of claim 13, wherein the neurological disorder is migraine. The method of claim 14, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR 6 - (((2S) -2- (carboxy) -4,4-difluoropyrrolidinyl) methyl) 1,2,3,4,4a 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid D - (-) mandelic acid. The method of claim 14, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR ethyl 6 - (((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) 1,2,3,4, 4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate 1,5-naphthalene disulfonic acid. A method of treating a neurological disorder or neurodegenerative disease, comprising administering to a patient in need thereof an effective amount of a pharmaceutically acceptable salt of claim 6. 32138 / B The method of claim 17, wherein the neurological disorder is migraine. The method of claim 17, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR 6 - (((2S) -2- (carboxylic acid) -4,4-difluoropyrrolidinyl) methyl) 1,2,3,4,4a, 5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid D - (-) mandelic acid. The method of claim 17, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR ethyl 6 - (((2S) -2- (ethoxycarbonyl) -4,4-difluoropyrrolidinyl) methyl) 1,2,3,4, 4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate 1,5-naphthalene disulfonic acid. A pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of claim 1, in combination with a pharmaceutically acceptable carrier, diluent, or excipient. A pharmaceutical composition comprising an effective amount of a pharmaceutically acceptable salt of claim 6, in combination with a pharmaceutically acceptable carrier, diluent or excipient. Use of a compound according to claim 1 for the manufacture of a pharmaceutical composition for the treatment of migraine. Use of a compound according to claim 6 for the manufacture of a pharmaceutical composition for the treatment of migraine. 32138 / B Use of a compound according to claim 1 for the treatment of migraine. Use of a compound according to claim 6 for the treatment of migraine. A process for preparing a compound of the formula: where R ¹ and R ² each independently represent hydrogen, (C 1 -C 6) alkyl, (C 2 -C 6) alkenyl, (C 1 -C 6) alkylaryl, (C 1 -C 6 alkyl) -C 1-6 cycloalkyl, (C 1 -C 6 alkyl-NN-C 1 -C 6 dialkylamine, (C 1 -C 6) alkyl-pyrrolidine, (C 1 -C 6) alkyl-piperidine or (C 1 -C ₆ ) alkyl-morpholine, with the proviso that at least one of R ¹ and R ² is other than hydrogen, comprises a compound having the structure (2): (2) Wherein R ² is as defined above, Pg is a suitable nitrogen protecting group and LgO is a suitable leaving group, with a suitable base in a suitable solvent, followed by the addition of a compound having the structure (3): wherein R ¹ is as defined above, followed by oxidation to a compound having the structure (5): followed by halogenation and removal of the nitrogen protecting group.