GB2276163A - Pyridine compounds. - Google Patents

Pyridine compounds. Download PDF

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GB2276163A
GB2276163A GB9305509A GB9305509A GB2276163A GB 2276163 A GB2276163 A GB 2276163A GB 9305509 A GB9305509 A GB 9305509A GB 9305509 A GB9305509 A GB 9305509A GB 2276163 A GB2276163 A GB 2276163A
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evaporated
mixture
give
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solid
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GB9305509D0 (en
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William Leonard Mitchell
John Watson Clitherow
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides

Abstract

Compounds of the formula (I): <IMAGE> or a physiologically acceptable salt or solvate thereof, in which R<1> represents a hydrogen atom or a halogen atom or a C1-6alkyl or C1-6alkoxy group; R<2> and R<3>, which may be the same or different, each independently represent a hydrogen atom or a halogen atom, or a C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkoxy, hydroxy, CN, -NO2,-CO2R<6>, -COR<6>, -CONR<6>R<7> or (CH2)mOC(O)C1-4alkyl group; R<4> and R<5>, which may be the same or different, each independently represent a hydrogen atom or a halogen atom, or a hydroxy, C1-6alkoxy or C1-6alkyl group; R<6>, R<7> R<8> and R<9>, which may be the same or different, each independently represent a hydrogen atom or a C1-6alkyl group; or -NR<6>R<7> forms a saturated heterocyclic ring which has 5 or 6 ring members which, when there are 6 ring members, may optionally contain in the ring one oxygen or sulphur atom; X represents -CONH-, -NHCO-, -CH2NH- or -NHCH2-; m represents zero or an integer from 1 to 3; and p represents an integer from 2 to 4; are 5-HT1D antagonists useful in the treatment of CNS disorders, endocrine disorders and sexual dysfunction.

Description

CHEMICAL COMPOUNDS This invention relates to novel aniline and benzanilide derivatives, to processes for their preparation, and to pharmaceutical compositions containing them.
According to the present invention there is provided compounds of the general formula (I) :
or a physiologically acceptable salt or solvate thereof, in which R' represents a hydrogen atom or a halogen atom or a Cl4alkyl or C1-6alkoxy C1.6alkoxy group; R2 and R3, which may be the same or different, each independently represent a hydrogen atom or a halogen atom, or a Cl4alkyl, hydroxyCl4alkyl, C1-6alkoxyC1-6alkyl, C,4alkoxy, hydroxy, -CN, -NO2, -CO2R6, -COR6, - CONR6R7or -(CH2)mOC(O)C1-4alkyl group; R4 and R5, which may be the same or different, each independently represent a hydrogen atom or a halogen atom, or a hydroxy, C1-6alkoxy or C,4alkyl group;; R6, R7 R8 and R9, which may be the same or different, each independently represent a hydrogen atom or a C,4alkyl group; or -NR6R7 forms a saturated heterocyclic ring which has 5 or 6 ring members which, when there are 6 ring members, may optionally contain in the ring one oxygen or sulphur atom; X represents -CONH-, -NHCO-, -CH2NH- or-NHCH2-; m represents zero or an integer from 1 to 3; and p represents an integer from 2 to 4.
It is to be understood that the present invention encompasses all geometric and optical isomers of the compounds of general formula (I) and their mixtures including the racemic mixtures thereof.
Physiologically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids (for example hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, ptoluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates, acetates or tricarballylates) and, where appropriate, inorganic base salts such as alkali metal salts (for example sodium salts).
In the compounds of formula (I), the term "C,,alkyl" or "C, 6alkoxy" as a group or part of a group means that the group is straight or branched and consists of 1 to 6 carbon atoms. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. The term "halogen" within the definition of R2 means fluorine, chlorine, bromine or iodine.
Within the above definition, when -NR6R7 represent a saturated heterocyclic ring, these contain 5 or 6 ring members, one of which (when there are 6 ring members) may be an oxygen or a sulphur atom. Suitable heterocyclic groups are a pyrrolidinyl, piperidinyl, morpholinyl or thiomorpholinyl group.
The pyridinyl ring may preferably be attached in the meta or more particularly the para position of the phenyl ring A relative to the group X.
When the pyridinyl ring is substituted by a single atom or group as defined above where possible the substituent is preferably attached in a position meta or para to the phenyl ring A in general formula (I). When the pyridinyl ring is substituted by two atoms or groups as defined above where possible one substituent is preferably attached in the position para to, and the other is in a position ortho to the phenyl ring A in general formula (I).
A preferred group of compounds of general formula (I) is that wherein the pyridinyl ring is substituted by one or two substituents as defined in general formula (I) wherein one substituent is in the position para to the phenyl ring A in general formula (I) the second substituent is in the position ortho to the phenyl ring A in general formula (I).
Another preferred group of compounds of general formula (I) is that wherein the pyridinyl ring is substituted by a single substituent as defined in general formula (I) wherein said substituent is in the position para to the phenyl ring A in general formula (I).
Another preferred group of compounds of general formula (I) is that wherein the pyridinyl ring is attached at the 3-position, or more preferably at the 4-position.
Another preferred group of compounds of general formula (I) is that wherein R2 and/or R3 each independently represent a hydrogen atom or a C,4alkyl, especially methyl, group. Particularly preferred are those compounds wherein R2 and/or R3 on the pyridinyl ring is in a position ortho to the bond to the phenyl ring A in general formula (I).
A further preferred group of compounds of general formula (I) is that wherein R' is a hydrogen atom, a halogen atom, especially a fluorine atom, or a group selected from C, 3alkyl, especially methyl, and C, 3alkoxy, especially methoxy.
Another preferred group of compounds of general formula (I) is that wherein R' is attached at a position ortho to the pyridinyl ring on the phenyl ring A in general formula (I).
Another preferred group of compounds of general formula (I) is that wherein R4 is attached in the para-position relative to the group X.
A further preferred group of compounds of general formula (I) is that wherein R4 is a halogen atom, especially a fluorine or chlorine atom, or a hydroxy or C,6alkoxy, especially methoxy, group.
Also preferred is the group of compounds of general formula (I) wherein R5 is a hydrogen atom or a fluorine atom.
A yet further preferred group of compounds of general formula (I) is that wherein R8 and R9 each represent a Cl4alkyl, especially methyl, group.
Also preferred is the group of compounds of general formula (I) wherein X is -NHCO- or -CONH-.
Another preferred group of compounds of general formula (I) is that wherein p is 3.
Preferred compounds of general formula (I) include: 2-methoxy-N,N-dimethyl-5-[[[4-(4-pyridinyl)phenyleamino]methyl]benzenepropanamine; 3 -[3 -(dimethylamino)propyl]-4-methoxy-N-[4-(2-pyridinyl)phenyl]benzamide; 4-methoxy-3 -[3-[methylamino] -[3 -[methylamino]propyl]-N-[4-(4-pyridinyl)phenyl]benzamide; 3 -[3 -(dimethylamino)propyl]-N-[4-[6-( 1 hydroxyethyl)-3 -pyridinyl] phenyl] -4methoxybenzamide; 4-bromo-3 -[3 -(dimethylamino)propyl]-N-[4-(4-pyridinyl)phenyl]benzamide; and their physiologically acceptable salts and solvates.
Particularly preferred compounds of general formula (I) include: 3 -[3 -(dimethylamino)propyl]-4-methoxy-N-[4-(4-pyridinyl)phenyl]benzamide; 3 [3.(dimethylamino)propyl]A-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide; 3 -[3 -(dimethylamino)propyl]-N-[4-[2-(hydroxymethyl)-5-pyridinyl]phenyl]-4- methoxybenzamide; 5-[4-[[3 -[3 -(dimethylamino)propyl]-4-methoxybenzoyl]amino]phenyl]-2- pyridinemethanol acetate (ester); 3 -[3 (dimethylamino)propyl]A-methoxy-N-[4-(3-methyl-4-pyridinyl)phenyl]benzamide; and their physiologically acceptable salts and solvates.
5-Hydroxytryptamine (serotonin) is a neurotransmitter which is widely distributed within the central nervous system (CNS), platelets and the gastrointestinal tract. Changes in transmission in serotonergic pathways in the CNS are known to modify, for example, mood, psychomotor activity, appetite, memory and blood pressure. Release of 5-hydroxytryptamine from platelets can mediate vasospasm while changes in free 5-hydroxytryptamine levels in the gastrointestinal tract can modify secretion and motility.
Abundant pharmacological studies have led to the discovery of multiple types of receptors for 5-hydroxytryptamine, thus providing a molecular basis to the diversity of its actions. These receptors are classed as 5-HTI, 5-HT2 and 5-HT3, with 5-HT, receptors being sub-classified as 5-HT,A, 5-HT,B, 5-HT,,, 5-HTID and 5-HTlD(like) receptors. The identification of these classes and sub-classes of receptor is based mainly on radioligand binding studies.
Compounds having a selective antagonist action at 5-HTID receptors such as those described herein may exhibit a beneficial effect on subjects suffering from CNS disorders.
In the present specification, a 5-HTlD antagonist is a non-naturally occurring (synthetic) compound that specifically and selectively antagonises 5-HT,D receptors, i.e.
blocks the specific actions of 5-hydroxytryptamine mediated by S-HTID receptors. Such compounds may be identified by a high level of affinity (pKi > 8) in the in vitro human cortex and guinea-pig striatum radioligand binding assays described by Hoyer et al, Neuroscience Letters, 1988, 85, p357-362. Activity at 5-HT,D receptors may be confirmed in vivo using the guinea pig rotation model described by G A Higgins et al, Br.
J. Pharmacol., 1991, 102, p305-310.
The affinity of a compound for 5-HTlA, 5-HT,c and/or 5-HT2 receptors is measured using the in vitro tests described in the following publications: 5-HTlA Gozlan et at, Nature, 1983, 305, p140-142 5-HTlc Pazos et al, Eur. J.Pharmacol., 1984, 106, p53 1-538 5-HT2 Humphrey et al, Br. J. Pharmacol 1988 94, pl 123-1132 (rabbit aorta model).
Thus, for example, compounds of the present invention have been shown to inhibit 5-hydroxytryptamine induced contraction of the dog isolated saphenous vein and to antagonise the 5-hydroxytryptamine induced inhibition of neurotransmission in central and peripheral neurones.
5-HTlD antagonists, and in particular the compounds of the present invention, may therefore be of use in the treatment of CNS disorders such as mood disorders, including depression, seasonal affective disorder and dysthymia; anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnestic disorders and age-associated memory impairment; and disorders of eating behaviour, including anorexia nervosa and bulimia nervosa. Other CNS disorders include Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
5-HTlD antagonists, and in particular compounds of the present invention, may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction.
Therefore, according to a second aspect of the invention, we provide a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy.
According to a further aspect of the present invention, we therefore provide a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment ofthe aforementioned disorders.
According to another aspect of the invention, we provide the use of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a therapeutic agent for the treatment of the aforementioned disorders.
According to a further aspect of the invention, we provide, a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof.
In particular, according to another aspect of the present invention, we provide a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression.
It will be appreciated that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as tricyclic antidepressants (e.g.
amitriptyline, dothiepin, doxepin, trimipramine, butriptyline, clomipramine, desipramine, imipramine, iprindole, lofepramine, nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g. isocarboxazid, phenelzine or tranylcyclopramine) or 5-HT reuptake inhibitors (e.g. fluvoxamine, sertraline, fluoxetine or paroxetine), and/or antiparkinsonian agents such as dopaminergic antiparkinsonian agents (e.g. Ievodopa, preferably in combination with a peripheral decarboxylase inhibitor e.g. benserazide or carbidopa), or a dopamine agonist (e.g. bromocriptine, lysuride or pergolide). It is to be understood that the present invention covers the use of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof in combination with one or more other therapeutic agents.
Thus there is provided in a further or alternative aspect of the present invention a compound of general formula (I) or a physiologically acceptable salt or solvate thereof and an antidepressant agent in the presence of each other in the human or non-human animal body for use in the treatment of the aforementioned disorders.
While it is possible that a compound of general formula (I) may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
The compounds of general formula (I) and their physiologically acceptable salts and solvates may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions comprising at least one compound of general formula (I) or a physiologically acceptable salt or solvate thereof Such compositions may be presented for use in a conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Thus, the compositions according to the invention may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred.
Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxypropyl methylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
The composition according to the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
For administration by inhalation either orally or nasally the compositions according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation the compositions according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
The pharmaceutical formulations according to the invention may also contain other active ingredients such as antimicrobial agents, or preservatives.
The compositions according to the invention may be prepared by mixing the various ingredients using conventional means.
It will be appreciated that the amount of a compound of general formula (I) required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or veterinarian. In general, however, a proposed dose of the compounds of the invention for administration in man is 0.5 to 1000mg, preferably I to 200mg ofthe active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
The compounds of the invention may be prepared by a number of processes as described in the following. In describing the processes which may be used for preparing the compounds of general formula (I) or intermediates useful in the preparation thereof, any of Rl-R9, m and p in the various formulae are as defined in general formula (I) unless otherwise stated.
It will be appreciated that in the following methods for the preparation of compounds of general formula (I), for certain reaction steps it may be necessary to protect various reactive substituents in the starting materials for a particular reaction and subsequently to remove the protecting group. Such protection and subsequent deprotection may be particularly pertinent where R6, R7, R8, and/or R9 in intermediates used to prepare compounds of general formula (I) are hydrogen atoms. Standard protection and deprotection procedures can be employed, for example formation of a phthalimide (in the case of a primary amine), benzyl, trityl, benzyloxycarbonyl or trichloroethoxycarbonyl derivatives. Subsequent removal of the protecting group is achieved by conventional procedures. Thus a phthalimide group may be removed by treatment with hydrazine or a primary amine, for example methylamine.Benzyl or benzyloxycarbonyl groups may be removed by hydrogenolysis in the presence of a catalyst e.g. palladium, and trichloroethoxycarbonyl derivatives may be removed by treatment with zinc dust. Trityl groups may be removed under acidic conditions using standard procedures.
It may also be necessary in some cases to protect carboxylic acid groups (e.g. as esters) or aldehyde or ketone groups (e.g. as acyclic or cyclic acetals or ketals or as thioacetals or thioketals). Subsequent removal of these protecting groups is achieved by conventional procedures. Thus for example alkyl esters may be removed under conditions of acidic or basic hydrolysis, benzyl esters may be removed by hydrogenolysis in the presence of a catalyst e.g. palladium. Acyclic or cyclic acetals or ketals may be removed under conditions of acidic hydrolysis and thioacetals and thioketals may be removed using a mercuric salt.
Hydroxyl groups may also need protection and these may be adequately protected under amenable conditions as their esters or trialkylsilyl, tetrahydropyran and benzyl ethers. Such derivatives may be deprotected by standard procedures.
According to one general process (1A), the compounds of general formula (I) in which X represents the group -CONH-, may be prepared by a carbonylation reaction involving an aniline (II)
(where R4, R5, R8, R9 and p are as defined in general formula (I)) and a halophenyl compound (III)
(where R1, R2 and R3 are as defined in general formula (I) and Y is a bromine or iodine atom or the group -OSO2CF3).
Alternatively, according to the general process (1B), the compounds of general formula (I), in which X represents the group -NHCO-, may be prepared by a carbonylation reaction involving a halophenyl compound (IV)
(where R4, R5, R8, R9 and p are as defined in general formula (I) and Y represents a bromine or iodine atom or the group -OSO2CF3) and an aniline of formula (V)
(where Rl, R2 and R3 are as defined in general formula (I)).
Both reactions take place, for example, in the presence of carbon monoxide using a palladium salt as a catalyst. The reaction is effected in the presence of a suitable base e.g.
a trialkylamine such as triethylamine or tri-n-butylamine and may be conducted in a suitable solvent such as an amide e.g. dimethylformamide or a nitrile e.g. acetonitrile at a temperature within the range of-100C to +1500C.
Suitable palladium salts for the reaction include triarylphosphine palladium (II) salts such as bis(triphenylphosphine)palladium (II) chloride.
According to another general process (2A), the compounds of general formula (I), in which X represents the group -CONH-, may be prepared by reacting an aniline of formula (11) with an activated carboxylic acid derivative of formula (VI)
(where Z is a leaving group).
Alternatively, according to the general process (2B), the compounds of general formula (I), in which X represents the group -NHCO-, may be prepared by reacting an aniline of formula (V) with an activated carboxylic acid derivative of formula (VII)
(where Z is a leaving group).
Suitable activated carboxylic acid derivatives represented in formulae (VI) and (VII) include acyl halides (e.g. acid chlorides) and acid anhydrides including mixed anhydrides.
These activated derivatives may be formed from the corresponding acids of formulae (VIII) or (IX)
respectively, by well known procedures. For example, acid chlorides may be prepared by reaction with phosphorus pentachloride, thionyl chloride or oxalyl chloride and acid anhydrides may be prepared by reaction with an appropriate acid anhydride (e.g.
trifluoroacetic anhydride), an acid chloride (e.g. acetyl chloride), an alkyl or aralkyl haloformate (e.g. ethyl or benzyl chloroformate) or methanesulphonyl chloride.
Activated carboxylic acid derivatives of formulae (VI) and (VII) may also be prepared in situ by the reaction of the corresponding acids of formulae (VIII) and (IX), respectively, with a coupling reagent such as 1,1 '-carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazide.
The conditions under which the activated carboxylic acid derivatives of formulae (VI) and (VII) are formed and subsequently reacted with the anilines of formulae (II) and (V), respectively, will depend upon the nature of the activated derivative. However, in general the reaction between the compounds (II) and (VI), or (V) and (VII), may be carried out in a non-aqueous medium such as, for example, dimethylformamide, tetrahydrofuran, acetonitrile or a halohydrocarbon such as dichloromethane at a temperature within the range -250C to +1200C. The reaction may optionally be carried out in the presence of a base such as triethylamine or pyridine and the base may also be used as the solvent for reaction.
Where acid chlorides are used, the reaction may be carried out using the Schotten-Baumann technique in the presence of a suitable base, for example, aqueous sodium hydroxide, conveniently at a temperature between 0 C and 100"C, for example, room temperature.
According to another general process (3A), the compounds of general formula (I) may be prepared by treating a compound of formula (Xa)
(where Y represents a bromine or iodine atom or the group -OSO2CF3) with a compound of formula (via)
or an ester, an anhydride or a salt (e.g. lithium) thereof.
Alternatively, according to the general process (3B), the compounds of general formula (I) may be prepared by treating a compound of formula (Xb)
or an ester, an anhydride or a salt (e.g. lithium) thereof, with a compound of formula (XIb)
where Y represents a bromine or iodine atom or the group -OSO2CF3.
Both reactions may be effected in the presence of a transition metal catalyst such as (Ph3P)4Pd (where Ph represents phenyl) in a suitable solvent such as an ether (e.g.
I ,2-dimethoxyethane or tetrahydrofuran) in the presence or absence of water, or an aromatic hydrocarbon (e.g. benzene). The reaction is preferably carried out in the presence of a base such as an alkali or alkaline earth metal carbonate (e.g. sodium carbonate) at a suitable temperature up to reflux.
According to another general process (4), the compounds of general formula (I) may be prepared by reducing a compound of formula (XII)
(where W represents a group convertible to the group -(CH9pNR8R9 under reducing conditions).
Examples of the type of group W which may be converted into the group -(CH2)pNR8R9 are: -(CH)p ,CN, -(CH2)p lCHO, and when p is 3 -C=CCN, -CH=CHCN, -CH=CHCHO, -CH=CHCH2NR8R9 or-C=CCH2NR8R9. When W contains an aldehyde as defined above, the conversion is carried out in the presence of an appropriate amine of formula NHR8R9. When W contains a nitrile as defined above, the conversion may be carried out in the presence of an amine of formula NHR8R9, with the proviso that R8 and R9 do not both represent a hydrogen atom, in order to obtain a secondary or tertiary amine of general formula (I).
The reaction may be effected using an alkali or alkaline earth metal borohydride, e.g.
sodium borohydride, or hydrogen and a metal catalyst such as palladium or platinum or oxides thereof The reaction may be carried out at a temperature between 0 C and 100"C, conveniently at room temperature, and preferably in a solvent.
Suitable solvents for chemical reduction include ethers e.g. tetrahydrofilran, or alcohols e.g. ethanol. Suitable solvents for catalytic reduction include alcohols e.g.
ethanol, ethers e.g. dioxan, amides e.g. dimethylformamide or a mixture of solvents e.g.
ethanol/dimethylformamide.
According to another general process (5), the compounds of general formula (I) in which X represents either of the groups -NHCH2- or -CH2NH- may be prepared by reduction of the corresponding compounds of general formula (I) in which X represents the groups -NHCO- or -CONH-, respectively, except that the reaction cannot be used to prepare compounds in which R2 and/or R3 represents another group reducible under the reaction conditions, for example, CONR6R', CO2H, COR6, CN, NO2 or ~(cH2)moc(o)cl4alkyl.
The reduction may be effected using a suitable metal hydride such as lithium aluminium hydride in a solvent e.g. an ether (such as tetrahydrofuran) at a temperature in the range of-10 C to +100"C.
According to another general process (6A), the compound of general formula (I) in which X represents the group -NHCH2- may be prepared by reacting an aniline of formula (V) with an aldehyde of formula (XXIII)
under reducing conditions.
Alternatively, according to general process (6B), the compounds of general formula (I) in which X represents the group -CH2NH- may be prepared by reacting an aniline of formula (II) with an aldehyde of formula (XXIV)
under reducing conditions.
Both reactions may conveniently take place in the presence of a solvent such as an alcohol e.g. methanol or ethanol using for example a hydride reducing agent such as an alkali or alkaline earth metal borohydride (e.g. sodium borohydride or sodium cyanoborohydride). The reactions may be carried out at a temperature in the range from 0 to 600C, conveniently at room temperature.
Compounds of general formula (I) in which R2, R3, R4 and R5 have a particular meaning may be converted into another compound of the invention by standard methods of interconversion.
For instance, when R2 and/or R3 represents a hydroxy or alkoxy group and/or when R4 and/or R5 represents hydroxy or alkoxy these groups may be interchanged by standard methods of O-alkylation or 0-dealkylation. Thus, for example, a compound in which R4 represents hydroxy may be prepared by treating a corresponding compound in which R4 represents methoxy with a reagent system capable of removing the methyl group e.g. a mercaptide such as sodium ethylmercaptide in a solvent such as dimethylformamide, lithium iodide in collidine, boron tribromide in a halohydrocarbon solvent e.g. methylene chloride or molten pyridine hydrochloride.
When R2 represents a hydroxymethyl group this may be converted by oxidation into a corresponding compound of general formula (I) in which R2 represents a group COR6 (where R6 is a hydrogen atom) or CO2H. Thus, for example, oxidation may be effected using a suitable oxidising agent such as a manganese oxidising agent (e.g. manganese dioxide) in a solvent such as an ether (e.g. 1,4-dioxan) at a suitable temperature up to reflux, a chromium oxidising agent (e.g. Jones reagent) or pyridinium dichromate in a suitable solvent such as a halohydrocarbon (e.g. methylene chloride).
When R2 represents an aldehyde group this may be converted by oxidation into a corresponding compound of general formula (I) in which R2 represents a group CO2H.
Thus, for example, oxidation may be effected using a suitable oxidising agent such as a source of silver (I) (e.g. silver nitrate) in aqueous alkali optionally in the presence of a cosolvent such as an alcohol (e.g. methanol).
Intermediates of formula (II) may be prepared by reduction of a compound of formula (XIII)
(where W is as defined in formula (XII)) under the reducing conditions described for process (4).
Compounds of formula (XIII) may be prepared by reduction of the corresponding nitro compounds of formula (XIV)
Suitable reducing conditions include, for example, catalytic hydrogenation using a metal catalyst such as palladium oxide on- a support such as charcoal, optionally in a solvent such as an alcohol (e.g. ethanol) or an ether (e.g. tetrahydrofuran). Under such conditions, the group W may also be reduced and hence the intermediates of formula (II) may be prepared directly from the compounds of formula (XIV) without prior isolation of the compounds of formula (XIII).
The nitro compounds of formula (XIV) may be prepared from the corresponding halo compounds of formula (XV)
(where Hal is bromine or iodine) using standard methodology.
Intermediates of formula (IV) may be prepared by the following reaction sequence:
Step (a) is carried out using suitable halogenating conditions, for example, when Hal represents iodine the iodine atom may be introduced using iodine monochloride in a solvent such as methylene chloride; step (b) is carried out under standard brominating conditions such as using phosphorous tribromide in a halohydrocarbon solvent or using carbon tetrabromide in the presence of triphenylphosphine; and step (c) is carried out using an amine R8R9NH in a suitable solvent such as ethanol, preferably in the presence of a base; with the proviso that either R4 or R5 is a directing group (i.e. fluorine, chlorine, hydroxy, C,4alkoxy or C1alkyl) in a position either ortho or para to the group -(CH2)nOH.
Intermediates of formula (V) may be prepared by reaction of a compound of formula (XIa) or (XIb) with a compound of formula (XVIa) or (XVIb), respectively,
according to the method of general process (3).
Intermediates of formula (II) or (V) may also be prepared from the corresponding carboxylic acid of formula (IX) or (Vm), respectively, using conventional procedures (e.g. by Curtius rearrangement).
Intermediates of formula (Xa) and (Xb), in which X is -CONH-, may be prepared by reaction of a compound of formula (11) with a compound of formula (XVIIa) or (XVIIb), respectively,
according to the method of general process (2).
Intermediates of formulae (Xa) and (Xb), in which X is -NHCO-, may be prepared by reaction of a compound of formula (VII) with a compound of formula (XVIa) or (xVIb), respectively, according to the method of general process (2).
Intermediates of formula (XII), in which X is -CONH-, may be prepared by reaction of a compound of formula (XIII) with a compound of either formula (III) or (VI) according to the method of general process (1) or (2), respectively.
Alternatively, intermediates of formula (XII), in which W is -CH=CHCHO, -CH=CHCN, -CH=CHCH,NR8R9 or -C=CCH2NR8R9, may be prepared from a compound of formula (XVIII)
(wherein Hal is the only bromine or iodine atom in the molecule) by reaction with an alkene: H:2C=CHCHO, H2C=CHCH2NR8R9 or EI2C=CHCN; or an alkyne: HC=CCH2NR8R9.
The reaction may be effected in the presence of a palladium reagent and preferably in the presence of a base. The palladium reagent may be, for example, a palladium salt derived from an organic acid (e.g. an acetate) or derived from an inorganic acid (e.g. a chloride or bromide), a palladium complex such as a triarylphosphine palladium complex (e.g. triphenylphosphine or tri(2-methylphenyl)phosphine palladium complex), or a finely divided palladium metal such as palladium on charcoal. The triarylphosphine palladium complex may be generated in situ by reacting a palladium salt (e.g. palladium acetate) with the appropriate triarylphosphine.
Suitable bases include tertiary amines (e.g. triethylamine or tri-n-butylamine) or alkali metal (e.g. sodium or potassium) carbonates, bicarbonates and acetates.
The reaction may be effected in the presence or absence of a solvent. Suitable solvents include nitriles (e.g. acetonitrile), amides (e.g. dimethylformamide, N-methylpyrrolidinone) and water. The reaction may conveniently be carried out at a temperature between room temperature and 200"C, preferably between 50"C and 160"C. Compounds of formula (XVIII) may be prepared by the reaction of a compound of formula (V) or (VI) with a compound of formula (XIX) or (XX), respectively,
according to the method of general process (2).
Alternatively, intermediates of formula (XII) in which W is -(CH2)p,CN or -(CH8) > lCHO may be prepared by the reaction of a compound of formula (III) or (V) with a compound of formula (XXI) or (XXII), respectively,
(wherein W' represents -(CH2)plCN or -(CH2)plCHO), according to the method of general process (1).
Intermediates of formulae (XXI) and (XXII) in which W' contains a nitrile group may be prepared from the cdrresponding halo (e.g. bromo) compound using standard methodology.
It will be appreciated that, where necessary, a halogen substituent may be converted into a carboxyl group using standard methodology thus, for example, compounds of formula (VIII) or (IX) may be prepared from an intermediate of formula (III) or (IV), respectively, by lithiation using, for example, n-butyl lithium followed by quenching with carbon dioxide.
The boronic acid intermediates of formulae (Xb), (XIa), (XVIb) and (XVIIb) or their esters, anhydrides or salts may be used in situ under the conditions described above for general process (3).
The aldehydes of formula (XXIII) or (XXIV) may be prepared from an intermediate of formula (IV) or (III), respectively, by lithiation using, for example, n-butyl lithium followed by formylation using, for example, dimethylformamide.
Intermediates of formulae (III), (XIa), (XIb), (XV), (XVIa), (XVIb), (XVIIa), (XVIIb), (XIX) and (XX) are either known compounds or may be prepared by standard methodology or methods analogous to those described herein.
Physiologically acceptable acid addition salts of the compounds of general formula (I) may be prepared by treating the corresponding free base with a suitable acid using conventional methods. Thus, for example, a generally convenient method of forming the acid addition salts is to mix appropriate quantities of the free base and the acid in an appropriate solvent e.g. an alcohol such as ethanol or an ester such as ethyl acetate.
Inorganic basic salts of compounds of general formula (I) may be prepared by treating the corresponding acid of general formula.(I) (i.e. a compound of general formula (I) in which R2 and/or R3 represents the group CO2H) with a suitable base using conventional methods.
Salts of compounds of general formula (I) may also be converted into different physiologically acceptable salts of compounds of general formula (I) using conventional methods.
The invention is illustrated but not limited by the following examples in which temperatures are in OC Thin layer chromatography (T.l.c.) was carried out on silica plates. 'Dried' refers to drying using sodium sulphate or magnesium sulphate unless otherwise stated. Flash column chromatography (FCC) was carried out on silica gel (Merck 9385) unless otherwise stated. Short path column chromatography (SPC) was carried out on silica gel (Merck 7747) unless otherwise stated.
The following solvent systems were used: System A - dichloromethane:ethanol:0.88 ammonia; System B - dichloromethane:ethanol; System C - hexane:diethyl ether; System D - dichloromethane:hexane; System E - ethyl acetate:ethanol:triethylamine; System F dichloromethane: methanol :0.88 ammonia.
The following abbreviations are used: ether - diethyl ether; THF - tetrahydroffiran; DME - 1,2-dimethoxyethane; DMF - dimethylformamide.
Intermediate 1 (E)-3-(2-Cvanoethenvl)A-methoxybenzoic acid mixture with (Z)isomer (2:1) A stirred mixture of 3-iodo-4-methoxybenzoic acid (18.06g), 2-propenenitrile (5.4ml), triethylamine (22.5ml), palladium (II) acetate (300mg), and acetonitrile (30ml) were heated at 1000 in an autoclave. After 36h, the reaction was incomplete. Half of the reaction mixture was removed, treated with palladium (lI) acetate (300mg) and this mixture heated at 1000 for 1 8h in an autoclave. The cooled reaction mixture was filtered, evaporated, and the residue treated with water (100ml), aqueous saturated sodium bicarbonate (150ml), and aqueous 2M-sodium hydroxide (50ml). The mixture was extracted with ethyl acetate (100ml) and the organic extract discarded.The aqueous extract was acidified to pH 1 by the addition of aqueous 2M-hydrochloric acid, extracted with ethyl acetate and the combined, dried extracts were evaporated. The residue was crystallised from ethanol to give the title compound (3.37g) as cream-coloured microcrystals, T.l.c. (ether:acetic acid 100:1) Rf 0.58.The mother liquors from the above crystallisation were concentrated and crystallised to give a second crop of the title compound (1.15g). Evaporation of the mother liquors afforded a further quantity of the title compound (1.15g).
Intermediate 2 (E)-3 -(2-Cvanoethenvl)A-methoxy-N-F4-(4-pvridinvl)phenvlibenzarnide A suspension of Intermediate 1 (3.50g) in THE (35ml) was treated with triethylamine (4.8ml) at 0-50 under nitrogen, with stirring, and after lOmin methanesulphonyl chloride (1.33ml) was added dropwise over lOmin. After lh, THF (75ml) was added, followed by solid 4-(4-pyridinyl)benzeneamine (2.93g) and the mixture stirred for 1h at 0-5 , then at room temperature for 64h. The mixture was evaporated, treated with aqueous saturated sodium bicarbonate (200ml), and extracted with ethyl acetate (5x200ml).The combined, dried organic extracts were evaporated onto silica gel (Merck 7734, 30g) and the resultant solid purified by SPC eluting with ethyl acetate:triethylamine (99:1) to give 4-(4-pyridinyl)benzenamine, followed by a solid which crystallised from acetonitrile to give the title compound (1.87g) as fine cream-coloured crystals.
Analysis Found: C,74.35;H,4.9;N,11.85.
C22H17NO2 requires C,74.35;H,4.8;N,1 1.8%.
Intermediate 3 (B) 3 -(2-Cvanoethenvl)A-metho::y-N-[4-(3-pyridinyl)phenylibenzamide Methanesulphonyl chloride (2.0ml) was added, under nitrogen to an ice-cooled, stirred solution of Intermediate 1 (5.0g) and triethylamine (7.6ml) in a mixture of dry DMF (15mi) and dry THF (50ml). The brown suspension was stirred at 00 for 1h and then a solution of 4-(3-pyridinyl)benzeneamine (4.0g) in dry DMF (15ml) was added over 0.25h.
Stirring was continued at 00 for lh, at room temperature for 46.5h and finally at reflux for 69h. The resultant brown suspension was left to stand at room temperature for 5 days and was then poured into 2N hydrochloric acid (500ml). The precipitated solid was filtered off, washed with water (3x100ml) and dried in vacuo at 600. The resultant brown solid (6.3g) was stirred in 2N sodium carbonate (70ml) for 2h, filtered, washed with water (3x25ml) and dried. The resultant solid was stirred with refluxing absolute ethanol (150my), filtered, and allowed to cool. The crystallised solid was filtered off, washed with absolute ethanol (2x25ml) and dried in vacuo at 600 to give the title compound.(1 .04g) as a fawn solid, m.p. 232 -233.5 .
Intermediate 4 4-(2-Pvridinvl)benzeneamine A solution of N-(phenylmethyl)-N-[4-(2-pyridinyl)phenyl]benzenemethanamine (5.65 6g) and 2N hydrochloric acid (16ml) in absolute ethanol (400ml) was hydrogenated at room temperature and pressure, using 10% pre-reduced palladium oxide on carbon (1.0g of 50% w/w wet material) as catalyst. After 21 h, the reaction mixture was evaporated to dryness and then, transferred under nitrogen, shaken with 8% aqueous sodium bicarbonate (300ml) and ethyl acetate (300ml), prior to filtration. The aqueous layer in the filtrate was separated and further extracted with ethyl acetate (2x100ml). The combined extracts were dried and evaporated to dryness to give a pale brown crystalline solid.A solution of this solid in toluene was filtered slowly through a pad of Merck 9385 silica gel, prepared and eluted with methanol:dichloromethane (1:9). The filtrate was evaporated to dryness to give a pale brown oil. A solution of this oil in toluene (50ml) was filtered and evaporated to dryness again. A solution of the residue in toluene (15ml) was diluted slowly with hexane (4ml) and then left to crystallise after seeding. After crystallisation was complete, more hexane (4ml) was slowly added. The resulting crystals were washed with toluene:hexane (1:1), followed by hexane and dried to give the title compound (1.61 lg) as yellow buff crystals.
T.l.c. ethyl acetate:hexane (1:1) Rf0.19.
Intermediate 5 3-[3-(Dimethvlamino!propyl]4-methoxybenzoic acid A solution of Intermediate 1 (2.00g) in a mixture of 33% ethanolic dimethylamine (60ml) and DMF (10ml) was hydrogenated at room temperature and pressure over 10% pre-reduced palladium oxide on carbon (2.00g) in ethanol (10ml) for 2.25h. The catalyst was filtered off; replaced with fresh catalyst (2.0g) and hydrogenation continued for a further 19.25h. The catalyst was filtered off, the filtrate concentrated in vacuo. and the residual white oil was triturated with hexane (3x200ml). The resultant white solid was filtered off and dried. A portion of this material (1.20g) was crystallised from acetonitrile (65ml) to give the title compound (0.84g) as white crystals m.p. 140-141.50.
Intermediate 6 \4-Bis(phenvlmethvl)aminoiphenvliboronic acid n-Butyllithium (1.60M in hexane, 98ml) was added dropwise under nitrogen to a stirred solution of N-(4-bromophenyl)-N-(phenylmethyl)benzenemethanamine (50.0g) in dry THF (500ml) at -67 to -650 over 30 min. After Ih, triisopropylborate (57ml) was added dropwise over 20min and the mixture allowed to stir at 230 for 16h. Water (80ml) was added, the mixture was evaporated, and then co-evaporated with ethanol (2x100ml). The residue was treated with dichloromethane (200ml) and the slurry purified by FCC eluting with System B (1:0 to 97:3) to give the title compound (5.6g) as fine cream-coloured crystals.
T.l.c. System B (50:1)Rf0.16.
Intermediate 7 6-4-(Bis(phenyimethvi)amino1phenvl1-3 -pyridinecarboxvlic acid A catalytic quantity of tetrakis(triphenylphosphine)palladium (0) (876mg) was added to a degassed mixture of 6-chloro-3-pyridinecarboxylic acid (3.00g), Intermediate 6 (6.00g), and sodium carbonate (3.024g) in DME (75ml) and water (36ml). The reaction mixture was then heated at reflux for 24h, under nitrogen. The solvent was evaporated and aqueous sodium bicarbonate (1M; 250ml) was added. The resulting mixture was extracted with dichloromethane (5x200ml). The combined extracts were dried, filtered, and evaporated to give a yellow solid (12.0g). The solid was purified by FCC eluting with dichloromethane:glacial acetic acid (19:1) to give the title compound (5.908g) as a yellow solid.
T.l.c. dichloromethane:glacial acetic acid (9: 1) Rf 0.20.
Intermediate 8 Methyl 4-[4- [Bis(phenylmethyl)aminol phenvll-2-pvridinecarboxylate A catalytic quantity of tetrakis(triphenylphosphine)palladium (0) (476mg) was added to a degassed mixture of 4-bromo-2-pyridinecarboxylic acid (2.089g), Intermediate 6 (3.284g), and sodium carbonate (1.64g) in DME (50ml) and water (25ml). The reaction mixture was then heated at reflux for 18h. The reaction mixture was poured into aqueous sodium bicarbonate (ism; 200ml) and extracted with dichloromethane (Sxl50ml). The combined extracts were dried, filtered and evaporated to give a yellow gum (5.0g). The gum was dissolved in methanol (180ml) and concentrated sulphuric acid (20ml) was carefully added.The resulting solution was heated at reflux for 1 8h then the solvent was evaporated and the residue was carefully basified with aqueous sodium bicarbonate (1M).
The aqueous phase was extracted with dichloromethane (4x150ml) and the combined extracts were dried, filtered and evaporated to give a brown gum (4.3g). The gum was purified by FCC eluting with dichloromethane:methanol (99:1) to give the title compound (3.lg) as a yellow gum.
T.l.c. dichloromethane:methanol (97:3) Rf 0.49.
Intermediate 9 6-(4-Aminophenvl)-3 -pyridinecarboxylic acid A solution of Intermediate 7 (5.88g) in dry DMF (400ml) and hydrochloric acid (2N; 14.9ml) was hydrogenated over 5% palladium on carbon (5.0g) for 24h. The catalyst was filtered off, washed with methanol, and the filtrate evaporated. The residue was purified by FCC eluting initially with dichloromethane:methanol:glacial acetic acid (94:5:1) then (89:10:1) and finally neat methanol. The residue (4.0g) was further purified by FCC eluting with System A (25:8:1) and then (10:8:1) to give a yellow solid (2.80g).
The residue was dissolved in aqueous sodium hydroxide (2N), evaporated to dryness and purified by FCC eluting with System A (10:8:1) to give a yellow solid (938mg). The solid (938mg) was dissolved in aqueous sodium hydroxide (2N; 10ml), the solvent was evaporated and the residue was purified by FCC eluting with System A (10:8:1) to give the title compound (753mg) as a yellow solid.
T.l.c. System A (10:8:1)Rf0.38.
Intermediate 10 Methvl 4-(4-aminophenyl)-2-pvridinecarboxvlate dihvdrochloride.
A solution of Intermediate 8 (3.0g) in methanol (50ml) was treated with excess ethereal hydrogen chloride and the solvent was evaporated. A solution of the residue in methanol (100ml) was hydrogenated over 5% palladium on carbon catalyst (2.3g), for 3h. The catalyst was filtered off and thoroughly washed with methanol. The filtrate was evaporated to give the title compound (2. 125g) as a yellow crystalline solid.
T.l.c. dichloromethane:methanol (97:3), Rf 0.39 (free base).
Intermediate 11 4-(4-Aminophenvn-2-pvridinecarboxamide A solution of Intermediate 10 (658mg) in methanol (10ml) and 0.88 ammonia solution (20ml) was stirred at room temperature for 18h. The resulting mixture was dissolved in methanol and purified by FCC eluting with dichloromethane:methanol (19:1) to give the title compound (333mg) as an off-white solid m.p. 215-2160.
Intermediate 12 4-Methoxy-3-[3-[methyl(phenylmethyl)amino]-1-propynyl]benzoic acid hvdrochloride A mixture of 3-iodo-4-methoxybenzoic acid (20g), N-methyl-N-2-propynylbenzene methanamine (17.2g, 18ml), copper (I) iodide (0.72g), bis(triphenylphosphine) palladium (11) chloride (1.4g), triethylamine (160ml) and DMF (80ml) was stirred at reflux under nitrogen for 2.5h at 75o When cool the mixture was evaporated. The residue was purified by FCC eluting with System A (670:300:30) to give the free base of the title compound (7.64g) as a dark brown viscous oil, as well as a further quantity (14.8g).A portion of the free base (1.0g) was converted to the hydrochloride, by addition of ethereal hydrogen chloride to a solution of the free base in ethanol, until the mixture became acidic (pH 4.0). The precipitate was filtered off and dried to yield a pale brown, powdery solid (0.58g). The second sample of free base, was converted in a similar fashion to afford the title compound (12.7g). m.p. 274-2760C.
Intermediate 13 4-Methoxv-3 -[3 -[methyl(phenylmethyl)aminoi 1 -propynvli-N-[4-(4-pvridinyl) Dhenvllbenzamide Intermediate 12 (6.0g) was treated with thionyl chloride (29ml) at room temperature for 15min and then evaporated. The residue was co-evaporated with toluene (2x20ml) to dryness and then added in portions to a stirred solution of 4-(4-pyridinyl)yl)benzeneamine (1.97g) in dry pyridine (40ml) at OOC, under nitrogen, over 30min. After 30min at O"C, the solution was stirred at 230 for 45min, then at 800 for 30min. Aqueous sodium bicarbonate solution (50ml) was added and the mixture evaporated.The residue was adsorbed from ethanol (50ml) onto silica gel (Merck 7734,25g) and purified by SPC eluting with System A (967:300:3 to 670:300:30) to afford three fractions containing the desired compound. The third and final fraction to be eluted yielded the title compound as a yellow orange powdery solid (287mg).
Analysis Found: C,77.0; H,5.9; N,8.97.
C30EI27N302.0.248 H2O requires C,77.3; H,5.95; N,9.0%.
Water Assay Found 0.96% wlw H2O -- 0.248mol H2o.
Intermediate 14 5-(3-(Dimethvlamino)-1 propvnvll-2-hvdroxvbenzoic acid A mixture of 2-hydroxy-5 -iodobenzoic acid (10. or), N,N-dimethyl-2-propynamine (3.65g), diethylamine (50ml), bis(triphenylphosphine)palladium (11) chloride (0.5g) and copper (I) iodide (50mg) was stirred under nitrogen for 18h and evaporated. The residue was partitioned between phosphate buffer (pH 6.5; 150ml) and dichloroinethane (3 x 100ml) and the dried organic phase was evaporated to leave an orange gum (2.3g). The inorganic phase was saturated with sodium chloride and extracted with dichloromethane (5 x 100ml). The dried extract was evaporated to leave the diethylamine salt of the desired acid.The salt was dissolved in sodium hydroxide (2N) and diethylamine was removed by azeotroping with toluene (100ml). The residual aqueous layer was neutralised with hydrochloric acid, saturated with sodium chloride and extracted with dichloromethane (4 x 100ml). The dried extract was evaporated to leave an orange solid which was triturated with boiling isopropanol to leave the title compound as a white powder (1.2g) m.p. 193"(dex).
Similarly prepared was : Intermediate 15 Methyl 5-[3-(dimethylamino)l-prnpvnvl}-2-methoxybenzoate as an orange gum (4.5g) T.l.c. ethyl acetate, RfO.15.
From methyl 5-iodo-2-methoxybenzoate (14.0g) and N,N-dimethyl-2-propynamine (5.0g)) in the presence of diisopropylamine (25ml) instead of diethylamine. Purification by FCC eluting with System A (1:1) followed by ethyl acetate:triethylamine (99:1) afforded the title compound.
Intermediate 16 5- r3 -(Dimethvlamino)propvl]-2-hvdroxybenzoic acid hvdrochloride A solution of Intermediate 14 (1.2g) in methanol (30ml) and hydrochloric acid (2N;10ml) was hydrogenated over 10% palladium on charcoal (400mg) for 16h. The resulting suspension was filtered and evaporated. The resulting solid was found to contain large amounts of alkene and was resubmitted to hydrogenation for 18h. The resulting suspension was filtered and evaporated to give the title compound as a yellow solid (1.4g).
Similarly prepared was Intermediate 17 Methvl 5-[3 -(dimethvlamino)propvl]-2-methoxybenzoate hvdrochloride as a yellow solid (8.0g), m.p. 89-920C.
From Intermediate 15 (7.5g).
Intermediate 18 5-[3 -(Dimethvlamino)propvl]-2-methoxybenzoic acid. hvdrochloride A solution of Intermediate 17 (7.5g) in methanol (40ml) and sodium hydroxide solution (5N;25ml) was stirred at room temperature for 18h. The solution was acidified with hydrochloric acid (2N) and evaporated to dryness. The mixture was treated with ethanol (3 x 100ml) and re-evaporated. The resulting semi-solid was treated with ethanol (70ml) filtered and evaporated to give the title compound as a hygroscopic foam (6.7g).
n.m.r. 1.99 6 (2H,m), 2.65 5 (2H,t), 2.84 5 (6H,s), 3.08 6 (2H,m), 3.83 6 (3H,s), 7.0 6 (1H,d), 7.28 5 (lH,dd), 7.48 6(1H,d).
Intermediate 19 5-Bromo-a-methvI-2-Pvridinemethanol Methylmagensium bromide (1.5M solution in THE:toluene (25:75), 8.3ml) was added dropwise over 12 min to a stirred solution of 5-bromo-2-pyridinecarboxaldehyde (2. 10g) in dry THF (22ml) at -50 to -700 under nitrogen. After 5 min the solution was allowed to reach 230 over 40 min by removing the cooling bath. The solution was poured into aqueous saturated ammonium chloride (SOml), extracted with ethyl acetate (2 x 80ml), and the combined, dried organic extracts were evaporated. The residual oil was purified by FCC eluting with ethyl acetate:hexane (1:3) to give the title compound as a pale yellow oil (1.99g).
Analysis found: C,41.4; H,4.0; N,7.0; Br,39.2 C,H8BrNO requires C,41.6; H,4.0; N,6.9; Br,39.55% Intermediate 20 (E!-3-(2-Cyanoethenvl!benzoic acid. mixture with (Z) isomer (68:32) A stirred mixture of 3-iodobenzoic acid (10.00g), palladium (II) acetate (0.72g), triethylamine (14.0ml), 2-propenenitrile (3.3ml) and acetonitrile (19ml) was heated at 900 for 17h in an autoclave. The mixture was filtered, evaporated, and treated with a mixture of aqueous saturated sodium bicarbonate (150ml) and brine (150ml). The mixture was extracted with ethyl acetate (2x100ml), the organic extracts were discarded and the aqueous phase was filtered. The filtrate was acidified with aqueous SM-hydrochloric acid, extracted with ethyl acetate (4x150ml), and the combined, dried organic extracts were evaporated. The residue was crystallised from acetonitrile to give the title compound (1.25g) as a cream-coloured powder.
Analysis Found: C,69.4; H,4.l; N,8.1.
C,oH7NO2 requires: C,69.2; H,4.0; N,7.8% Concentration of the mother liquors afforded a further crop of the title compound (E!:(Z) (37:63) (2.04g).
Intermediate 21 (E)-3 -(2-Cvanoethenyl)-N-[(4-pvridinyl)phenyl]benzamide A stirred suspension of Intermediate 20 (2.5g) in DMF (15ml) and THF (15ml) was treated under nitrogen with triethylamine (4.0ml) and followed at -5 to OOC by the addition of methanesulphonyl chloride (1.12my). After 1.5h, 4-(4-pyridinyl) benzeneamine (2.45g) was added and stirring continued for 1h at -10 to -150C, for 16h at 23"C, then at reflux for 1 .5h. The mixture was evaporated, the residue treated with aqueous saturated sodium bicarbonate (100ml) and the solid filtered off.This was crystallised from ethanol to give the title compound (1.22g) as a brown solid, Tic ether:ethanol:triethylamine (93:5:2) Rf 0.11.
Intermediate 22 3 -[3 -(Dimethvlamino)propvllA-methoxybenzoyl chloride hydrochloride Thionyl chloride (3.5ml, 5.7g) and dry DMF (2 drops) was added to Intermediate 5 (1.5g) and the mixture heated on a steam bath for 5 min. The excess thionyl chloride was evaporated under reduced pressure whilst heating and the solid residue which formed re-evaporated with dry toluene (15ml x 2) then dried in vacuo to give the title compound as a buff powder (1.88g).
Intermediate 23 N-(4-Bromophenvl)-3 -[3-(dimethylamino-propyl]-4-methoxybenzamide Intermediate 22 (5.84g) was treated with 4-bromobenzeneamine (3.4g) and dry pyridine (20ml) and heated at reflux under nitrogen for 1.5h. When cool, water (20ml) was added, followed by solid sodium carbonate (lug) and the solution evaporated in vacuo affording a grey-white residue which was washed with water, filtered, air-dried, and recrystallised from ethyl acetate to give the title compound as a cream-coloured solid (3.93g) m.p.
145.5-146"C. Evaporation of the filtrate yielded further solid, which was re-crystallised from ethyl acetate to give a second crop of crystals (1.79g) m.p. 145.5-146"C.
Intermediate 24 [4-[[3-[3-(Dimethylamino)propyl]-4-methoxybenzoyl]amino]phenyl]boronic acid A stirred solution of Intermediate 23 (3g) in dry THF (125ml), under nitrogen at -780C was treated dropwise with n-butyllithium (10.lml of a 1.52M solution in hexane). After ih, triisopropylborate (4.4ml) was added dropwise at -780C, and the reaction was allowed to stir for 30min. The cooling bath was then removed, and the reaction was stirred under nitrogen at 230C for 17h. Hydrochloric acid (2N,4ml) and water (50ml) were added and the reaction mixture evaporated to dryness. Purification by FCC eluting with System A (75:23:2) gave the title compound as a cream-coloured foam (1.14g).
T.l.c. System A (60:40:4) Rf 0.26 Intermediate 25 4-Iodo-3-methvlpvridine hvdrochloride A solution of 4-amino-3-methylpyridine (6.00g) and iodoform (65.64g) in dry THF (180 mi) was treated with t-butyl nitrite (25 ml) and stirred at reflux under nitrogen for 6h.
Further t-butyl nitrite (10ml) was added after 3 hours and again after a further 4h and heating continued for 4h. When cool, ethanol (200 ml) was added, and the mixture warmed to dissolve the solids. The solution was evaporated onto silica gel (Merck 7734, 400 ml) and purified by FCC. Elution with ether:hexane:triethylamine (5:94:1) afforded the free base of the title compound (5.37g). A mixture of the free base (5.37g) in ether (130 ml) was filtered and the filtrate acidified to pHi by the addition of ethereal hydrogen chloride. The resultant precipitate was collected to give the title compound as light brown crystals (5.29g).
T.l.c. ether:hexane:triethylamine (49:50:1) Rf. 0.21 Intermediate 26 N-[4-(3-methvlA-pvridinvl)phenvlj-N-(phenvlmethvl) benzenemethanamine A stirred mixture of Intermediate 25 (2.01g) and Intermediate 6 (2.50g) in hot DME (70 ml) was treated with a hot solution of sodium carbonate (2.5 it) in water (35 ml), followed by tetrakis(triphenylphosphine)palladium (0) and the mixture heated at reflux under nitrogen for 4h. The mixture was evaporated and the residue stirred in hot ethanol (200 ml). The mixture was adsorbed onto silica gel (Merck 7734, 60 ml) and purified by SPC.Gradient elution with ethyl acetate:hexane:triethylamine (25:74:1 to 635:64:1) afforded a solid which crystallised from ethyl acetate (10 ml) to give the title compound as light orange/yellow crystals (1.56g), m.p. 135-136.50.
Intermediate 27 4-(3 -MethvlA-pvridinvi)benzenamine A solution of Intermediate 26 (1.58g) in DMF (25ml) and ethanol (10ml) was added to a pre-reduced suspension of dry 10% palladium oxide on carbon (1.00g) in ethanol (25ml) and the stirred mixture hydrogenated at room temperature and pressure. After 5 days the catalyst was filtered off, the filtrate evaporated, and the residue adsorbed from ethanol (100ml) onto silica gel (Merck 7734, 16ml). Purification by SPC eluting with ethyl acetate:hexane:triethylamine (35:63:2) afforded firstly recovered starting material followed by the title compound as a solid (608mg). A portion of this (530mg) was crystallised from hot ethyl acetate (6ml) to give the title compound (178mg) as off-white crystals.
Analysis found: C,77.8; H,6.5; N, 14.9 C12H12N2 requires: C,78.2; H,6.6; N.15.2% Intermediate 28 (E)-3-(2-Methoxy-5-nitrophenyl)-2-propenenitrile mixture with (Z) (I: 1) A solution of 2-iodo-1-methoxy-4-nitrobenzene (500g), acrylonitrile (0. 14ml), triethylamine (0.62ml) and acetonitrile (1.2ml), was treated with palladium (II) acetate (28mg) and heated at 1100 for 16h. When cool the mixture was poured into aqueous saturated sodium bicarbonate (30ml), extracted into ethyl acetate (3x30ml), and the combined, dried organic extracts were evaporated and purified by SPC eluting with System C (4: 1 to 7:3) to give the title compound (128mg) as white crystals.
T.l.c. System C (2:1) Rf0.11 Intermediate 29 5 -Amino-2-methoxv-N,N-dimethvlbenzenepropanamine A solution of Intermediate 28 (4.33g) in dry THF (80ml) and ethanolic dimethylamine (33% w/v, 80ml) was added to a suspension of 10% pre-reduced palladium oxide on carbon (2.00g) in ethanol (30ml) and the stirred mixture hydrogenated at room temperature and pressure for 5h. The catalyst was filtered off and the filtrate evaporated.
The catalyst was replenished as above and the stirred mixture hydrogenated at room temperature and pressure for 16h. The catalyst was once again replenished as above and hydrogenation continued for 70h. The catalyst was filtered off and the filtrate was purified by SPC with gradient elution using System A (945:50:5 to 12:80:8) to afford the title compound (3.20g) as a light brown oil.
T.l.c. System A (89:10:1) Rf 0.12.
Intermediate 30 4-Bromo-N-[3 -[3-(dimethvlamino)propyl]-4-methoxvphenvllbenzamide Sodium hydroxide (1 10mug) in water (5ml), was added to a solution of Intermediate 29 (250mg) and 4-bromobenzoyl chloride (263mg) in THF (5ml) at room temperature, under nitrogen. The solution was stirred at room temperature for 3h. The mixture was evaporated to dryness and water (10ml) added. This was extracted with ethyl acetate (4x20ml) dried and evaporated to yield a brown/white solid (335mg). This was purified by FCC eluting with ethyl acetate:methanol:ammonia (940:50:10) to give the title compound (218mg) as an off-white solid.
Ti 1 .c. ethyl acetate:methanol:ammonia (940:50:10) Ref 0.10.
Intermediate 31 4-Amino-3 -[3 -(dimethvlamino)- 1 -propvnvllbenzoic acid A stirred mixture of 4-amino-3-iodobenzoic acid (20,0g) and l-(dimethyamino)-2-propyne (16.4ml) in DMF (60ml) and triethylamine (loom) was treated with copper (I) iodide (1.16g) and bis(triphenylphosphine)palladium (II) chloride (2.16g) and stirred at room temperature under nitrogen for 4h. The mixture was evaporated and the residue purified by FCC. Gradient elution with System A (715:250:25 to 50:45:5) afforded four fractions of 2.23g, 6.22g, 2.58g and 1.89g. A portion (523mg) of the largest fraction was crystallised from water (4ml) to give a solid (237mg) which was further crystallised from hot water (3ml) to give a solid (142mg).A portion (130mg) of this was crystallised from ethanol (20ml) to give the title compound (104mg) as fine off-white crystals, m.p. 218-219 .
Intermediate 32 4-Amino-3-{3-(dimethylamino]propyl]benzoic acid hvdrobromide A suspension of Intermediate 31 (500mg) in ethanol (15ml) containing hydrobromic acid (49%, 0.27ml) was added to a mixture of 5% pre-reduced palladium oxide on carbon (500mg) in ethanol (50ml) and hydrogenated at room temperature and pressure until uptake ceased. The catalyst was filtered off, the filtrate evaporated, and the residue crystallised from ethanol (4ml) to give the title compound (245mg) as pale tan-cream crystals.
T.l.c. System A (50:45:5) Rf 0.04.
Intermediate 33 4-Bromo-3 -[3 -(dimethylamino)propyilbenzoic acid hvdrobromide A solution of sodium nitrite (269mg) in water (1 ml) was added dropwise at--5 to 0 to a stirred solution of 49% hydrobromic acid (0.65ml) in water (4ml) and after 15 min a solution of Intermediate 32 (500mg) and 49% hydrobromic acid (0.43 ml) in water (2ml) was added at -5 to 00. After 1 .5h at -100 to 0 , the solution was added to a stirred mixture of copper (I) bromide (1.23g) in 49% hydrobromic acid (4ml) at - 10 to 0 and the stirred mixture allowed to warm to 230 over 1.5h. The mixture was stirred at 90" for 1.5h, cooled, basified with 0.88 ammonia and evaporated. The residue was purified by FCC eluting with System A (615:350:35 to 560:400:40) to give a white semi-solid (743mg). This was treated with hot acetonitrile (9my), and on cooling, the title compound (139mg) crystallised as fine white crystals.
T.l.c. System A (615:350:35) Rf 0.23.
Intermediate 34 (E)-3-(2-Cvanoethenv1)4-fluorobenzoic acid. mixture with (Z) (65:35) A mixture of 4-fluoro-3-iodobenzoic acid (423mg), acrylonitrile (0. 126ml), triethylamine (0.55ml), palladium (II) acetate (25mg) and acetonitrile (2ml) was stirred at 100" for 16h.
The cooled mixture was filtered, evaporated, treated with aqueous 2N-hydrochloric acid (30ml), and extracted with ethyl acetate (3x30ml). The combined, dried organic extracts were evaporated and the residue (240mg) was crystallised from ethyl acetate (1.5ml) to give the title compound (43mg) as a light brown crystalline solid.
Analysis Found C,62.5;H,3 .2;N,7. 1 C,oH6FNO2 requires C,62.8; H,3.2; N,7.3% Intermediate 35 (E)-3-(2-Cvanoethenvl!-4-fluoro-N-[4-(4-pvridinvl?phenvl]benzamide A stirred solution of Intermediate 34 (2.50g) in dry THF (40ml) and dry DMF (30ml) under nitrogen was treated at -5 to -10" with triethylamine (3.65ml) followed by methanesulphonyl chloride (1.01ml). After 3h at .100, followed by 2h at room temperature, the mixture was re-cooled to -10" and 4-(4-pyridinyl)benzeneamine (2.22g) was added. The mixture was treated with aqueous 2M-hydrochloric acid (70ml), and the solid was filtered off.The solid was suspended in aqueous 8% sodium bicarbonate (50ml), filtered-off, dried in vacuo over phosphorous pentoxide, and then recrystallised from ethanol to give the title compound (235mg) as cream-coloured crystals.
Analysis Found: C,73.0; H, 4.2; N 11.95 C2,H,4FN30 requires C,73.5;H, 4.1;N, 12.2% Example 1 3 -[3 -(Dimethylamino)propvl]A-methoxy-N-[4-(4-pvridinvl)phenvllbenzamide dihvdrochloride A solution of Intermediate 2 (2.46g) in DMF (220ml), ethanol (lSOml), and ethanolic dimethylamine (33% w/v in ethanol, 80ml) was added to a stirred suspension of 10% pre-reduced palladium oxide in carbon (1.5g) in ethanol (30ml) and the mixture hydrogenated at room temperature and pressure. The mixture was filtered and the mixture hydrogenated at room temperature and pressure for a further 68h. The mixture was filtered and the filtrate evaporated.The residue was purified by SPC (Merck 7729) eluting with System A (89: 10: 1) to give the free base of the title compound (1.42g). A solution of the free base . (400mg) in hot ethanol was treated with ethanolic hydrogen chloride whilst stirring and the solution diluted with ether (50ml). The precipitate was collected to give the title compound (462mg) as a cream-coloured powder.
T.l.c. System A (89:10:1) Rf0.18 Analysis Found: C,60.95;H,6.75;N,8.7;Cl, 15.25.
C24EI29N302.2HCI.0.69EI20 requires C,60.7;H,6.45;N,8.85;Cl,14.95%.
Example 2 3-[3 -(Dimethylamino)propyl]-4-methoxy-N-[4-(3-pyridinyl)phenyl]benzamide hvdrochloride A solution of Intermediate 3 (1.5g) in a mixture of dry DMF (25ml) and 33% ethanolic dimethylamine (50ml) was hydrogenated at room temperature and pressure over 10% pre-reduced palladium oxide on carbon (1.0g) in ethanol (lSml) for 6h. The catalyst was filtered off, washed with ethanol (15ml) and the filtrate reduced in volume (to 40ml). The residual solution was partitioned between ethyl acetate (150ml) and water (3x1 00ml).
The aqueous solution was extracted with ethyl acetate (1 00ml) and the combined organic solutions dried and concentrated in vacuo to give a yellow oil which slowly crystallised.
This was purified by FCC eluting with System A (150:10:1) to give a colourless oil which was dissolved in absolute ethanol (loll). The solution was stirred, and treated with ethereal hydrogen chloride (1 ml) and dry ether (30ml). The resultant solid was filtered off, washed with dry ether (3x20ml) and dried at 500 for 19h to give the title compound (0.89g) as a white solid m.p. 1860.1890.
T.l.c. System A (150:10:1) Rf 0.20.
Example 3 2-MethoXv-N.N-dimethvl-S-rf [4-(4-pyridinyl)phenyl]amino]methyl]benzenepropanamine dihvdrochloride A solution of Example 1 (929mg) in dry THF (25ml) was added with stirring under nitrogen to a stirred suspension of lithium aluminium hydride (227mg) in dry THF (10ml) and the stirred mixture heated under reflux for 2h. The cooled mixture was treated cautiously with water (4ml) in THF (16ml), and the mixture filtered. The filtrate was evaporated and the residual oil purified by FCC eluting with System A (89:10:1) to give a solid. This was purified by SPC eluting with System A (189:10:1 to 186:13:1.3) to give the free base of the title compound (577mg) as a cream-coloured crystalline solid.A solution of the free base (567mg) in ethanol (25ml) was acidified with ethereal hydrogen chloride, and the mixture diluted with ether (35ml) to precipitate the title compound as orange/yellow crystals n.m.r. (DMSO-d6) 5 1.94(2H,m), 2.58 (2H,t) 2.70 (6H,d), 3.02 (2H,m) 3.80 (3H,s) 4.35 (2H,s) and 6.8-8.8 (llH,m).
Analysis Found: C,61 .0;H,7.2;N,8.7;Cl, 17.4.
C24H39N30.2.4HCl.0.074C2H5OH.0.067 H2O requires C,60.9;H,7.0;N,8.6;Cl, 17.4%.
Example 4 3-[3 -(Dimethyl]amino]propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide dihvdrochloride Sodium hydride (1.06g of a 78% dispersion in oil) was washed under nitrogen with hexane (3x10ml) and dry DMF (lOml) was added. The stirred suspension was treated at 5 to 150 with a solution of ethanethiol (2.54ml) in dry DMF (20ml) over 10 min, stirred at room temperature for 30 min and a solution of the free base of Example 1 (1.34g) in dry DMF (20ml) was added. The mixture was heated at 1450 for 15h, cooled, and poured into hydrochloric acid (SM, 80ml). The mixture was treated with aqueous saturated sodium bicarbonate to adjust the pH to 8.5, extracted with ethyl acetate (5x250ml) and the combined, dried organic extracts were evaporated.The residue was purified by FCC eluting with System A (89:10:1) to give the free base of the title compound (1.13g) as a solid. A hot solution of the free base (300mg) in ethanol (30ml) was acidified with ethanolic hydrogen chloride, cooled, and the precipitate collected to give the title compound (294mg) as pale yellow microcrystals, T.l.c. (free base) System A (89:10:1) Rf0.18 Analysis Found: C,58. 1 5;H,6.5;N,Cl, 1 5.5;N,8.9.
C23H25N302.2HCI.1.32 H2O requires C,58.5;H,6.3;N,Cl,15.0;N,8.9%.
Example 5 3-[3-(Dimethylamino)propyl]-4-hydroxy-N-[4-pyridinyl)phenyl]benzamide 4-methylbenzenesulphonate salt (1:2) The product of Example 4 (2.52g) was treated with aqueous saturated sodium bicarbonate (200ml), extracted with ethyl acetate (5x400ml), and the combined, dried extracts were evaporated. The residue was absorbed from hot ethyl acetate onto silica gel (Merck 7734) and purified by SPC, eluting with System A (945:50:5 to 917:75:8) to give the free base of the title compound (1.960g). The free base (1.944g) in hot ethanol (230ml) was treated with a hot solution of 4-methylbenzenesulphonic acid monohydrate (2.023g) in ethanol (20ml). The solution was concentrated (to 50ml) from which the title compound (2.72g) crystallised as a light cream-yellow powder.
T.l.c. (free base) System A (89:10:1) Rf O.18 Analysis Found: C,61.8; H,5.8; N,5.7.
C23H25N302.2C7H803S requires C,61.7; H,5.7; N,5.8%.
Example 6 3-[3-(Dimethylamino)propyl]-4-propoxy-N-[4-(4-pyridinyl)phenyl]benzamide maleate Sodium hydride (75mg of a 78% dispersion in oil) was added to a solution of the free base of the product of Example 4 (800mg) in DMF (lOml) at room temperature under nitrogen with stirring. After 15 min, a solution of propyl 4-methylbenzenesulphonate (46mg) in DMF (5ml) was added at 00 and after 2h, the reaction was stirred at room temperature for 15h. The reaction was poured into aqueous saturated sodium bicarbonate (50ml), extracted with ethyl acetate (3x50ml), and the combined, dried organic extracts were evaporated. The residue was purified by SPC eluting with System A (934:60:6) to give a solid. A solution of the solid in ethanol (8ml) was acidified with ethanolic hydrogen chloride and then diluted with ether to give a hygroscopic cream-coloured solid.This was treated with aqueous saturated sodium bicarbonate (30ml), extracted with ethyl acetate (3x50ml), and the combined, dried extracts were evaporated. The residue (140ml) in hot ethanol (20ml) was treated with a solution of maleic acid (39mg) in warm ethanol (2ml), the resultant solution evaporated and the residue crystallised from hot ethanol (4ml) to give the title compound (106mg) as fine white crystals, m.p.168-1700 Analysis Found: C,67.6; X6.8; N,7.8.
C26H31NO2. C4H4O4 requires C,67.5; X6.6; N,7.9%.
Example 7 3-[3 -(Dimethvlamino!propvl]4-methoxv-N-[4-(2-pyridinvl)phenvlzbenzamide A stirred mixture of Intermediate 5 (593mg) and dry DMF (2 drops) in thionyl chloride (5ml) was heated at 90-1000 until gas evolution ceased (15 min.). The solution was cooled and evaporated to dryness to give an oil, which was treated with dry toluene (loll) and evaporated to dryness again to give a colourless solid. A mixture of this solid in dry pyridine (10ml) under anhydrous conditions was stirred for 15 min. to give a fine suspension. Intermediate 4 (426mg) was added with stirring to give a red solution. After 30 min. at 300, the resulting dark pink suspension was heated at 600 for 3h. After cooling, the suspension was stirred with water (I ml) for 5 min. to give a red solution. Aqueous sodium carbonate (2N; 10my) was added and the mixture evaporated to dryness. Residual pyridine was removed- by addition of ethanol and evaporation to dryness again. The residue was treated with 2N aqueous sodium carbonate (1 00ml) and extracted with ethyl acetate (5x50ml). The combined extracts were dried and evaporated to dryness to give a buff solid and purified by FCC eluting with System F (90: 10: 1) to give a crystalline solid.
Crystallisation from toluene (45ml) gave the title compound (775mg) as almost colourless crystals, m.p. 152.5-154.50.
T.l.c. dichloromethane:methanol (9:1) Rf 0.15.
Example 8 6[4[[3-3-(Dimeth"lamino)propylImethoxvbenwvl1amino]phenvl]-3 pyridinecarboxylic acid A mixture of Intermediate 22 (1.Olg) and Intermediate 9 (0.737g) in dry pyridine (30ml) was heated at reflux for lh. Water (10ml) was added and the reaction mixture was stirred at room temperature for 30min. Aqueous sodium hydroxide (2N; 10ml) was then added and the solvent was evaporated to give a light brown solid (1.80g). The solid was purified by SPC (Merck 7729) eluting with System A (15:8:1) to give an off-white solid (730mg). The solid was further purified by heating under reflux in absolute ethanol (200ml). The mixture was cooled and the solid was filtered off, washed with dry ether and dried under vacuum to give the title compound (345mg) as a white solid m.p.255-2580C.
T.l.c.SystemA (10:8:1) Ref0.49.
Example 9 Methyl 4-[4-[[3-[3-(dimethylamino)propyl]-4-methoxybenzoyl]amino]phenyl]-2- pyridinecarboxylate ethanedioate (1:1) A mixture of Intermediate 42 (814mg) and Intermediate 10 (800mg) in dry pyridine (25ml) was heated at reflux for 1.5h. The pyridine was removed under reduced pressure and the residue was partitioned between aqueous sodium bicarbonate (1M; 50ml), brine (50ml) and dichloromethane (50ml).The aqueous phase was further extracted with dichloromethane (2x50ml) and dichloromethane:isopropanol (4:1; 2x50ml). The combined extracts were dried, filtered and evaporated to give a brown gum (1.1 5g). The gum was purified by FCC eluting with dichloromethane:methanol (19:1 to 9: 1) to give a white foam (988mg). A solution of the foam (200mg) in ethyl acetate (1 SmI) was treated with a solution of anhydrous ethanedioic acid (40mg). The resulting solid was filtered off, triturated in boiling ethyl acetate (10ml) and filtered and washed with ethyl acetate then dried under vacuum to give the title compound (83mg) as a yellow crystalline solid m.p. 175-1770.
Analysis Found: C,61.8; 11,5.8; N,7.5.
C2611,N3O4.C2H,-O4.0.2611,O requires C,62.0; 11,5.9; N,7.8%.
Water Analysis:- indicates 0.26EI20 Example 10 4-[4-[[3-[3 -(Dimethylamino)propyl]-4-methoxybenzoyl]amino]phenyl]-2- pvridinecarboxamide A mixture of Intermediate 22 (500mg) and Intermediate 11 (300mg) in pyridine (lOml) was heated at reflux for lh. The solvent was evaporated and the residue purified by FCC eluting with System A (75:8:1) to give a yellow solid (360mg). The solid was further purified by FCC eluting with System A (75:8:1) to give an off-white solid (185mg). The solid was crystallised from toluene (lOml) to give the title compound (112mg) as an off-white crystalline solid, m.p. 189-1920C.
T.l.c. System A (50:8:1), Rf0.15.
Example 11 4-r4-[[3 -[3 (Dimethylamino)propyl]-methoxybenzoyl]amino]phenyl]-2- pyridinecarboxylic acid A solution of the free base of the product of Example 9 (592mg) and lithium hydroxide monohydrate (61mg) in water (6ml) and THF (50ml) was stirred at room temperature for 24h. The solvent was evaporated and the residue was purified by FCC eluting with System A (10:8:1) to give a glass (458mg). The glass was crystallised from methanol (30ml). The resulting solid was filtered-off, washed with ether and dried under vacuum to give the title compound (261mg) as a white crystalline solid m.p. 188-1900C.
T.l.c. System A (10:8: 1) Rf 0. I 1.
Example 12 4-Methoxy-3-[3-[methylamino]propyl]-N-[4-(4-pyridinyl)phenylbenzamide A solution of Intermediate 13 (1.874g) in DMF (50ml) was added to a pre-hydrogenated suspension of dry 10% palladium on carbon (0.97g) in DMF (20ml) and hydrogenated at room temperature and pressure until uptake ceased. The suspension was filtered and the filtrate evaporated. The residue was purified by FCC eluting with System A (890:100:10 to 868:120:12) to give the title compound as a white crystalline solid (708mg), m.p.
144-1470C.
Analysis Found: C,73.4; H,6.7; N,11.0.
C23H25N3O2.0.08H2O requires C,73.6; H,6.7; N,11.2%.
Water assay Found: 11,0, 0.24 w/w = 0.08mmol.
Example 13 4-Methoxy-3-[3-[methyl(propyl)amino]propyl]-N- [4-(4-pvridinyl)phenvl]benzamide l-Bromopropane (0.14ml) and diisopropylethylamine (0.27ml) were added to a solution of the product of Example 12 (582mg) and sodium iodide (0.23g) in DMF (25ml) and the stirred mixture was then heated in an autoclave at 80 C for 4h. When cool, the resultant mixture was added to an aqueous saturated solution of sodium bicarbonate (25ml) and then evaporated. The residue was stirred in refluxing ethanol (30ml) and the mixture adsorbed onto silica gel (Merck 7734, 10ml). Purification by FCC eluting with System A (945:50:5 to 934:60:6) afforded a solid (372mg). The solid was crystallised from ethyl acetate (2ml) to give the title compound (331 mg) m.p. 133-l360C.
Analysis Found: C,74.6; H,7.5; N,10.1.
C26H31N3O2.0.074H2O requires C,74.6; H,7.5; N,10.0%.
Water assay Found: 0.32% H2O w/w = 0.074mol.
Example 14 5-[3-(Dimethylamino)propyl]-2-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide A solution of Intermediate 16 (300mg) in thionyl chloride (Iml) was refluxed for 30min and evaporated. The resulting gum was treated with toluene (2ml) and re-evaporated.
The residue in pyridine (6ml) was treated with 4-(4-pyridinyl)benzenamine (200mg) and stirred at room temperature for 18h and at reflux for 1h. The mixture was treated with aqueous sodium bicarbonate (1N; SOml) and extracted with dichloromethane (3 x 70ml).
The dried extract was evaporated and the residue was purified by FCC eluting with System F (190:10:1) to give a beige solid (120mg). The solid was treated with ethanol (5 ml), heated to reflux, cooled and filtered to give the title compound as a cream-coloured solid (75mg).
T.l.c. System F (90:10:1), Rf0.4.
Analysis Found: C,71.8; H,6.9; N,10.7; C23H25N3O2.0.5H2O requires C,71.9; H,6.8; N,10.9% Similarly prepared was : Example 15 5-[3-(Dimethylamino)propyl]-2-methoxy-N-[4-(4-pyridinyl)phenyl]benzamide as a pink solid (250mg).
T.l.c. System F (90:10:1), Rf 0.4.
Analysis Found: C,73.1; H,6.8; N,10.5; C24EI2N302 0 3HzO requires C,73.0; 11,7.0; N,10.6; From Intermediate 18 (350mg) and 4-(4-pyridinyl)benzenamine (255mg).
Example 16 3 -[3 -(Dimethylamino)propyl]-N-[4-[6-( 1-hydroxyethyl)-3 -pyridinyli phenyli-4- methoxvbenzamide A stirred mixture of Intermediate 19 (1.20g) and Intermediate 24 (2. 14g) in DME (76ml) was treated with a hot solution of sodium carbonate (1.27g) in water (38ml) followed by tetrakis(triphenylphosphine)palladium (0) (347mg) and heated at reflux under nitrogen for 6h. When cool, the residue was treated with 4% aqueous sodium bicarbonate (100ml) and ethyl acetate (1 00m1). The mixture was filtered and the precipitate dried in vacuo to give a solid. The filtrate was separated and the aqueous layer extracted with ethyl acetate (4 x 100ml). The combined, dried organic extracts were evaporated, combined with the solid, and purified by FCC.Gradient elution with System A (945:50:5 to 878:110:11) afforded firstly slightly impure product (0.52g) followed by a solid (1.45g). This solid was stirred in hot ethyl acetate (120ml), filtered, and stood at 230 for 16h. The solution was scratched to initiate crystallisation and after 4h the precipitate was filtered off to give the title compound as fine white crystals (752mg), m.p. 174i790.
Analysis Found: C,71.5; H,7.1; N,9.4; C26H31N3O3.0.09H2O requires C,71.8; H,7.2; N,9.7% Water assay Found : H20, 0.36% w/w = 0.09mol.
Similarly prepared was : Example 17 3-[3-(Dimethylamino)propyl]-N-[4-[2-(hydroxymethyl)-5-pyridinyl]phenyl]-4- methoxybenzamide as a white solid (409mg), m.p. 183.5-1860C.
Analysis Found: C,70.9; H,7.0; N,9.7; C25H23O3.0.05H2O requires C,71.4; 11,7.0; N,10.0% Water assay Found 0.21% w/w H,O = 0.05mol.
From 5-bromo-2-pyridinemethanol (264mg) and Intermediate 24 (500mg). Purification by SPC eluting with System A (89:10:1) afforded the title compound.
Example 18 5-[4-[[3-[3-(Dimethylamino)propyl]-4-methoxybenzoyl]amino]phenyl]-2- pvridinemethanol acetate (ester) Acetic anhydride (0.12ml) was added at -5 to 0 to a stirred solution of the product of Example 17 (207mg) in pyridine (Sml) under nitrogen and stirring continued for 2h at -10 to -5 , then at 230 for 2h. Aqueous saturated sodium bicarbonate (5ml) was added and the mixture evaporated. Water (30ml) was added and the mixture extracted with ethyl acetate (5 x 50ml). The combined, dried organic extracts were evaporated and the residue dissolved in hot ethyl acetate (20ml). The cloudy mixture was filtered and the filtrate evaporated.The residue (206mg) crystallised from ethyl acetate (4ml) to give the title compound as fine white crystals (66mg), m.p. 154i57o.
Analysis Found: C,69.7; H,6.6; N,8.8; C2,H3,N304.0.07H20 requires C,70.1; H,6.8; N,9.1% Water assay Found : HoO, 0.27% w/w = 0.07mol.
Example 19 N-[4-(6-Acetyl-3-pyridinyl)phenyl]-3-[3(dimethylamino)propyl]-4- methoxvbenzamide A mixture ofthe product of Example 16 (500mg) and manganese (IV) oxide (502mg) in 1,4-dioxan (10ml) was stirred at reflux under nitrogen for 2h. The mixture was filtered and the filtrate evaporated. The residue was purified by FCC eluting with System A (945:50:5 to 923:70:7) to give a solid (393mg). This was re-crystallised from ethyl acetate (20ml) to give the title compound as cream-coloured crystals (191mg), m.p.
183.5-186.5 .
Analysis Found: C,72.3; H,6.9; N,9.7.
C2611,9N303 requires C,72.4; H,6.8; N,9.7% Example 20 3 -[3 -(Dimethylamino)propyl]-4-methoxy-N-[4-(3 -methyl-pyridinyl)phenyl]benzamide dihvdrochloride Intermediate 22 (643mg) was added portionwise over 30 min to a stirred solution of Intermediate 27 (393mg) in pyridine (7 ml) at 0 under nitrogen. After 30 min at 23 , the mixture was stirred at 900 for 40 min. When cool, the mixture was treated with aqueous saturated sodium bicarbonate (20 ml) and then evaporated. The residue was stirred in hot ethanol (80 ml), treated with silica gel (Merck 7734, 20 ml) and evaporated. Purification by FCC eluting with System A (89: 10: 1) gave the free base of the title compound as a foam (829 mg).A hot solution of this in ethanol (10 ml) was treated with ethanolic hydrogen chloride to adjust the acidity to pHI, and on cooling, the title compound crystallised as fine cream-coloured crystals (689mg).
Tic. System A (89:10:1) Rf. 0.22.
Analysis Found: C, 61.9; H, 7.05; N, 8.6; Cl,14.4.
C2511,9N302. 1 .92HCl.0.79H2O requires C, 61.6; H, 6.7; N, 8.6, Cl,14.0% Water assay Found: H20, 2.89% = 0.79 mole.
Example 21 3-[3-(Dimethylamino)propyl-N-[4-(4-pyridinyl)phenyl]benzamide. bis(4-methyl benzenesulphonate) A solution of Intermediate 21 (569mg) in DMF (35ml) and dimethylamine (30% w/v in ethanol 80ml) was added to a suspension of pre-reduced palladium oxide on carbon (300mg) in ethanol (10ml) and the mixture hydrogenated at room temperature and pressure for 6h. The catalyst was filtered off, the filter pad washed with ethanol, and the combined filtrate and washings were concentrated to 35ml. A solution of the filtrate in dimethylamine (30% w/v in ethanol, 80ml) was hydrogenated at room temperature and pressure for a further 4 days as above. The catalyst was filtered off, the filter pad washed with ethanol and the combined filtrate and washings were evaporated.The residue was purified by SPC eluting with System A (945:50:5 to 934:60:6) to give a solid (396mg).
A portion of the solid (358mg) in ethanol (10ml) was treated with a solution of 4-methylbenzenesulphonic acid monohydrate (398mg) in hot ethanol (5ml) and further ethanol was added at reflux until the precipitate dissolved. On cooling, the precipitate was collected to give the title compound as fine cream-coloured crystals (599mg) m. p.
209-211.5 .
Analysis Found C,62.1; H,6.0; N,5.75; S,8.6 C2311,5N30.2CHIO3S .0.4711,0 requires C,62.4;H,5.9;N,5.9; S,9.0% Water Assay Found 1.18%H,O 0.47mol H,O Example 22 N-[3-[3-(Dimethylamino)propyl]-4-methoxyphenyl]-4-pyridinyl)benzamide Intermediate 30 (194mg), 4-pyridinylboronic acid (61mg), sodium carbonate (2N, 2ml), DME (8ml) and tetrakis(triphenylphosphine)palladium (0) (50mg) was heated at reflux under nitrogen for 4h.After cooling, water (30ml) was added and the mixture extracted with dichloromethane (3x50ml), dried and evaporated to yield a pale yellow solid (194mg). Purification by FCC eluting with ethyl acetate:methanol:0.88 ammonia (890:100:10) afforded the title compound (123mg) as an off-white solid.
T.l.c. ethyl acetate:methanol:0.88 ammonia (890:100:10) Rf= 0.09.
Analysis Found C,73.15; H, 7.1; N, 10.55 C2411,7N302 requires C,74.0; H,7.0; N. 10.8% Example 23 4-Bromo-3 -[3 -(dimethvlamino)Dropvll -N-T4-(4-Dvridinvl)Dhenvllbenzamide Intermediate 33 (5.00g) was treated with thionyl chloride (20ml) and stirred at reflux for 8 min. When cool, the mixture was evaporated and then co-evaporated with toluene (2 x 20ml). The reside was treated with 4-(4-pyridinyl)benzeneamine (2.32g), followed by pyridine (20ml) and stirred at reflux for 1.5h. When cool, the mixture was treated with aqueous saturated sodium bicarbonate (60ml) and evaporated. The residue was absorbed from refluxing methanol (120ml) onto silica gel (Merck 7734, 30g) and purified by FCC.
Gradient elution with System A (945:50:5 to 912:80:8) afforded firstly 4-(4-pyridinyl)benzeneamine and secondly, a brown/cream-coloured solid (3.85g). A portion of the solid (350mg) was crystallised from ethanol to give the title compound (187mg) as fine white crystals. m.p. 171-172.5 .
Analysis Found C,62.9; H,5.4; N,9.4; C23H24BrN30. 0.0611,0 requires C, 62.9;H,5.5; N, 9.6; Water Assay Found 0.25% H2O=0.06 mole Example 24 3-[3-(Dimethylamino)propyl]-4-methyl-N-[4-(4-pyridinyl)phenyl]benzamide dimaleate A solution of the product of Example 23 (500mg), tetrakis(triphenylphosphine)palladium (0) (50mg), tetramethyltin (0.18ml) and hexamethylphosphoramide (3ml) was heated at 85" under nitrogen in a sealed vessel for 18h. When cool, the solution was poured into aqueous saturated sodium bicarbonate (30ml) and extracted with ethyl acetate (4x50ml).
The combined, dried organic extracts were evaporated and the residue purified by FCC.
Gradient elution with System A (945:50:5 to 934:60:6) afforded a solid (380mg) which crystallised from ethyl acetate (3ml) to give white crystals of the impure free base (206mg). This was combined with the mother liquors of the above crystallisation and evaporated. The residue (325mg) was treated with maleic acid (250mg) and ethanol (25ml) and heated to reflux. On cooling the title compound (400mg) crystallised as fine cream-coloured crystals, m.p. 162-164.5 .
Analysis Found C,63.4; H,5.8; N,6.8.
C24H27N30. 2C4H404 requires C,63.5; 11,5.8; N,6.9% Example 25 3 -[3-(Dimethylamino)propyl]-4-fluoro-N-[4-(4-pyridinylphenyl)]benzamide dimaleate A solution of Intermediate 35 (415mg) in DMF (32ml) and dimethylamine (33% w/v in ethanol (85ml) was added to a suspension of 10% pre-reduced palladium oxide on carbon (300mg) in ethanol (20ml) and the stirred mixture hydrogenated at room temperature and pressure for 3 days. The catalyst was filtered off, replaced and the stirred mixture hydrogenated for 24h. The catalyst was replaced in the same way once more and the stirred mixture hydrogenated for 24h. The catalyst was filtered off; the filtrate evaporated and the residue purified by FCC eluting with System A (945:50:5 to 84:15:1) to give a solid (82mg). A solution of the solid in ethanol (2ml) was treated with a solution of maleic acid (29mg) in ethanol (2ml) and the solution evaporated. The residue crystallised from ethanol to give the title compound (26mg) as cream-coloured crystals, m.p.
159-163 .
Analysis Found: C,60.15; H,5.3; N, 6.7.
C23H24FN30.C4H404. 0.5H20 requires C,60.2; 11,5.4; N,6.8%.

Claims (2)

Claims
1. Compounds of the general formula (I) :
or a physiologically acceptable salt or solvate thereof, in which R1 represents a hydrogen atom or a halogen atom or a Ci 6a1ky1 or Ci - 6alkoxy group; R2 and R3, which may be the same or different, each independently represent a hydrogen atom or a halogen atom, or a C1 6alkyl, hydroxyC1 alkyl, C1-6alkoxyC1-6alkyl, C1-6alkoxy, hydroxy, -CN, -NO2, -C02R6, -COR6, - CONR6R7or (CH2)m0C(O)C1Aalkyl group; R4 and R5, which may be the same or different, each independently represent a hydrogen atom or a halogen atom, or a hydroxy, C1-6alkoxy or C1-6alkyl group; ; R61 R7 R8 and R9, which may be the same or different, each independently represent a hydrogen atom or a C1-6alkyl group; or -NR6R7 forms a saturated heterocyclic ring which has 5 or 6 ring members which, when there are 6 ring members, may optionally contain in the ring one oxygen or sulphur atom; X represents -CONH-, -NHCO-, -CH2NH- or -NHCH2-; m represents zero or an integer from 1 to 3; and p represents an integer from 2 to 4.
2. Compounds as claimed in Claim 1 for use in therapy.
GB9305509A 1993-03-17 1993-03-17 Pyridine compounds. Withdrawn GB2276163A (en)

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WO1998000401A1 (en) * 1996-06-28 1998-01-08 Merck & Co., Inc. Fibrinogen receptor antagonist prodrugs
US5932582A (en) * 1996-06-28 1999-08-03 Merck & Co., Inc. Fibrinogen receptor antagonist prodrugs
US5945545A (en) * 1996-12-13 1999-08-31 Merck & Co., Inc. Fibrinogen receptor antagonists
WO2005030753A2 (en) * 2003-09-22 2005-04-07 Euro-Celtique S.A. Therapeutic agents useful for treating pain
WO2005070460A2 (en) * 2004-01-22 2005-08-04 Recordati Ireland Limited Combination therapy with 5-ht1a and 5-ht1b receptor antagonists
EP2017276A1 (en) 2003-09-22 2009-01-21 Euro-Celtique S.A. Phenyl-carboxamide compounds useful for treating pain
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US7615651B2 (en) 2006-11-13 2009-11-10 Pfizer Inc. Diaryl, dipyridinyl and aryl-pyridinyl derivatives and uses thereof
JP2011502983A (en) * 2007-11-01 2011-01-27 アキュセラ インコーポレイテッド Amine derivative compounds for the treatment of eye diseases and disorders
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
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WO1998000401A1 (en) * 1996-06-28 1998-01-08 Merck & Co., Inc. Fibrinogen receptor antagonist prodrugs
US5932582A (en) * 1996-06-28 1999-08-03 Merck & Co., Inc. Fibrinogen receptor antagonist prodrugs
AU719102B2 (en) * 1996-06-28 2000-05-04 Merck & Co., Inc. Fibrinogen receptor antagonist prodrugs
US5945545A (en) * 1996-12-13 1999-08-31 Merck & Co., Inc. Fibrinogen receptor antagonists
US7994177B2 (en) 2003-09-22 2011-08-09 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US7772254B2 (en) 2003-09-22 2010-08-10 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US8129388B2 (en) 2003-09-22 2012-03-06 Purde Pharma L.P. Therapeutic agents useful for treating pain
WO2005030753A2 (en) * 2003-09-22 2005-04-07 Euro-Celtique S.A. Therapeutic agents useful for treating pain
EP2017276A1 (en) 2003-09-22 2009-01-21 Euro-Celtique S.A. Phenyl-carboxamide compounds useful for treating pain
US7964606B2 (en) 2003-09-22 2011-06-21 Purdue Pharma L.P. Therapeutic agents useful for treating pain
US7799807B2 (en) 2003-09-22 2010-09-21 Purdue Pharma L.P. Therapeutic agents useful for treating pain
WO2005030753A3 (en) * 2003-09-22 2005-05-06 Euro Celtique Sa Therapeutic agents useful for treating pain
WO2005070460A3 (en) * 2004-01-22 2007-02-08 Recordati Ireland Ltd Combination therapy with 5-ht1a and 5-ht1b receptor antagonists
WO2005070460A2 (en) * 2004-01-22 2005-08-04 Recordati Ireland Limited Combination therapy with 5-ht1a and 5-ht1b receptor antagonists
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8592486B2 (en) 2005-01-07 2013-11-26 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US7615651B2 (en) 2006-11-13 2009-11-10 Pfizer Inc. Diaryl, dipyridinyl and aryl-pyridinyl derivatives and uses thereof
JP2011502983A (en) * 2007-11-01 2011-01-27 アキュセラ インコーポレイテッド Amine derivative compounds for the treatment of eye diseases and disorders
WO2009075874A1 (en) * 2007-12-13 2009-06-18 Amgen Inc. Gamma secretase modulators
WO2022050385A1 (en) * 2020-09-07 2022-03-10 大日本住友製薬株式会社 Phenol derivative

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