WO2009138778A1 - Dérivés de cyclopropyl benzamide utilisés en tant qu'intermédiaires pour des inhibiteurs de cytokines - Google Patents

Dérivés de cyclopropyl benzamide utilisés en tant qu'intermédiaires pour des inhibiteurs de cytokines Download PDF

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Publication number
WO2009138778A1
WO2009138778A1 PCT/GB2009/050493 GB2009050493W WO2009138778A1 WO 2009138778 A1 WO2009138778 A1 WO 2009138778A1 GB 2009050493 W GB2009050493 W GB 2009050493W WO 2009138778 A1 WO2009138778 A1 WO 2009138778A1
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formula
alkyl
amino
compound
group
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PCT/GB2009/050493
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English (en)
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Felix Beijer
Simon Fenner
Peter Van Eijk
Matthew James Welham
Vanessa Wyatt
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2009138778A1 publication Critical patent/WO2009138778A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to novel processes for the preparation of intermediate compounds which can be used to prepare therapeutic agents.
  • the present invention also relates to novel intermediate compounds which can be used to prepare therapeutic agents.
  • Cytokines are produced by a wide variety of cells such as monocytes and macrophages and they give rise to a variety of physiological effects which are believed to be important in disease or medical conditions such as inflammation and immunoregulation.
  • TNF ⁇ and IL-I have been implicated in the cell signalling cascade which is believed to contribute to the pathology of disease states such as inflammatory and allergic diseases and cytokine-induced toxicity. It is also known that, in certain cellular systems, TNF ⁇ production precedes and mediates the production of other cytokines such as IL-I.
  • cytokines have also been implicated in, for example, the production of physiologically-active eicosanoids such as the prostaglandins and leukotrienes, the stimulation of the release of proteolytic enzymes such as collagenase, the activation of the immune system, for example by stimulation of T-helper cells, the activation of osteoclast activity leading to the resorption of calcium, the stimulation of the release of proteoglycans from, for example, cartilage, the stimulation of cell proliferation and to angiogenesis.
  • physiologically-active eicosanoids such as the prostaglandins and leukotrienes
  • proteolytic enzymes such as collagenase
  • the activation of the immune system for example by stimulation of T-helper cells
  • osteoclast activity leading to the resorption of calcium the stimulation of the release of proteoglycans from, for example, cartilage
  • the stimulation of cell proliferation and to angiogenesis to angiogenesis.
  • Cytokines are also believed to be implicated in the production and development of disease states such as inflammatory and allergic diseases, for example inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis, Crohn's disease and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease and adult respiratory distress syndrome), and in the production and development of various cardiovascular and cerebrovascular disorders such as congestive heart failure, acute heart failure, myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, reperfusion injury, vascular injury including restenosis and peripheral vascular disease, and, for example, various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteop
  • Excessive cytokine production has also been implicated in mediating certain complications of bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome and in mediating certain complications of CNS surgery or injury such as neurotrauma and ischaemic stroke.
  • Excessive cytokine production has also been io implicated in mediating or exacerbating the development of diseases involving cartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renal fibrosis, the cachexia found in certain chronic diseases such as malignant disease and acquired immune deficiency syndrome (AIDS), chronic obstructive pulmonary disease, tumour invasiveness and tumour metastasis and multiple sclerosis.
  • Excessive cytokine production has also been is implicated in pain.
  • WO 2005/061465 discloses a series of compounds having the structure (A) below which inhibit the effects of cytokines by virtue of inhibition of the enzyme p38 kinase :-
  • Q a is phenyl or heteroaryl, and Q a may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, amino, (l-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and (1- 6C)alkoxycarbonyl; Ri and R 2 are each independently selected from hydrogen, (l-6C)alkyl, (2-6C)alkenyl and (2-6C)alkynyl; and
  • Qb is phenyl, heteroaryl or heterocyclyl, and Qb may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(l-6C)alkyl, (l-6C)alkoxy, (3-6C)cycloalkoxy, (3-6C)cycloalkyl-(l-6C)alkoxy, carboxy, (l-6C)alkoxycarbonyl, N-(l-6C)alkylcarbamoyl, N,N-di-[(l-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (l-6C)alkylamino, di-[(l-6C)alkyl]amino, halogeno-(l-6C)alkyl, hydroxy-(l-6C)alky
  • WO 2005/061465 also describes methods of synthesising further intermediate compounds useful in the preparation of compounds of the structure (A). Examples of certain further such methods are described in WO 2005/042502, WO 2005/042537, WO 2004/099156 and Hynes et al, Bioorg. & Med. Chem. Lett., 18 (2008), 1762-1767, but none of these documents describes a process according to the present invention as described herein. There remains a continuing need for new methods of synthesising compounds of formula (A) and hence for new and efficient methods for preparing intermediates useful in the preparation of such therapeutic compounds.
  • the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • Q a is phenyl or heteroaryl, and Q a may optionally bear one or two substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, amino, (l-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and (l-6C)alkoxycarbonyl; and wherein any of the substituents on Q a defined hereinbefore which comprise a CH 2 group which is attached to 2 carbon atoms or a CH 3 group which is attached to a carbon atom may optionally bear on each said CH 2 or CH 3 group one or more substituents selected from hydroxy, cyano, amino, (l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylamino and di-[(l-6C)alkyl]amino; which process comprises reacting
  • a suitable activated derivative of an acid of the formula (III) is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloro formate such as isobutyl chloro formate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester such as pentafluorophenyl trifluoroacetate or an alcohol such as N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbod
  • the compound of formula (III) is an acyl halide, preferably an acyl chloride.
  • the reaction is carried out in the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as an alkyl-lithium, for example n-butyl-lithium, or a dialkylamino -lithium, for example lithium di-isopropylamide, or, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene.
  • a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate,
  • the base is an organic amine base, preferably triethylamine.
  • the process of the invention is typically conveniently conducted in the presence of a suitable base only and does not require the use of a coupling agent such as HATU (i.e. 2- (1 H-9-azabenzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate) .
  • HATU i.e. 2- (1 H-9-azabenzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate
  • the reaction is also preferably carried out in a suitable inert solvent or diluent, for example tetrahydrofuran, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at a temperature in the range, for example, -78 to 15O 0 C, conveniently at or near ambient temperature of about 20 to 25°C.
  • a suitable inert solvent or diluent for example tetrahydrofuran, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone
  • the solvent is dichloromethane.
  • the process of the invention provides a convergent synthesis for the preparation of compounds of formula (I) whereby large fragments are coupled together in a final step, the fragments themselves being individually elaborated at an earlier stage.
  • This process therefore provides a practical and efficient route for the manufacture on a commercial scale of compounds which are useful as intermediates in the preparation of therapeutic compounds.
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • protecting groups are given below for the sake of convenience, in which "lower”, as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1 to 4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
  • a carboxy protecting group may be the residue of an ester- forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (for example isopropyl, tert-butyl); lower alkoxy lower alkyl groups (for example methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (for example 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (for example benzyl, p_-methoxybenzyl, o-nitrobenzyl, p_-nitro
  • hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for example benzoyloxycarbonyl, p_-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p_-nitrobenzyloxycarbonyl); tri lower alkylsilyl groups (for example trimethylsilyl, tert-butyldimethylsilyl) and aryl lower alkyl groups (for example benzyl).
  • lower alkyl groups for example tert-butyl
  • lower alkenyl groups for example allyl
  • lower alkoxycarbonyl groups for example tert-butoxycarbonyl
  • amino protecting groups include formyl, aralkyl groups (for example benzyl and substituted benzyl, p_-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p_-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for example benzyloxycarbonyl, p_-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p_-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene); benzylidene and substituted benzylidene groups.
  • aralkyl groups for example
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as p_-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as o-nitrobenzyloxycarbonyl.
  • no protecting group(s) are used, thereby obviating the need for protection and deprotection steps and so leading to a more efficient and economical synthesis.
  • Suitable pharmaceutically-acceptable salts include acid-addition salts with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric, maleic, tartaric, fumaric, hemifumaric, succinic, hemisuccinic, mandelic, methanesulphonic, dimethanesulphonic, ethane- 1 ,2-sulphonic, benzenesulphonic, salicylic or 4-toluenesulphonic acid.
  • the term 'alkyl' when used alone or in combination, refers to a straight chain or branched chain alkyl moiety.
  • a 1-6C alkyl group has from one to six carbon atoms including methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl, n- hexyl and the like.
  • a suitable value for Q a when it is heteroaryl is, for example, an aromatic 5- or 6- membered monocyclic ring, a 9- or 10-membered bicyclic ring or a 13- or 14-membered tricyclic ring each with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, and provided that when Q a is heteroaryl, it is not a pyridyl or pyrazinyl group.
  • a suitable value for Q a when it is heteroaryl is furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, carbazolyl, dibenzofuranyl, dibenzothiophenyl, S,Si-dioxoxo
  • Q a in formula (I) and formula (III) is phenyl, optionally substituted by 1 or 2 substituents as hereinbefore defined.
  • Suitable values for various substituents on Q a include :- for halogeno: fluoro, chloro, bromo and iodo; for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (2-6C)alkenyl: vinyl and allyl; for (2-6C)alkynyl: ethynyl and 2-propynyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (l-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert- butoxycarbonyl; for (l-6C)alkylamino: methylamino, ethylamino and propylamino; for di-[(l-6C)alkyl] amino: dimethylamino, diethylamino and N-
  • carboxy-(l-6C)alkyl carboxymethyl, 1-carboxy ethyl, 2-carboxyethyl,3-carboxypropyl and 4-carboxybutyl; for (l-6C)alkoxycarbonyl-(l-6C)alkyl: methoxycarbonylmethyl, ethoxycarbonylmethyl,tert-butoxycarbonylmethyl, 1 -methoxycarbonylethyl, 1 - ethoxycarbonylethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 3- methoxycarbonylpropyl and 3-ethoxycarbonylpropyl.
  • Q a in formula (I) and in formula (III) is phenyl, and Q a may optionally bear one or two substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, amino, (l-6C)alkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (l-6C)alkoxy, (l-6C)alkylamino, di-[(l-6C)alkyl]amino and (1- 6C)alkoxycarbonyl; and wherein any of the substituents on Q a defined hereinbefore which comprise a CH 2 group which is attached to 2 carbon atoms or a CH3 group which is attached to a carbon atom may optionally bear on each said CH 2 or CH 3 group one or more substituents selected from hydroxy, cyano, amino, (l-6C)alkyl, (l-6C)alkoxy, (1- 6C)alkylamino and di-[(
  • Q a in formula (I) and in formula (III) is phenyl, and Q a may optionally bear one or two halogeno (especially fluoro) substituents.
  • Q a in formula (I) and formula (III) is phenyl substituted by one or two halogen substituents, preferably two halogen, especially fluoro, substituents.
  • the compound of formula (III) is a compound of formula (III A):
  • a further process of the present invention is for preparing a compound of formula (IA) or a pharmaceutically acceptable salt thereof:
  • Certain compounds of formula (I) are novel and these, and their pharmaceutically acceptable salts, form a further aspect of the invention.
  • the present invention further provides a compound of formula (IA):
  • NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz using perdeuterio dimethyl sulfoxide (DMSO-d ⁇ ) as solvent unless otherwise indicated; the following abbreviations have been used: s, singlet; bs, broad singlet; d, doublet; dd, doublet of doublets; t, triplet; at, apparent triplet; q, quartet; m, multiplet; br, broad.
  • HPLC was performed using the following conditions:- Column, 15 cm ACE 3, C18, 4.6 mm, 3 ⁇ , Eluent A:100% Water, 1% Formic Acid. Eluent B:100% MeCN, 1% Formic Acid. Timetable
  • the volatiles were removed by atmospheric distillation to adjust to target solution concentration of iV-cyclopropyl-3-(3,4-difluorobenzamido)-4- methylbenzamide (28 to 32% w/w).
  • the batch was cooled to 20 to 25 0 C, stirred for 1 hour and demineralised water (47 L) added over 30 minutes.
  • the batch was stirred for 1 hour and isolated by filtration.
  • the product was sequentially washed with demineralised water (10 L), aqueous KOH solution (10.06 Kg, 5.57 % w/w) and demineralised water (10 L).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un composé de formule (I) ou d'un sel pharmaceutiquement acceptable de ce dernier. Dans la formule (I), Qa est tel que défini dans la description. Les composés sont utiles dans la préparation d 'agents thérapeutiques, notamment des inhibiteurs de cytokines. De nouveaux composés de formule (I) sont également présentés.
PCT/GB2009/050493 2008-05-12 2009-05-11 Dérivés de cyclopropyl benzamide utilisés en tant qu'intermédiaires pour des inhibiteurs de cytokines WO2009138778A1 (fr)

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US61/052,363 2008-05-12

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042502A1 (fr) * 2003-10-24 2005-05-12 Astrazeneca Ab Derives d'amides
WO2005061465A1 (fr) * 2003-12-20 2005-07-07 Astrazeneca Ab Derives amide supportant un substituant cyclopropylaminoacarbonyle utiles en tant qu'inhibiteurs de cytokine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042502A1 (fr) * 2003-10-24 2005-05-12 Astrazeneca Ab Derives d'amides
WO2005061465A1 (fr) * 2003-12-20 2005-07-07 Astrazeneca Ab Derives amide supportant un substituant cyclopropylaminoacarbonyle utiles en tant qu'inhibiteurs de cytokine

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