IL178102A - Formamide derivatives, pharmaceutical compositions comprising them and use thereof in the preparation of medicaments for therapy - Google Patents
Formamide derivatives, pharmaceutical compositions comprising them and use thereof in the preparation of medicaments for therapyInfo
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- IL178102A IL178102A IL178102A IL17810206A IL178102A IL 178102 A IL178102 A IL 178102A IL 178102 A IL178102 A IL 178102A IL 17810206 A IL17810206 A IL 17810206A IL 178102 A IL178102 A IL 178102A
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A61P11/08—Bronchodilators
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- 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
- C07C237/30—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 the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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- 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
- C07C237/32—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 the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/46—Y being a hydrogen or a carbon atom
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- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
- C07C323/41—Y being a hydrogen or an acyclic carbon atom
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- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
- C07C323/40—Y being a hydrogen or a carbon atom
- C07C323/42—Y being a carbon atom of a six-membered aromatic ring
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- 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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
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- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/24—Camphidines
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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- C07C2601/14—The ring being saturated
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- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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- C07C2603/58—Ring systems containing bridged rings containing three rings
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Description
178102/2
"PI ETO"? nisnn norm απιτοπ ΙΓΠ Ν o^ nn D^mgi D'TODD , ΠΝΤΠΊΕΙ JITITJ]
FOPvMAMIDE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS COMPRISING THEM AND USE THEREOF IN THE PREPARATION OF MEDICAMENTS FOR
THERAPY
r
This invention relates to β2 agonists of general formula:
in which R1, R2, n and Q1 have the meanings indicated below, and to processes
for the preparation of, compositions containing and the uses of such derivatives.
EP 1 235 787 and WO 01/42193 relate to aminoethanol multibinding compounds which are beta2-adrenergic receptor agonists useful in treating respiratory diseases.
CH 686 869 teaches that using the active enantiomer of beta-2-sympathomimetic broncho dilators, reduces the likelihood of side effects. ES 2 005 492 discloses the preparation of
N-hydroxyphenyl formamide derivatives. US 2004/006102 relates to alkoxy aryl compounds useful for treating diseases associated with beta-adrenergic receptor activity, such as asthma and chronic obstructive pulmonary disease. WO 03/042160 discloses arylaniline derivatives as beta-2-adrenergic receptor agonists, useful for treating pulmonary disease. RU 2006 113 700 and US 2005/0113411 relate to amino-substituted ethylamino derivatives, which are beta-adrenergic receptor agonists useful to treat pulmonary diseases. US 2002/0026065 relates to 2-Hydroxy-3-(4-hydroxy-3-sulfamidophenyl)-propylamines, which are beta-3 adrenergic agonists, useful in the treatment of e.g. diabetes, obesity and depression. US 4,478,849 relates to
N-substituted-methyl-2-hydroxy-2-phenyl-ethanamine derivatives which are useful as anti-obesity and anti-hyperglycaemic agents.
Adrenoceptors are members of the large G-protein coupled receptor
super-family. The adrenoceptor subfamily is itself divided into the a and β
subfamilies with the β sub-family being composed of at least 3 receptor subtypes: β1, β2 and β3. These receptors exhibit differential expression patterns in
tissues of various systems and organs of mammals. β2 adrenergic (β2)
receptors are mainly expressed in smooth muscle cells (e.g. vascular,
bronchial, uterine or intestinal smooth muscles), whereas β3 adrenergic
receptors are mainly expressed in fat tissues (therefore β3 agonists could
potentially be useful in the treatment of obesity and diabetes) and β1
adrenergic receptors are mainly expressed in cardiac tissues (therefore β1
agonists are mainly used as cardiac stimulants).
The pathophysiology and treatments of airway diseases have been
extensively reviewed in the literature (for reference see Barnes, P.J. Chest,
1997, 111:2, pp 17S-26S and Bryan, S.A. et al, Expert Opinion on
investigational drugs, 2000, 9:1, pp25-42) and therefore only a brief summary
will be included here to Drovide some background information.
Gluracorticosteroids, antMeukotrienes, theophylline,, cromones, anti-. cholinergics and β2 agonists constitute drug classes that are currently used to treat allergic and non-allergic airways diseases such as asthma and chronic obstructive airways disease (COPD). Treatment guidelines for these diseases include both short and long acting inhaled β2 agonists. Short acting, rapid onset β2 agonists are used for "rescue" bronchodilation, whereas, long-acting forms provide sustained relief and are used as maintenance therapy.
Bronchodilation is mediated via agonism of the β2 adrenoceptor expressed on airway smooth muscle cells, which results in relaxation and hence bronchodilation. Thus, as functional antagonists, β2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins. Because β2 receptors are so widely distributed in the airway, β2 agonists may also affect other types of cells that play a role in asthma. For example, it has been reported that β2 agonists may stabilize mast ceils. The inhibition of the release of bronchoconstrictor substances may be how β2 agonists block the bronchoconstrictlon induced by allergens, exercise and cold air. Furthermore, β2 agonists inhibit cholinergic neurotransmission in the human airway, which can result In reduced cholinergic-reflex bronchoconstriction.
(n addition to the airways, it has also been established that β2 adrenoceptors are also expressed in other organs and tissues and thus β2 agonists, such as those described in the present invention, may have application in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, * inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
However, numerous β2 agonists are limited in their use due to their low selectivity or adverse side-effects driven by high systemic exposure and mainly mediated through action at β2 adrenoreceptors expressed outside the airways
3
(muscle tremor, tachycardia, palpitations, restlessness). Therefore there is a need for improved agents in this class.
Accordingly, there fs still a need for novel β2 agonists that would have an appropriate pharmacological profile, for example in terms of potency, selectivity, pharmacokinetics or duration of action. In this context, the present invention relates to novel β2 agonists.
Various formamide derivatives have already been disclosed. For example, US2004/0006112 discloses compounds active as β2 agonist, of formula:
US2003/0229058 discloses selective β2 agonists of formula :
R13
However, none of the above formamide derivative have shown a pharmacological profile allowing them to be used as efficient drugs in the treatment of p2-mediated diseases and/or conditions, such as allergic and non- allergic airways diseases; In particular by the inhalation route.
The invention relates to the compounds of general formula (1):
wherein the (CH2)n-C(=0)Q1 group is in the meta or para position,
- R1 and R2 are independently selected from H and C1-C4 alkyl;
- n is 0, 1 or 2;
- Q1 is a group selected from,
wherein p is 1 or 2 and q is 1 or 2, said group being optionally bridged by one carbon atom,
and a group *-NR8-Q2-A, wherein Q2 is a C1-C4 alkylene, R8 is H or C1-C4 alkyl and A is pyridyl, C3-C10 cycloalkyi, said cycloalkyi being optionally bridged by one or more, preferably 1 , 2, 3 or 4, carbon atoms, tetrahydropyranyl, piperidlnyl, tetrahydrothiopyranyl or a group
O 2l)05/U«J284<) PCT/IB20()5/0U061!>
- R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1-C4 alkyl. OR9, SR9, SOR9, S02R9. halo. CN, C02R9, CF3, OCF3, S02NRBR10, CONR9R10, NR9R10, NHCOR10 and phenyl optionally substituted with 1 to 3 groups selected from OR9, halo and C1-C4 alkyl
- R9 and R10 are the same or different and are selected from H or C1-C4 alkyl and the * represent the attachment point to the carbonyl group;
or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof.
The compounds of formula (1) are agonists of the β2 receptors, that are particularly useful for the treatment of p2-mediated diseases and/or conditions, by showing excellent potency, in particular when administered via the inhalation route.
In the here above general formula (1), C1-C4 alkyl and C1-C4 alkylene denote a straight-chain or branched group containing 1 , 2, 3 or 4 carbon atoms. This also applies if they carry substituents or occur as substituents of other radicals, for example in 0-(Ci-C4)alkyl radicals, S-(Ci-C4)alkyl radicals etc... . Examples of suitable (Ci-C4)alkyi radicals are methyl, ethyl, /i-propyl, /so-propyl, n-butyl, feo-buty!, sec-butyl, fert-butyl.... Examples of suitable 0-(Ci-C4)alkyl radicals are methoxy, ethoxy, n-propyloxy, /so-propyloxy, n-butyloxy, feo-butyloxy, sec-butyloxy and feri-butyloxy.
The C3-C10 cycloalkyi wherein 2 carbon atoms or more are optionally bridged by one or more carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, adamantyl, bicyclo[3.1.1]heptane,
bicydo[2.2.1]heptane, bicyclo[2.2.2loctane. Preferred cyctaalkyl groups are cyclohexyl and adamantyl.
Finally, halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.
In the following, the free bond on the phenyl group such as in the structure below,
means that the phenyl can be substituted in the meta or para position.
The compounds of the formula (1 )
can be prepared using conventional procedures such as by the following illustrative methods in which Q1, Q2, R\ R2, A and n are as previously defined for the compounds of the formula (1 ) unless otherwise stated.
The amide derivatives of the formula (1) may be prepared by coupling an acid of formula (2):
with an amine of formula NHR8-Q2-A (3),
O 20(>5/(>ί)2840 PCT/IB2005/000619
7
The coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g^ 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride , N, Af-dicyclohexylcarbodiimide or 0-(1W-benzotriazol-l-ylJ-W.W.A/'.A -tetramethyluronium hexafluorophosphate), optionally in the presence of a catalyst (e.g. l-hj/droxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazoJe), and optionally In the presence of a tertiary amine base (e.g. N-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may be undertaken in a suitable solvent such as pyridine, dimethylformarnide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10°C and 40°C (room temperature) for a period of 1-24 hours.
Said amine (3), (3'), (3") or (3"') is either commercially available or may be prepared by conventional methods well known to the one skilled in the art (e.g. reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection etc..) from commercially available material.
The acid of formula (2) may be prepared from the corresponding ester of formula (4):
wherein Ra is a suitable acid protecting group, preferably a benzyl group or a (C1-C4) alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule. For example, the
ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen, chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, 1 ,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 20°C and 100°C, for a period of 1 to 40 hours. Alternatively, if the ester is a benzyl group, the ester may be rtydrogenated in the presence of a suitable catalyst (e.g. palladium-on-carbon, or palladium hydroxide-on-carbon) in a suitable solvent such (methanol, ethanol, 2M ammonia in methanol) at a temperature comprised between 20 °C and 50 °C for 1-48 h at 1-4 atmospheres of hydrogen.
The ester of formula (4) may be prepared by reaction of an amine of formula (5) :
wherein Ra and n are as previously defined, with a bromide of formula (6) :
In a typical procedure, the amine of formula (5) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. drrnethylsulfoxide, toluene, N, Akiimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. trlethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 80°C and 120°C, for 12 to 48 hours.
The bromide of formula (6) may be prepared according to the method disclosed in Organic Process Research and Development 1998, 2, 98-99".
The amine of formula (5), where R1 is Me .and R2 is H, may be prepared as either the (R) or {S) enantiomer from the corresponding protected amine of formula (7) :
wherein Ra and n are as previously defined and Rb and Rc represent any suitable substituents so that HNRbRc is a chiral amine (for example, Rb may be hydrogen and Rc may be α-methylbenzyl), provided that the bonds between N and Rb and N and Rc can be easily cleaved to give the free amine of formula (5) using standard methodology for cleaving nitrogen protecting groups, such as those found in the text book Protective Groups in Organic Synthesis Third Edition by T. W. Greene and P. G. M. Wuts, John Wiley and Sons Inc., 1999.
The amine of formula (7) may be prepared as a single diastereomer by reaction of an amine of formula HNRbRc with a ketone of formula (8):
wherein Ra, Rb, Rc and n are as previously defined.
In a typical procedure, the reaction of the ketone of formula (8) with the amine of formula HNRbRc leads to a chiral intermediate which is in turn reduced by a suitable reducing agent (e.g. sodium cyanoborohydride of formula NaCNBH3 or sodium triacetoxyborohydride of formula Na(OAc)sBH) optionally in the presence of a drying agent (e.g. molecular sieves, magnesium sulfate) and optionally in the presence of an acid catalyst (e.g. acetic add) to give the amine of formula (7) as a mixture of diastereomers. The reaction is generally done in a solvent such as tetrahydrofuran or dichloromethane at a temperature comprised between 20°C and 80°C for 3 to 72 hours. The resulting product is then converted to the hydrochloride or nitrate salt and selectively crystallised from a suitable solvent or mixture of solvents (e.g. isopropanol, ethyl acetate,
WO 2005/092840 PCT/IB20U5/0(M)6]!>
1»
ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol) to give (7) as a single diastereomer.
The ketone of formula (8) where n=1 may be prepared by palladium mediated coupling of an aryl halide of formula (9):
wherein Ra is as previously defined and Hal represents an halogen atom, which includes, but is not limited to bromo and iodo, with an enolate or enolate equivalent
In a typical procedure, the aryl halide of formula (9) is reacted with a tin enolate generated in-situ by treatment of isopropenyl acetate with tri-n-butyltin methoxide of formula Bu3SnOMe in the presence of a suitable palladium catalyst (palladium acetate/ tri-orf/jo-tolylphosphine of formula Pd(OAc)2 P(o-Tol ) in a non-polar solvent (e.g. toluene, benzene, hexane). Preferably, the reaction is carried out at a temperature comprised between 80°C and 11 °C for 6 to 16 hours.
The aryi haiide of formula (9) may be obtained by esterification of the corresponding acid of formula (10):
wherein Hal is as previously defined, according to any method well-known to the one skilled in the art to prepare an ester from an acid, without modifying the rest of the molecule.
In a typical procedure, the acid of formula (10) is reacted with an alcoholic solvent of formula RaOH, wherein Ra is as previously defined, in the presence of an acid such as hydrogen chloride at a temperature between 10°C and 40°C (room temperature) for 8 to 16 hours. Alternatively, the acid of
WO 204)5/092840 PCT/IB2()()5/0(M)61!»
11
formula (10) is reacted with a base (for example cesium or potassium carbonate) and treated with an alkyl halide (for example methyl iodide, benzyl bromide) in an appropriate solvent such as N, Akiiemthylformamide at a temperature between 0 X and 40 °C (room temperature) for 1 to 20 h.
The acid of formula (10) is a commercial product.
The amine of formula (5), where R1 and R2 are both C1-C4 alkyl, may be prepared according to the following scheme:
Scheme 1
wherein R1, R2 and Ra are as previously defined.
In a typical procedure, the ester of formula (1 1) is reacted with an "activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCI or R2Li) to give the corresponding tertiary alcohol of formula (12) using the method described above.
Said tertiary alcohol of formula (12) is then treated with an alkyl nitrite . (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulphuric acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks. The resulting amino acid is then esterified using the method described herein to give the amine of formula (5).
WO 2000092840 PCT/IB2IM)5/0006J9
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Alternatively, the amine of formula (5), where R are R2 both C1-C4 alkyl and n=0, may be prepared according to the following scheme:
Scheme 2
(15) (5)
wherein R\ R2 and Ra are as previously defined.
In a typical procedure, the ester of formula (13) is reacted with an "activated" alkyl (organometalHc alkyl such as R2MgBr, R2MgCI or R2Li) to give the corresponding tertiary alcohol of formula (14) using the method described above.
Said tertiary alcohol of formula (14) is then treated with an alkyl nttrile
(e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulphuric acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those mentioned In textbooks to give the bromo amine (15).
The" resulting bromo amine (15) is treated with a suitable palladium catalyst " (e.g. [1,1'-bis(diphenylphosphino)fenOcene]dichloropalladium(ll)f palladium(ll) acetate 1 ,1'-bis(diphenylphosphino)ferrocene], tris(dibenzylideneacetone)dipalladium(0), 2,2'-bis(diphenylphosphino)-1 , 1 - binaphthyldichloropalladiurn(ll)) under an atmosphere of carbon monoxide using RaOH as solvent (e.g. eOH, EtOH, benzyl alcohol), or alternatively
using a co-solvent such as DMF, at elevated ternjaerature (10Q°O) and pressure (1 OOpsi) to give the ester of formula (5).
The ketone of formula (8) where n=2 may e prepared by reduction of an alkene of formula (16) :
in a typical procedure, a solution of the olefin of formula (16) in a suitable solvent (e.g. methanol, ethanol, ethyl acetate}* is treated with a palladium catalyst (e.g. 10% palladium on charcoal) and sirred under an atmosphere of hydrogen, optionally at elevated pressure (e.g. 60 psi), at temperature between room temperature and 60°C for 8-24 hours.
»
The alkene of formula (16) may be prepared by a palladium, mediated coupling of an activated olefin with an aryl halide of formula (17):
In a typical procedure, the aryl halide (17) is coupled with a vinyl ester
(e.g. methyl acrytate) in the presence of a suitable palladium catalyst (e.g. tetrakis(triphenylphosphi.ne)palladlum(0) of formula Pd(PPh3)4, palladium acetatertri-o/too-tolylphosphine of formula Pd(OAc)2 P(o-Tol)3 or (diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdCI2) in a suitable solvent (e.g. acetonitrile, N, dimethylformamide, toluene), optionally in the' presence of a base such as triethylamine at a temperature between 40°C and 110°C for 8 to 24 hours.
The ketone of formula (1 ) is a commercial product
WO 2005/0i>2840 Ρ€Τ/ΙΒ2005/00(Κ»19
14
Alternatively a compound of formula (1) may be prepared, by reaction of a bromide of formula (6) and an amine of formula (18):
where R\ R2, Q1and n are as previously defined for the compounds of the formula (1 ) unless otherwise stated.
In a typical procedure, the amine of formula (18) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethylsulfoxide, toluene, N, W-dimethylformarnide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamlne, diisopropylethyiamine, potassium carbonate) at a temperature comprised between 80eC and 120°C, for 12 to 48 hours.
The amide of formula (18) may be prepared by coupling an acid of formula (19) incorporating a suitable amine protecting group P1:
with an amine of formula NHR8-Q2-A (3),
' The coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, ΛΓ-dicyclohexylcarbodiirnide), optionally in the presence of a catalyst (e.g. l-hydroxybenzotriazole hydrate or 1-hydroxy-7-
azabenzotriazole), and optionally In the presence of a tertiary amine base (e.g.. /V-methylmorpholine, triethylamine or dBsopropylethylamine). The reaction may be undertaken In a suitable solvent such as pyridine, A/.W-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10°C and 40°C (room temperature) for a period of 1-24 hours.
Said amine (3), (3'). (3") and (3'") is either commercially available or may be prepared by conventional methods well known to the one skilled in the art (e.g. reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection etc...) from commercially available material.
The acid of formula (19) may be prepared from the corresponding ester of formula (5).
The acid of formula (19), where R1 and R2 are both C C4 alkyi, may be prepared from the ester (5) incorporating a suitable amine protecting group P1 either before or after the acid formation:
wherein Ra is a suitable acid protecting group, preferably a (C C4)alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule. For example, the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or .mixture of solvents (e.g. water, 1,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 20°C and 100°C, for a period of 1 to 40 hours.
The amine of formula (5), where R1 and R2 are both H, may be prepared according to the following scheme:
Scheme 3
WO 2005/092840 PCT/IB20(»5/00061!>
If.
wherein R1, R2 and Ra are as previously defined.
In a typical procedure, the acid of formula (20) is preferentially reduced to the corresponding alcohol (21) in the presence of the ester. This may be performed by formation of the acyl imidazole or mixed anhydride and subsequent reduction with sodium borohydride or another suitable reducing agent.
Said primary alcohol of formula (21) is then converted into a leaving group such as mesylate, tosyJate, bromide or iodide and displaced with an appropriate amine nucleophile. The preferred nucleophile is an azide ion which can then be reduced to the primary amine via hydrogenation or triphenylphosphine. Alternative nucleophiles could include ammonia or alky!amines such as benzyiamine or allylamine and subsequent cleavage of the aikyf group to furnish the amine.
WO 2005/092840 Ρ<Π7ΙΒ20«5ΛΜΜΗί19
17
Alternatively, the amide of formula 22, can be prepared as outlined earlier using, standard amide bond forming reactions. The compound of formula 22 can then be reacted with a protected vinylamine (e.g. W-vinylphthalimide) in the presence of a suitable catalyst (e.g. pa!ladium(ll)acetate) and a phosphine (e.g. triphenylphosphine, tri-orfno-tolylphosphine) in the presence of a base (e.g. N, N-diisopropylethylamine) in a solvent (e.g. Ν,Ν-dimethylformamide, acetonitrile) at a temperature comprised between 20 °C and 120 *C and for 1 to 48 hours. The alkene of formula 23 can then be reduced to an alkane of formula 24 using standard hydrogenation conditions and the protecting phthalimide group removed using standard protecting group removal. The amine of formula 25 can be reacted with a bromide of formula 6 to give a compound of formula 1 using conditions outlined earlier.
For some of the steps of the here above described process of preparation of the compounds of formula (1), it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T. W. Greene and P. G. M. Wuts (Protective Groups in Organic Synthesis, John Wiley and Sons Inc., 1999) or by P. J. Kocienski {Protecting groups, Georg Thieme Verlag, 1994), can be used.
All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.
Also, the compounds of formula (1) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.
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Subgroups of compounds of formula (1) containing the following substituents. are preferred:
Preferably Q1 is a group *-NH-Q2-A, wherein A is cyclohexyl or adamantyl.
Preferably, Q1 Is
wherein R3. R4, R5 and R6 are H.
Preferably Q1 is
wherein one of R to Re is OH and the others are H.
Preferab1y,.Q1 is a group *-NH-Q2-A, wherein A is a group
R3 ' ,R4
WO 2005/092840 PCT/fB20O5/0(HI619
19
wherein R3, R4, R5, Re and R7 are the same or different and. are selected from H, C,-G* a!kyl, OR9, SR¾, SOR9, S02Re, halo, CN, C02R9, CF3, OCF3, SO2NRsR10f CONR9R10, NR9R10, NHCOR10 and. phenyl optionally substituted with 1 to 3 groups selected from OR9, ha and C1-C4. alkyl provided at least 2 of R3 to R7 are equal to H; wherein R9 and R10 are the same or different and are selected from H or C1-C4 alkyl.
More preferably, Q1 is a group *-NH-Q2-A, wherein A is a group
wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, OH, CH3, OCH3, OCF3, OCHrCH3> SCH3, N(CH3)2, N(C=0)CH3, C(=0)NH2 , COOCH3, SO2CH3, S02NH2| halo, CN, CF3 and phenyl opt'onally substituted with OH provided at least 2 of R3 to R7 are equal to H.
In a preferred embodiment, A is a group
wherein one of R3 to R7 Is OH or phenyl substituted with OH.
In a preferred embodiment, A is a group
2(1
wherein one of R3 to R7 is OH or phenyl substituted with OH and the other are selected from H, CI or CH3 provided at least 2 of R3 to R7 are H.
Preferably A is naphthyl optionally substituted with OH.
Preferably, A is naphthyl substituted with OH.
In the above groups of compounds, the following substituents are particularly preferred:
Q2 is -CH , -(CH2)r. -(CH2)3-, -CH2-C(CH3)r or -C(CH3)r, preferably -CH_r or - (CH&- R is H or C1-C4 alkyl and R2 is C1-C4 alkyl. More preferably, R1 is H or CH3 and R2 is H or CH3,
n is O or l.
R1 is H and R2 is CH3 and n is 0 or 1.
R is CH3, R2 is CH3 and n is 0 or 1.
Particularly preferred are the compounds of the formula (1) as described - in the Examples section hereafter, i.e. :
A/-Benzyl-2-(3-{2-I(2 ?)-2-(3-formylamina -hydroxyphenyl)-2- hydroxyethylamino]-2-methylpropyI}phenyl)acetamide;
/V-(3, ~Dinrethylbenzyl)-2-(3^2-[(^^
hydroxyethylamino]-2-methylpropyl}phenyl)acetamide;
W-[2-(4-CWorophenyl)ethyl>3-{2-K^^
hydroxyethylaminoI-2-methylpropyl}benzamide;
N-[2-(2-Chlorophenyl)ethyl]-3^2-[(2R)-2-^^
hydroxyethylamino]-2-methylpropyl}benzamide;
3^2^{2/?)-2^3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropyl}- V-<2-naphthalen-1-ylethyl)benzamide;
3^2-I(2R)-2^3-Formylamlno^- ydroxyphenyl)-2-hydroxyethylarr»ino]-2-met ylpropyl}-W-[2-{4-methylphenyl)ethyl]benzamide;
W42-(2,6-Dimethylphenyl)ethyl]-3^-[(2^^
2-hydroxyethy)amino]-2-methy)propyl}benzamide;
/V-[2-(2,3-Dimethylpheny!)ethyn-3^2-[{2^
2-hydroxyethylamino]-2-methyipropylbenzamide;
3^2-[(2R)-2-(3-Formylamino^-hydroxyphenyl)-2-hydroxyethylam
methylpropyl}-W-[2-(4-hydfoxy-2,3^imethylphenyl)ethyI]benzamide;
3-{2-[(2R)-2-(3-FormyIamino-4-hydroxyphenyl 2-hydroxyethylamino]-2-met ylpropyl}-/V-{2-(4-methoxyphenyl)et yl]benzamide;
3^2-[(2R)-2^3-Formylamino^-hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropyl}-W-phenethyI-benzamide
W tyclohexyl ethyl^2-[(2R)-2-(3-fo^
hydroxyethylaminoi-2-methylpropyl}benzamide;
/V-[5-((1 /?)-2-{1 , 1 -Dimethyl-2-[3-(piperidine-1 -carbonyl)phenyl]ethylamino}-1 -hydroxyethyl)-2-hydroxyphenyl]fofmamide;
3^2-[(2R)-2-(3-Formylamino^hydroxyphenyl)-2- ydroxyethylamino]-2- methylpropyl}-W-[2-(3-trifluoromethylphenyl)ethyQbenzamide;
3-{2-[(2R)-2-(3-Formylamino^hydroxyphenyl)-2-^ydroxyethyiamino]-2- methylpropyl}-AK3-phenylpropyl)benzamide;
3^-[(2/^2-(3-Formylamino^-hydroxyphenyl)-2 iydroxyethylamino]-2- methylpropyl}-A/-indan-2-ylbenzamide'1
3^2-I(2R 2 3-Formylamino-4-hydro)(yphenyl)-2-iiydroxyethylamino]-:2- met ylpropyl)-W-(2-pyridin-2-ylethyl)benzamide;
3^2r{(2R)-2-(3-FormylamincH^-hydroxypheny!^2-hydroxyethylamino]-2- methylpropyl}-N-[2-(4-sulfamoyIphanyl)ethyI]benzamicl€;
W-(4^imethy!aminobenzyl)-2^
hydroxyphenyi)-2-hydroxyethylamino]propyl}phenyl)acetamide;
W-[5-(2-{{1 R)-2-[3-(3,4-Dihydro-1 H-isoquinoline-2-carbonyl)-phenyI]-1 ,1 -dimethyl-ethylamino}-1-hydroxyethyl)-2-hydroxyphenyl]formamide;
3^^(2R)-2-(3-Formylamino-4-hydroxyphenyJ)-2-hydroxyethylaminoI-2-methyIpropy^A/-(4-hydroxyblphenyl-3-yliTiethyl)benzamide
3^2-[(2R)-2-(3-Formylamino - ydroxyphenyl)-2-hydroxyethy amino]-2^ methylpropyl}-A/-I2-(4-hydroxy-2,5-dimethylphenyl)ethyl]benzamide;
3- {2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylarnino]-2-methylpropy!}-W-[2-(4-hydroxy-3-meth^
W-(4-Acety1aminobenzyl>2-(3-{(2R)-2-[(2R
2- hydroxyethylamino]propyI}p enyl)acetamide;
4- {I2-(3-{(2R)-2-I(2R>.2-(3-Formylamino-4- ydroxyphenyl)-2-hydroxyet ylamino]propyl}phenyl)acetylamino]methyl>benzamide;
-Adamantan-1 -yl-3-{2-I(2R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropy0benzarnide;
3^2-[(2R)-2^3-Formylamino-4-hydroxyp enyl)-2-hydroxyethylamino3-2-methylpropyl}-N-(2-hydroxy-naphthaien-1-ylmethyl)ben2amide;
3- {2-[(2R)-2-(3-Formylamina^- ydroxyphenyl)-2-hydroxyethirtamino>2- methylpropyl}-/V-(4-hydfOxy-3l5-dimethylbenzyl)benzamide;
3^2-[{2R)-2-(3-Formylamino-4-hydroxyphenyl>-2-hydroxyethylarnino]-2- meth^propyl}- V-(6-hydroxy-naphthal8N-2-ylmet yl)ben2amide;
W-(3,6-Dich(oro-2 iydraxybercy1)-3-{2-[(2R)-2-(3-formylamino-4- hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropyl}benzamide;
Nr(3,4-Dimetoylbenzyl)-2-(3-{2-[(2R)-2 3^^^
hydroxyethylamino]ethyi}phenyl)acetamide;
3^-[(2R)-2-(3-Formylamino^-hydroxyphenyl>-2-hydroxyethylamino]-2- methylpropyl}-W-[2-(4-hydroxyphenyl)-2-rT»ethylpropyl]benzamide;
3^-[(2R 2-(3-Formylamino^-hydroxypheny()-2-hydroxyethyJaminoJ-2- methylpropylVA 4'-hydroxybip enyl^ylmet yl)benzamide;
A/-Adamantan-1-yl-2-(3^(2R 2-K2R)-2-(3-formylamino-4- ydrDxyp enyl 2- hydroxyethylamino]propyI}phenyl)acetamide;
WO 2(105/092840 PCT/IB20<l5A)0<>61i>
23
W-[5-(2-{2-l3-(10-Aza-tricyclo[6.3.1.0*2 ,7*]dodeca-2(7),3.5-tri8.ne-10r carbonyl)p enyl]-1 limet ylethylamlno 1-hydroxyethyl)-2-hydroxyptienylJ-formamide;
2-(3 (2R 2-[(2R)-2-(3-Formylamino-4-hydroxyphenyl)-2-hydroxyethylaminolpropylJphenylJ-A^i^-hydroxybiphenyl-S-ylmethy acetamide; 4-{{2 3-{2-[(2R)-2-(3-Formylamino-4-hydroxypte^
methyipropyl}phenyl)-acetylaminojmethyl}benzoic acid methyl ester,
2^3^(2R)-2-[(2R)-2-(3-Formyiamino^hydrox^
methylpropyl}phenyl)-W 4-trifluoromethoxy-ben2yl)acetarnide;
AK2-Chloro^-hydroxybenzyl M-ethy^
hydroxyphenylV2-hydroxyethylamino]-2-^^
W-(2-Ch)oro^hydroxybenzyl)-2^(2R)-2-i(2R>2-(3-formylamlno-^
hydroxyphenyl)-2-hydroxyethylamino]-2-methylpropy0^henyl)ac^mide 2-(3-{(2R)-2-[(2R)-2-(3 ormylamino-4-hydroxyphenyl)-2-hydroxyethylaminoJpropyl}phenyl)-/V-^
2-(3-{(2R)-2-[(2R -2-(3-Formylamlno-4-hydroxyphenyl)-2- hydroxyethylamino]propyl}phenyl)-/V-(2-hydrOxynaphthalen-1- ylmethyl)acetamide;
N-(5-C loro-2- ydroxybei^l)-2^{(2R)-2-[(2R).2-(3-foi nylamino-4- hydroxyphenyf)-2-hydroxyethylammolprapyl}phenyl)acetarn(de;
AH3,5-Dichloro-24iydroxybenzyl)-2-(3^(2R^^^^
hydroxyphenyl)-2-hydroxyethylamino]propyl}phenyl)acetamide;
2-(3-{(2R)-2-i(2R)-2-(3-Formylamino-4-hydroxyphenyl>2- hydroxyethylamino]propyl}phenyl)-W-(6-hydroxynap thalen-2- ylmethy!)acetamlde;
2-(3-{(2R -2-[(2R)-2-{3-Formylamino-4-hydroxyphenyl)-2- hydroxyethylamir >]propyl}phenyl)-A^
W-(4-Cyano-benzyl)-2-(3^2-[(2R 2-(3-formylamino-4-hydroxyphenyl 2- hydroxyethylamino]-2-methylpropyl}-phenyi)-acetamlde;
2-(3^2-[(2R)-2-(3-Formylamlno-4-hydroxypbeny))-2^ydr6xyethylamino]-2- methylpropyl}-phenyl)-A/-(4-methanesulfon>4-benzy])-acetamide;
2-(3-{2^(2R)-2-(3'FormylammcH^hydroxyphenyl) 2-hydroxy^ methylpropyl)-phenyl)- -(4-metfiylsuIfanyl-benzyl)-acetarnide;
2-(3-{2-[(2R)-2 3-Formylamino^-hydroxyphanyl)-2^ydiOxyethylarninoI-2-metbylpropyl}-phenyl)-/V-(44rifluorornBthyl-benzyl)-acetarnide;
2-(3^2-[(2R)-2-(3-Formy1amino-4-hydroxypheny^
methylpropy phenyl)-W-(4'-hy^
/V-[2-(5-Chloro-2-hydroxyphenyl>emyO-3^[(2R)-2^3 omylamino^
hydroxyphenyl)-2-hydroxyethylaminol-2-methylpropyl}-benzamide;
2- (342-[(2R)-2-(3-Fomiylamino^-hydroxyphenyl)-2-h^
methylpropyl}phenyl)-W-(4'-^
3^2-[(2R)-2-(3-Formylamino^hydroxyphenyf)-2-hy^
[2-(4-hydroxyphenyl)-2-methylpropyl]-ben2amide;
A^(2-Chloro^hydroxyben2yl 2 3^(2R 2-[(2RH2R)-2-(3-formylammo-4-hydroxyphenyl)-2-hydroxyethylamino]propyI}phenyl)acetarnide;
AH2-(5~Chloro-2-hydroxyphenyl)^thy^
hydroxyphenyl)-2-hydroxyethylaminoI-2-methylpropyl}benzamide;
3- {2 (2R)-2-(3-Forrriylamino^ydroxyphenyl)-2-hydroxyethylam
[2-(4-hydroxyphenyl 2-methylpropyi]benzamide;
2^3^2-[(2R)-2-(3-Formytamino-4-hydroxyphenyl)-2-hydroxyethyJam
methylpropyl}phenyJ)-A/-(tetrahydiO hiopyran^-yl)acetamide;
N^5-Chloro-2-hydroxybenzyl)^
2-hydraxyethylarnino]-2-methylpropyl}phenyI)acetamide; and,
-{5-l(1 R)-2-((1 R>2-{3-[3-(3,4-Dihydro-1 H-isoquinolin-2*yl)-3- oxopropyl]phenyl}-1 -methylethylamino)-1 -hydroxyethyl]-2- hydroxyphenyl}formamide.
According to one aspect of the present invention, the compounds of formula (1) wherein the (CH2VC(s=0)Q1 group is in the meta position are generally preferred.
Pharmaceutically acceptable salts of the compounds of formula (1) include the acid addition and base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzdte, hydrochloride/chloride, hydrabromide bromide, hydroiodide/iodide, hydrbgen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2-napsyfate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen, phosphate/phosphate dihydrogen, pyroglutamate, saccharate, stearate, succinate, tannate, D- and L-tartrate, 1-hydroxy-2-naphthoate tosylate and xinafoate salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Pharmaceutically acceptable salts of compounds of formula (1) may be prepared by one or more of three methods:
(i) by reacting the compound of formula (1) with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (1) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or
(iii) by converting one salt of the compound, of formula .(1) to. another by. reaction with an appropriate acid or base or by means of a suitable ion exchange column.
All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent The degree of ionisatfon in the resulting salt may vary from completely ionised to almost non-ionised.
The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.
Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).
Hereinafter all references to compounds of formula (1) Include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof. "
The compounds of the invention include compounds of formula (1) as hereinbefore defined, including ail polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric
isomers) as hereinafter defined and isotopically-labeled compounds of formula (1).
As indicated, so-called 'pro-drugs'_of the compounds of formula (1) are also within the scope of the invention. Thus certain derivatives of compounds of formula (1) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (1) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and 'Bloreversible Carriers in Drug Design', Pergamdn Press, 1987 (ed. E. B Roche, American Pharmaceutical Association).
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula {1) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).
Some examples of prodrugs in accordance with the invention include:
(i) where the compound of formula (1) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (1 ) is replaced by (Ci-CB)alkyl;
(ii) where the compound of formula (1) contains an alcohol functionality (- OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (1) is replaced by (CrCeJalkanoyloxymethyl; and
(ill) where the compound of formula (1) contains a primary or secondary amino functionality (-NH2 or -NHR where R≠H), an amide thereof, for
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example, a compound wherein, as the. case may . be, one qr both hydrogens of the amino functionality of the compound of formula (1) Is/are replaced by <C C 0)alkanoyl. ,
Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found In the aforementioned references.
Moreover, certain compounds of formula (1) may themselves act as prodrugs of other compounds of formula (1 ).
Also included within the scope of the invention are metabolites of compounds of formula (1), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include
(i) where the compound of formula (1) contains a methyl group, an hydroxymethyl derivative thereof (-CH3 -> -CH2OH):
(ii) where the compound of formula (1) contains an alkoxy group, an hydroxy derivative thereof (-OR→ -OH);
(iii) where the compound of formula (1) contains a tertiary amino group, a secondary amino derivative thereof {-NR1 R2→ -NHR1 or -NHR¾
(iv) where the compound of formula (1 ) contains a secondary amino group, a primary derivative thereof (-NHR1→· -NH2);
(v) where the compound of formula (1) contains a phenyl moiety, a phenol derivative thereof (-Ph→ -PhOH); and
(vi) where the compound of formula (1) contains an amide group, a carboxylic acid derivative thereof (-CONH2→ COOH).
Compounds of formula (1) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (1) contains an alkenyl or alkenylene group, geometric cisltrans (or Z E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (tautomerism') can occur. This can take the form
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of proton tautomerism in compounds of formula (1) containing, for example, an. imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
Included within the scope of the present Invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, cMactate or /-lysine, or racemic, for example, {//-tartrate or c /-arginine.
C/s/frans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1 ) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantlomer(s) by means well known to a skilled person.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a
hydrocarbon, typically heptane or hexane, containing from 0 to 60% by volume, of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel (Wiley, New York, 1994).
According to one aspect of the present invention, the (R,R)-stereoisomer of the formula below, wherein R1 is hydrogen and R2 is CrC4 alkyl, preferably methyl, and n and Q1 are as defined above, is generally preferred:
The present invention includes all pharmaceutically acceptable isotopically- labelled compounds of formula (1) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates In nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and ' 14C, chlorine, such as ^CI, fluorine, such as 18F, iodine, such as 23l and 125l, nitrogen, such as 13N and 5N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulphur, such as 35S.
Certain isotopically-!abel!ed compounds of formula (1), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue
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distribution studies. The radioactive isotopes tritium, i.e. H. and carbon-.14, i.e.. 1 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased In vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, suc)h as 1 C, 18F, 150 and 13N, can be useful In Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of formula (1)L"can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D20, de-acetone, de-DMSO.
The compounds of formula (1), their pharmaceutically acceptable salts and/or derived forms, are valuable pharmaceutically active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the β2 receptor is involved or in which agonism of this receptor may Induce benefit, in particular the allergic and non-allergic airways diseases but also in the - treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.
Compounds of the invention intended for pharmaceutical use may be. administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form-
Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).
The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or- buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders,' lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations.
Liquid formulations include suspensions, solutions, syrups. and elixirs. Such formulations may be employed as fil lers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001 ).
For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. I n addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain 'diluents, such as lactose <monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet
Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
-Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
The formulation of tablets is discussed in Pharmaceutical Dosage Forms: ' Tablets, Vol. 1 , by H. Lieberman and L Lachman (Marcel Dekker, New York, ' 1980). "
Consumable oral films for human or veterinary use are typically pliable water- soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (1 ), a film-forming polymer, a binder, a solvent, a humectant, a plastlciser, a
stabiliser or emulsifier, a viscosity-modifying agent and a solvent . Some, components of the formulation may perform more than one function.
The compound of formula (1) may be water-soluble or insoluble. A water-soluble compound typically comprises from 1 weight % to 80 weig ht %, more typically from 20 weight % to 50 weight %, of the solutes. Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes. Alternatively, the compound of formula (1) may be in the form of multiparticulate beads.
The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the ra nge 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cool ing agents, co-solvents (including oils), emollients, bulking agents, anti-foam ing agents, surfactants and taste-masking agents.
Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing suppo rt or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freezer-drying or vacuuming.
Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On-line, 25(2), 1-14 , by Verma
ef a/ (2001). The use of chewing gum to achieve controlled Fejease .is described in WO 00/35298.
The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, Intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain exciplents such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of formula (1) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled*, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semisolid, or thtxotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug- coated stents and poiy(cfAlactic-cog!ycolic)acid (PGLA).microspheres.
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The compounds of the invention may also be administered topically "to the skin or mucosa, that is, cJermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and mlcroemuisions. Liposomes may also be used. Typical carriers Include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Spi, 88 (10), 955-958 by Finnin and Morgan (October 1999).
Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.
Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, . pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1',2-tetrafluonoethane or 1 ,1,1, 2,3, 3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesK e agent, for example, chitosan or cyclodextrin.
The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for
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example, ethanol, aqueous ethanol, or a suitable alternative agent for. dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable) excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1/ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from ifA to 10ΌμΙ. A typical formulation may comprise a compound of formula (1), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents, which may be -used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavours, such as menthol and levomenthoi, or sweeteners, such as saccharin or saccharin sodium, may be added to those -formulations of the invention intended for inhaled/intranasal administration.
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Formulations for inhaled/intranasal administration may be .formulated, to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-,
pulsed-, controlled-, targeted and programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff containing from 0.001 mg to 10mg of the compound of formula (1). The overall daily dose will typically be in the range 0.001 mg to 40mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
The compounds of formula (1) are particularly suitable for an administration by inhalation
The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention may also be administered directly to the eye or ear, typically In the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacryiic acid, polyvinyla!cohot, hyaluronic
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acid, a cellulosic polymer, for example, .hydroxypropytmethylceljulose,. hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
The compounds of the invention may be combined with soluble macromolecuiar entities, such as cyclodextrin and suitable derivatives thereof or polyethylene grycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within trie scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit Suitable for coadministration of the compositions.
41
Thus the kit of the invention comprises two or more separate pharmaceutical, compositions, at least one of which contains a compound of formula (1) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
The kit of the invention is particularly suitable for administering different dosage forms, for example parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.
For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0.001 mg to 5000mg depending, of course, on the mode of administration. For example, an intravenous daily dose may only require from 0.001 mg to 40mg. The total daily dose may be administered in single or divided doses_and may, at the physician's discretion, fall outside of the typical range given herein.
These dosages are based on an average human subject having a weight of about 65kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
For the avoidance of doubt, references herein to "treatment" include references ' to curative/palliative and prophylactic treatment
According to another embodiment of the present invention, the compounds of the formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some particularly desired therapeutic end result such as the treatment of pathophysiologically-reievant disease processes including, but not limited to (i)
bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v> signs and symptoms such as breathlessness, dough. The second and more additional therapeutic agents may also be a compound of the formula (1), or a pharmaceutically acceptable salt, derived forms or compositions thereof, or one or more p2 agonists known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents.
As used herein, the terms "co-administration", "co-administered" and "in combination with", referring to the compounds of formula (1) and one or more other therapeutic agents, is intended to mean, and does refer to and include the following:
• simultaneous administration of such combination of compound(s) of formula (1) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient,
• substantially simultaneous administration of such combination of compound(s) of formula (1) and therapeutic agent(s) to a patient In need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient,
• sequential administration of such combination compound(s) of formula .
(1 ) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, whereupon said components are released at substantially different times to said patient; and
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• sequential administration of such combination of compound(s) of formula.
(1) and therapeutic agent(s) to a patient in eed of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner whereupon they are concurrently, consecutively, and/or overlapingly administered at the same and/or different times by said patient,
where each part may be administered by either the same or different route.
Suitable examples of other therapeutic agents which may be used in combination with the compound(s) of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, include, but are by no means limited to :
(a) 5-Lipoxygenase (5-LO) inhibitors or 5-lip$xygenase activating protein (FLAP) antagonists,
(b) Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4, and LTE4,
(c) Histamine receptor antagonists including H1 and H3 antagonists,
(d) cci- and asradrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use,
(e) muscarinic M3 receptor antagonists or anticholinergic agents,
(f) PDE inhibitors, e.g. PDE3, PDE4 and PDE5 inhibitors,
(g) Theophylline,
(h) Sodium cromoglycate,
(i) COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors . (NSAIDs),
(j) Oral and inhaled glucocorticosteroids,
(k) Monoclonal antibodies active against endogenous inflammatory entities, (I) Anti-tumor necrosis factor (anti-TNF-a) agents,
(m)Adhesion molecule inhibitors including VLA-4 antagonists,
(n) Kinin-Bi - and B2 -receptor antagonists,
(0) Immunosuppressive agents,
(p) Inhibitors of matrix metalloproteases (MMPs), 1
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(q) Tachykinin i, NK2 and NK3 receptor antagonists,
(r) Elastase inhibitors, .
(s) Adenosine A2a receptor agonists,
(t) Inhibitors of urokinase,
(u) Compounds that act on dopamine receptors, e.g. D2 agonists,
(v) Modulators of the ΝΡκβ pathway, e.g. IKK inhibitors,
(w) modulators of cytokine signalling pathyways such as p38 MAP kinase or syk kinase,
(x) Agents that can be classed as mucolytics or anti-tussive,
(y) Antibiotics,
(z) HDAC inhibitors, and,
(aa) PI3 kinase inhibitors.
According to the present invention, combination of the compounds of formula (1) with :
- H3 antagonists,
- Muscarinic M3 receptor antagonists,
- PDE4 inhibitors,
- glucocorticosteroids,
- Adenosine A2a receptor agonists,
- Modulators of cytokine signalling pathyways such as p38 MAP kinase or syk kinase, or,
- Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4, and LTE4,
are preferred.
According to the present invention, combination of the compounds of formula (1) with :
- glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, tiunisolide, triamcinolone acetonide, beclomethasone dipropionate,
budesonide, fluticasone propionate, ciclesonide, and raometasone. furoate, or
- muscarinic M3 receptor antagonists or anticholinergic agents including in particular ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine, and telenzepine,
are further preferred.
It Is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment. The description, which follows, concerns the therapeutic applications to which the compounds of formula (1) may be put.
The compounds of formula (1) have the ability to interact with the β2 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role which the β2 receptor plays in the physiology of all mammals.
Therefore, a further aspect of the present invention relates to the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions in which the 62 receptor is involved. More specifically, the present invention also concerns the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions selected from the group consisting of :
• asthma of whatever type, etiology, or pathogenesis, in particular asthma ■ that is a member selected from the group consisting of atopic- asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or
46
inapparent cause, non-atopic asthma, bronchitic asthma,, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, wheezy infant syndrome and bronchiolytis,
chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema,
obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (A OS), exacerbation of airways hyperreactivity consequent to other drug therapy and airways disease that is associated with pulmonary hypertension,
bronchitis of whatever type, etiology, or pathogenesis, in particular, bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis,
acute lung injury,
bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cyllndric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.
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=17
A still further aspect of the present invention also relates to the use of. the compounds of formula (1 ), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug having a β2 agonist activity. In particular, the present inventions concerns the use of the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug for the treatment of β2-mediated diseases and/or conditions, in particular the diseases and/or conditions listed above.
As a consequence, the present invention provides a particularly interesting method to treat a mammal, including a human being, with an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof. More precisely, the present invention provides a particularly interesting method for the treatment of a p2-mediated diseases and/or conditions in a mammal, including a human being, in particular the diseases and/or conditions listed above, comprising administering said mammal with an effective amount of a compound of formula (1 ), its pharmaceutically acceptable salts and/or derived forms.
The following examples illustrate the preparation of the compounds of the formula (1):
Preparation 1 : (3-Ethoxycarbonylmethylphenyl)acetic acid ethyl ester
2,2'-(1,3-Phe'nylene)diacetic acid (10.0 g, 51 mmol) was dissolved in ethanol
• (100 mL) and the solution treated dropwise with acetyl chloride (2.5 mL). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated in vacuo. The residue was taken up in ethyl acetate (100 mL) and extracted with sodium bicarbonate solution (3x 50 mL) and brine (3x 50 mL). The organic phase was dried (MgS04), concentrated in vacuo and the residue triturated with pentane to yield the product (11.8 g).
PCT/lB2«()5/000fi19 O 2005/092840
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1HN R (CDC(3. 400 MHz) S: 1.31 (6H, t), 3.65 (4H, s), 4.20.(4H, q), 7.24-7.36. (4H, m); LRMS ESI m/z 251 [M+Hf
Preparation 2 : (3-EthoxycarbonylmethyIphenyl)acetic acid
A solution of preparation 1 (44.3 g, 177 mmol) and
acid (59.2 g, 308 mmol) in ethanol (24 mL) and dioxan (290 mL) was treated dropwise with hydrochloric acid (12 M, 4.9 mL, 58.8 mmol). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated to low volume. The reaction mixture was diluted with toluene (125 mL) and the resulting slurry filtered. The filtrate was concentrated in vacuo and the residue taken up in water and basified with sodium bicarbonate until pH neutral. The mixture was diluted with ethyl acetate (200 mL) and the organic layer was separated and washed with sodium bicarbonate solution (5x 30 ml) and brine (50 mL). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with diethylether (3x 30 mL). The organics were combined, dried (MgS04) and concentrated in vacuo. The residue was triturated with pentane to yield a colourless solid ( 0.8 g).
HNMR (CDgOD, 400 MHz) δ: 1.25 (3H, t), 3.60 (2H, m), 3.63 (2H, m), 4.15 (2H, q), 7.18-7.32 (4Hf m); LRMS ESI m z 245 iM+Naf
Preparation 3 : [3-(2-Hydroxy-2-methylpropyl)phenyl]acetic acid
Methyl magnesium chloride (51 mL of a 3M solution in tetrahydrofuran, 153 mmol) was added dropwise to a stirred solution of the preparation 2 ( 1.6 g, 51 mmol) (International Journal of Peptide and Protein Research, 1987, 29(3), 331) in tetrahydrofuran (300 mL) at 0 °C under nitrogen. The reaction was allowed to warm to room temperature overnight with the formation of a thick white precipitate and then water (50 mL) and 2N hydrochloric acid (80 mL) were
WO 20OS/O9284O PCT/JB2W)5/IM>0li19
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cautiously added. The aqueous was extracted with ethyl acetate (2x 300 mL). and the combined organics washed with brine $0 mL), dried (sodium sulfate), and the solvent removed in vacuo to fumish the htle compound as a golden oil (i i-2 g),
1HNMR (CDCI3, 400 MHz) δ: 1.22 (6H, s), 2.75 (2H, s), 3.63 (2H, s), 7.12-7.30 (4H, m); LRMS ESI m z 209 [M+H
Preparation 4 : (3-{2-[(Chloroacetyl)aminol-2-;fnethyIpropyl}phenyl) acetic acid
2-ChloroacetonitriJe (8.8 mL, 140 mmol) was added to a solution of preparation
3 (16.0 g, 70 mmol) in acetic acid (33 mL) and pooled to 0 °C. The resulting solution was treated with concentrated sulphuric acid (33 mL) and allowed to warm gradually to room temperature. After 4 hours the reaction mixture was poured onto ice and baslfied with solid sodium carbonate. The solution was extracted with ethyl acetate (2x 500 mL) and the combined organic extracts dried (MgS04) and concentrated in vacuo to give the title product as a colourless solid (19.0 g).
'HNMR (CDCI3, 400 MHz) δ: 1.36 (6H, s), 3.02 (2H, s), 3.62 (2H, s), 3.95 (2H, s), 6.19 (1H, m), 7.06-7.31 (4H, m);
LRMS ESI m/z 282 [M-HJ"
Preparation 5 : [3-(2-Amino-2-methylpropyl)phenyl]acetic acid methyl ester
A solution of preparation 4 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic add (18 mL) in ethanol (80 mL) was heated to reflux under a nitrogen atmosphere for 16 hours. The reaction mixture was allowed to cool to room
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temperature and filtered and the filtrate concentrated in vacuo. The residue, was dissolved in ethanol (150 mL), saturated with hydrogen chloride gas and the resulting solution heated to reflux for 16 hours. The mixture was concentrated in vacuo and ethyl acetate (200 mL) and 5% aqueous sodium carbonate solution (200 mL) added. The organic phase was washed with brine (100 mL), dried (MgSC ) and concentrated in vacuo. The residue was purified by strong cation exchange resin (methanol and then a 2M solution of ammonia In methanol) to give a yellow oil (2.68 g).
1HN R (CDCI3, 400 MHz) δ: 1.14 (6H, s), 2.68 (2H, s), 3.62 (2H, s), 3.69 (3H, s), 7.08-7.16 (3H, m), 7.23-7.27 (1H, m); LRMS ESI m/z 222 [M+Hf
Preparation 6 : [3-(2-ieri-Butoxycarbonylamino-2-methylpropyl)phenyl] acetic add methyl ester
A solution of di-ferf-butyldicarboxylate (8.19 g, 38.0 mmol) in dichloromethane (40 mL) was added to a solution of preparation 5 (6.4 g, 38.0 mmol) and triethylamine (5.2 mL, 38.0 mmol) in dichloromethane (60 mL) at 0-5 °C. The mixture was allowed to warm to RT and stirred overnight The solvent was removed and the residue treated with sodium carbonate solution and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (3x 20 mL) and dried (Na2SO.,). The product was purified by chromatography (0-80 % ethyl acetate in hexane) to yield a colourless oil. which was dissolved in diethytether (x3) and evaporated (10.1 g)
1HNMR (CDCl3l 400 MHz) δ: 1.26 (6H, s), 1.46 (9H, s), 2.97 (2H, s), 3.60 (2H, s), 3.68 (3H. s), 4.26 (1H, bs), 7.05-7.07 (2H, m), 7.13-7.17 (1H, m). 7.22-7.26 (1 H, m); LRMS ESI m/z 344 [M+Na
Preparation 7 : [3-(2-feri-Butoxycarbonylamino-2-methylpropyl)phenyl] acetic acid
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Preparation 6 (7.45 g, 23.0 mmol), sodium hydroxide solution (5 , 4.6 mL, 115 mmol), dioxane (30 mL) and water (8 mL) were stirred at RT for 18 h. The solvent was removed and the material dissolved in water, cooled and acidified to pH 3 with hydrochloric acid (2 ). The product was extracted with ethyl acetate (3.x 30 mL), and the organlcs washed with brine (3x 30 mL) and dried (Na2S04). The resulting oil was dissolved in diethylether and evaporated to yield a colourless gum (7.0 g).
1HNMR (CD3OD 400 MHz) S: 1.23 (6H, s), 1.48 (9H, s), 2.96 (2H, s). 3.57 (2H, s), 7.04-7.06 (2H, m), 7.11-7.13 (1H, m), 7.18-7.22 (1H, m); .
LRMS APCI m/z 308 [M+Hf
Preparation 8 : (2-{3-[(3,4-DIchlorobenz lcarbamoyl)methyl]phenyl}-1,1-dimethyl-ethyl)carbamic acid fert-butyl ester
3, 4-Dlchlorobenzylamine (1.30 mL, 9.76 mmol) was added to a solution of preparation 7 (3.00 g, 9.76 mmol), hydroxybenzotriazole hydrate (1.50 g, 9.76 mmol), 1-(3-dimethylaminopropyI)-3-ethylcarbodiimlde hydrochloride (1.87 g, 9.76 mmol) and triethylamine (4.07 mL, 11.2 mmol) and the resulting solution was stirred at RT for 8 h. The solvent was removed and the crude material taken up in ethyl acetate (50 mL) and washed with water (30 mL), sodium carbonate solution (2x 30 mL), brine (30 ml), hydrochloric acid (0.5 M, 2x 30 ml) and brine (30 mL) and then dried (Na2S04). The resulting white solid was triturated with diethylether (3.1 g).
'HNMR (CDCI3, 00 MHz) 6: 1.25 (6H, s), 1.45 (9H, s), 2.97 (2H, s)* 3.62 (2H, s), 4.22 (1H, bs), 4.34 (2H, d), 5.78 (1H, bs), 6.99-7.01 (1H, dd), 7.04 (1H, s), 7.07-7.09 (1H, d), 7.12-7.14 (1 H, d), 7.22 (1H, d), 7.27 (1H, d), 7.32 (1ΗΪ d); LRMS APCI m/z465 [M+HJ+
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Preparation 9 : (2- 3-[(3,4-Dimethylben2ylcarbamoyl)met yl]phenyl}-1,1-dimethyl-ethyl)carbamic acid tert-butyl ester
Prepared using the acid from Preparation 7 and the method described for Preparation 8 and 3,4-dimethylbenzylamine.
1HNMR (CDCI3.400 MHz) δ: 1.19 (6H, s), 1.46 (9H, s), 2.20 (6H, d), 2.95 (2H, s), 3.59 (2H, s), 4.15 (1H, bs), 4.32 (2H, d), 5.59 (1H, bs), 6.86-6.93 (2H, m), 7.02-7.06 <3H, m), 7.13-7.15 (1H, d), 7.23-7.27 (1H, m); .
LRMS APCI m/z 425 [M+H]+
Preparation 10: 2-[3-(2-Amlno-2-methylpropyl)phenyl]-W-(3,4-dichloro benzy])acetamide
Preparation 8 (3.0 g, 6.50 mmol) in dioxane (5 mL) was treated with hydrogen chloride (4M in dioxane, 20 mL) and the resulting solution left to stir at RT for 18 h. The solvent was removed and the compound re-dissolved in methanol (x2) and evaporated, then the resulting gum suspended in diethylether (x2) and evaporated to yield a white solid (2.7 g). mp (ethyl acetate-methanol) 214-216 (dec) °C.
1HNMR (CD3OD.400 MHz) δ: 1.33 (6H, s), 2.90 (2H, s), 3.59 (2H, s), 4.35 (2H, s), 7.13-7.19 (3H, m), 7.24-7.27 (1H, m), 7.31-7.38 (2H, m), 7.42 (1Hf d); .
LRMS ESI m/z 365 [M+H]+
Preparation 11: 2-[3-(2-Amino-24nethylpropyI)phenyl]-Af-(3,4-dimethyl benzyl)acetamide
O 2005 092H40 PCT/1B20 5/(MM)61
S3
Prepared using the amide from Preparation 9 and the method described for Preparation 10.
1HNMR (CD3OD, 400 MHz) δ: 1.32 (6H, s), 2.21 (6H, s), 2.89 (2H, s), 3.56 (2H, s), 4.29 (2H, s), 6.95-7.05 (3H, m), 7.14-7.16 (2H, m), 7.24-7.26 ( H, m), 7.31-7.35 (1H, m); .
LRMS ESI m/z 325 [M+Hf
Preparation 12: N-{2-Benzyloxy-5-[(iR)-2- romo-1-(terf- utyldlrnethyl siianyloxy)ethyl]pheny]}formamide
To a solution of A/-[2-benzyloxy-5-(2-bromo-1-hydrcxyethyl)phenyl]formamide (Organic Process Research and Development 1998, 2, 96-99) (4.12 g, 11.8 mmol) in Λί,Λί-dimethylformamide (25 mL) at RT under N2 was added i&rt-butyldimethylsilyl chloride (3.50 g, 23.2 mmol), imidazole (1.90 g, 27.9 mmol) and 4-(dimethylamino)pyridine (40 mg, 330 μπιοΙ). The resulting solution was stirred at RT overnight, the solvent was removed and the product taken up in ethyl acetate (70 mL). The organics were washed with water' (100 mL), and the aqueous extracted with ethyl acetate (20 mlmLThe combined organics were washed with hydrochloric acid (2 , 50 ml), brine ( 00 mL) and dried (MgS0>4). The crude material was purified by chromatography (5-25 % ethyl acetate in pentane) to yield a colourless oil (5.7 g).
HNMR (CDCI3, 400 MHz) δ : -0.08 to -0.05 (3H, m), 0.09-0.11 (3H, s), 0.89- 0.90 (9H. m), 3.38-3.55 (2H, m), 3.78-3.84 (1H, m), 5.06-5.11 (2H, m), 6.90-
6.97 (1H, m), 7.03-7.12 <1H, m), 7.24 (m), 7.36^7.43 (5H, m), 7.67-7.78 <m),.
7.88 (d), 8.74 (d);
LRMS APCI m/z 464/466 [ +H]*
Preparation 13 : 2-(3-{2-[(2R)-2-(4-Ben2 ioxy-3-formylanilnophenyl)-2-(iert-butyl-dimethylsilanyloxy)ethy!am!no]-2-methytpropyl}phenyl)-W-(3,4-dichlorobenzyl)acetamide
Preparation 12 (500 mg, 1.08 mmoi) and preparation 10 (780 mg, 216 mmol) were heated and stirred at 90 eC for 24 h. After cooling the material was dissolved in methanol and evaporated, the material was suspended in diethylether and the precipitate filtered off. The filtrate was evaporated and the material purified by chromatography (0-5 % methanol in dichloromethane) and then suspended in diethylether (x3) and evaporated to yield a foam (425 mg). 1HN R (CD3OD, 400 MHz) £: -0.20 to -0.18 (3H, m), -0.04 to 0.00 (3H, m), 0.78-0.81 (9H, m), 1.01-1.03 (3H, m), 1.05 (3H, bs), 2.62-2.74 (3H, m), 2.83- 2.88 (1H, m), 3.52 (2H, d), 4.31 (2H, s), 4.68-4.71 (1H, m), 5.17-5.19 (2H, m), 7.00-7.23 (7H. m), 7.29-7.41 (5H, m), 7.44-7.49 <2H, m), 8.57 (s); LRMS ESI m/z 748 [M+H]+;
HRMS C iH5iCI2 304Si 748.3099 [M+Hf found 74-8.3066. .
Preparation 14 : 2-(3-{2-t(2/?)-2-(4-Benzyloxy-3-'formylaminophenyl)-2-(iert- butyl-djmethylsflanyioxy)ethylamino]-2-methyip ropy!}phenyl)-A -(3,4- dimethylbenzyl)acetamlde
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Prepared using the amide from Preparation 13, fthe bromide from Preparation 12 and the method described for Preparation 11,
HN R (CDCI3> 400 MHz) δ: -0.17, -0.16 (3H, fcx s), -0.05 to -0.01 (3H, m), 0.78-0.82 (9H, m), 0.97-1.01 (6H, m), 2.19 (3H, S), 2.20 (3H, s), 2.56-2.90 (4H, m), 3.54-3.63.(2H, m), 4.28-4.35 (2H, m), 4.67-4.74 (1H, m), 5.06-5.09 (2H, m), 5.58-5.62 and 5.99-6.03 (1H, m), 6.87-7.25 (9H, m), 7.35-7.44 (5H, m), 7.68- 7.79 ( H, m), 8.30 (d), 8.43 (d).8.71 (s), 8.74 (s); LR S ESI m/z 748 ΓΜ+Hf ; HRMS C43H57N3O4S1708.4191 [M+Hf found 70ε .4156.
Preparation 15 : W-Benzyl-2-{3-{2-l(2R)-2-(feri-butyldimethylsilanyloxy)-2- (3-formylamino-4-hydroxyphenyl)ethylamino]-2- methylpropyl}phenyl)acetam1de
Preparation 13 (100 mg; 134 μΐτιοΙ) and palladium-on-carbon (10 %, 20 mg) in ' methanol ("10 mL) were hydrogenated at 50 psi RT for 6 h. The mixture was ' filtered through a 'filter-aid' and the solvent removed. The material was suspended in sodium hydrogen carbonate solution and extracted with ethyl acetate (30 mL). The organic layer was washed with sodium" hydrogen carbonate solution, brine (2x mL) and dried ( a2S04). The resulting material was suspended In diethylether (x3) and evaporated to yield a film (24 mg). .
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1HNMR (CDaOD.400 MHz) δ: -0.19 (3H, s), -0.02 (3H, s), 0.79 (9H, s), 1.04. (3H, s), 1.07 (3H, s), 2.62-2.89 (4H, m), 3.48-3.56 (2H, dd), 4.35 (2H, s), 4.61 (1H, bs), 4.69-4.72 (1H, m), 5.17-5.19 (2H, m), 6.79-6.85 OH, m), 6.91-6.94 (1H, m), 7.04-7.06 (1H, m), 7.11-7.28 (7H, m), 8.12 (1H, d), 8.27, 8.59 (1H, 2x s); .
LR S ESI m/z 590 [ +Hf;
H S C3 H47N3O4S1590.3402 [M+Hf found 590.3409.
Preparation 16 : 2-(3-{2-[(2/?)-2-(teri-Butyldimethylsilanyloxy)-2-(3-formylamino^-hydroxypheny ethylamfnoJ^-methylpropy p enylJ-iV^S^-dimethylbenzyl)acetamide
Prepared using the amide from Preparation 14 and the method described for Preparation 15. The product was purified by chromatography (0-3.5 % methanol in dichloromethane + 0.3 % ammonia) to yield a foam (85 mg).
1HNMR (CD3OD, 400 MHz) δ: -0.20 to -18 (3H, m), -0.03-0.O0 (3H, m), 0.79- 0.81 (9H, m), 1.02-1.05 (6H, m), 2.19 (3H, s), 2.20 (3H, s), 2.61-2.73 (3H, m), 2.83-2.88 (1H, m), 3.46 (2H, dd), 4.27 (2H, s), 4.65 (1H, dd), 5.78-7.22 (8H, m), 8.12 (d), 8.27 (s), 8.59 (s); .
LRMS E5l mz6 8 [M+H]+;
HR S C38H51N304Si 618.3722 [ +Hf found 618.3701.
Preparation 17: Methyl (3-bromophenyl)acetate
Acetyl chloride (0.7 mL, 9.3 mmol) was slowly- added to a solution of (3-bromo- phenyl)acetic acid (20.0 g, 93 mmol) in methanol (500 mL) at 0 °C under
nitrogen and the reaction was allowed to warm gradually to room temperature, over a period of 5 hours. The solvent was removed in vacuo and the residual oil was re-dissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to give the title compound as a colourless oil (20.6 g). 1H N (400MHz, CDCI3): δ: 3.59 (2H, s), 3.70 (3H, s), 7.17-7.24 (2H. m), 7.37-7.45 (2H, m); LRMS ESI m/z 253 [M+Naf
Preparation 18: Methyl [3-(2-oxopropyl)phenyl]acetate
Tributyltin methoxide (28.3 mL, 98 mmol), the product of preparation 17 (15.0 g, 65mmol), isopropenyl acetate (10.8 mL, 98 mmol), palladium(H)acetate (750 mg, 3.30 mmol) and tri-orffto-tolylphosphine (2.0 g, 6.5 mmol) were stirred together in toluene (75 mL) at 100 eC for 5 hours. After cooling, the reaction was diluted with ethyl acetate (150 mL) and 4M aqueous potassium fluoride solution (90 mL), and stirred for 15 minutes. The mixture was filtered through Arbocel® and the organic phase was separated and concentrated in vacuo. The residue was then purified by column chromatography on silica gel eluting with diethyl ether.pentane, 0:100 to 25:75, followed by dichloromethane to give the title compound as a pale yellow oil in 94% yield (12.6 g).
1H NMR (400MHz, CDCI3): δ: 2.15 (3H, s), 3.61 (2H, s), 3.69 (5H, s), 7.10-7.13 (2H, m), 7.19 (1H, d), 7,30 (1H, t); LRMS ESI: m z 229 [M+Naf
Preparation 19: Methyl [3-((2R)-2-{[(1R)-1-phenylethyl]amino}propyI)- phenyl]acetate hydrochloride
A solution of the product of preparation 18 (8.5 g, 41.2 mmol), {/?)-oc-methyI benzylamine (4.8 mL, 37.2 mmol), sodium triacetoxyborohydride (11.6 g, 56 mmol) and acetic acid (2.2 mL, 38 mmol) in dichloromethane (400 mL) was
S8
stirred at room temperature for 48 hours. The reaction mixture- was quenched by addition of saturated sodium hydrogen carbonate solution (200 mL) and allowed to stir until effervescence ceased. The aqueous phase was separated and extracted with dichloromethane (100 mL). The combined organic solution was then dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel, eluting with dichloromethaneimethanol: ammonia, 99:1:0.1 to 95:5:0.5, gave a 4:1 mixture of diastereomers {R,R major) as a pale yellow oil (8.71 g). Treatment with hydrogen chloride (40 mL of a 1M solution in methanol, 40 mmol) followed by three successive crystallisations (diisopropylether/methanol) gave the title compound as a white crystalline solid in 50% yield, 5.68 g.
1H NMR (400MHz, CD3OD): δ: 1.18 (3H, d), 1.68 (3H, d), 2.60-2.66 (1H, m), 3.15-3.26 (1H, m), 3.25-3.30 (1H, m), 3.31 (3H, s), 3.62 (2H, s), 4.59 (1H, q), 6.99-7.02 (2H. m), 7.17 (1H, m). 7.25-7.28 (1H, m), 7.48-7.52 (5H, m) LRMS ESI m/z 312 [M+H]+
Preparation 20: Methyl {3-[(2R)-2-aminopropyl]phenyl}acetate
A solution of the product of preparation 19 (7.69 g, 22 mmol) and ammonium formate (6.94 g, 110 mmol) was heated to 75 °C in the presence of 20% palladium hydroxide-on-charcoal (2.00 g). After 90 minutes the reaction mixture was cooled to room temperature, filtered through Arbocel® and the filtrate concentrated in vacuo. The residue was partitioned between dichloromethane (100 mL) and 0.88 ammonia (100 mL) and the phases were separated. The . aqueous phase was extracted with dichloromethane (100 mL) and the combined organic solution was dried over magnesium sulfate and concentrated ■ in vacuo to afford the title compound as a colourless oil in quantitative yield
(4.78 g).
1H NMR (400MHz, CD3OD): δ: 1.06 (3H, d), 2.57-2.67 (2H, m), 3.05-3.12 (1H, m), 3.63 (2H, s), 3.67 (3H, s), 7.09-7.13 (3H, m), 7.23-7.27 (1H, t); LRMS ESI m/z 208 [M+H]+
Preparation 21: Methyl (3-{(2f?).2-[(iert-biitoxycarbonyl)amirio]propyI} phenyl)acetate
The title compound was prepared from the product of preparation 20 and di-ierfbutyl dicarboxylate, using a method similar to that of preparation 6, as a yellow oil in 97% yield.
H NMR (400MHz, CD3CI$): δ: 1.07 (3H. d), 1.43 (9H, s), 2.61 (1H, dd), 2.&1 (1H, dd), 3.60 (2H, s), 3.69 (3H, s), 3.B9 {1 H, bs), 4.36 (1H, bs), 7;06-7.19 (3H, m), 7.22-7.27 ( H, m); LRMS APCi m/z 306 [M-H)"
Preparation 22: {3-{{2r)-2-[(iert-butoxycarbonyl)aminoIpropyl} phenyl) acetic acid
A mixture of preparation 21 (8.31 g, 27.1 mmol) and lithium hydroxide solutio n (1M in water, 54 mL, 54 mmol) in tetrahydrofuran (100 mL) was stirred at room temperature for 20 hours. The reaction mixture was then concentrated in vacuo and the aqueous residue was acidified to pH 2 with 2M hydrochloric acid. The mixture was then extracted with ethyl acetate (3x 75 mL) and the combined organic solution was washed with brine (100 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow oil in 82¾ yield (6.50 g)
1H NMR (400MHz, CD3CI3): δ: 1.07 (3H, d), 1.40 (9H, s), 2.61 (1H, dd), 2.7 - 2.88 (1H, bs), 3.62 (2H, s), 3.89 (1H, bs), 4.39 (1H, bs), 7.07-7.16 (3H, m), 7.22-7.27 (1 H. m); LRMS APCI m z 292 [M-H]"
Preparation 23: Benzyl (3-((2R)*2-[(iert-butoxycarbonyl)amino]propyI} phenyl)acetate
O 2005/092840 T>CT/IB2005/0tt0619
60
The product of preparation 22 {6.30 g, 21.5 mrnol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.14 g, 21.5 mrnol), 1-hydroxybenzotriazole hydrate (3.30 g, 21.5 mrnol) and triethytamine (4.85 mL, 43 mrnol) were stirred together in dichloromethane (100 mL) for 10 minutes at room temperature. Benzyl alcohol (2.2 mL, 21.5 mrnol) was then added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with dichloromethane (50 mL), washed with sodium hydrogen carbonate solution (100 mL) and brine (100 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a clear oil in 50% yield, 4.16 g.
1H NMR (400MHz, CD3CI3): δ: 1.04 (3H, d), 1.44 (9H, s), 2.59 (1H, dd), 2.81 (1H, dd), 3.64 (2H, s), 3.87 (1H, bs), 4.34 (1H, bs), 5.13 (2H, s), 7.07-7.11 (2H, m), 7.13 (1H, bd), 7.22-7.27 (1H, m), 7.29-7.38 (5H, m); LRMS APCl m/z 382 [M-HT
Preparation 24: Benzyl {3-[(2R)-2-aminopro yl]phenyl}acetate
Hydrogen chloride (4 in dioxane, 5.43 mL, 21.72 mrnol) was added to a solution of the product of preparation 23 (4.16 g, 10.86 mrnol) in dioxane (50 mL) and the resulting solution stirred at room temperature for 72 hours". The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed with sodium hydrogen carbonate solution (50mL) and brine (50mL). The organic solution was then dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow oil in 93% yield (2.85 g).
H NMR (400MHz, CD3CI3): δ: 1.09 (3H, d), 1.55 (2H, bs), 2.48 (1H, dd), 2.66 (1H, dd), 3.10-3.18 (1H, m), 3.65 (2H, s), 5.17 (2H, s), 7.09-7.13 (2H, m), 7.14- 7. 8 (1H, bd), 7.24-7.38 (6H, m); LRMS APCl m z 284 [M-HV
61
Preparation 25: Benzyl (3-{(2 )-2-[((2/?)-2-[4-(beri.:yloxy)-3- (formy1amino)phenyl]-24[.erf-butyl(dimethyl)sllyl]oxy}ethyl}amino]- propyl}phenyl)acetate
The title compound was prepared from the products of preparation 12 and preparation 24, using a similar method to that of preparation 13, as a brown oil in 25% yield
LR S APCI m/z 667 [M+H]+
Preparation 26: {3 (2R)-2-({(2R)"2-a(ert-Butyi( irnethyl)silyl]oxy>-2-l3- (formylamlno)-4-hydroxyphenyl]ethyl}amino)propyi]phenyl}acetic acid
The product- of preparation 25 (851 mg, 1.27 mmol) and 10% Pd/C (50 mg) were suspended in methanol and the mixture was stirred under 60psi of hydrogen gas, at room temperature for 72 hours. The reaction mixture was then filtered through Filter aid® and the filtrate was concentrated in vacuo to afford the title product as a brown foam in 94% yield, 580mg.
1H NMR (400MHz, CDCI3): δ: -0.09 (3H, s), 0.08 (3H, s), 0.88 (9H, s), 1.12,1.24 (3H, 2xd), 2.07-2.82 (2H, m), 2.99 (1H, dd), 3.18 (1H, dd), 3.60 (2H, s)» 4.16-
62
4.22 (1H, m). 4.97-5.07 (1H, m), 6.87 (1H, d), 6.99-7.32 (6H..m), 7.93 (s), 8.17. (d). 8.33 (s); LR S APCI m/z 487 [M+H]*
Preparation 27: 2-{3-[(2«)-2-({(2/?)-2-{[iert-Butyl(dimethyl)silyl]oxy}-2-I3-{formylamino)^-hydroxyphenyI]ethyl}amino)propynphenyl}-W-[4-(dimethyi amino)benzyl]acetamide
A mixture of the product of preparation 26 (100 mg, 206 μιιηο!), hydroxybenzotriazole hydrate (32 mg, 206 umol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 206 umol) and triethylamine (58 μί-, 412 μmol in N.N-dimethytformamide (2 mL) was stirred at room temperature for 10 minutes. 4-(Dimethyl amino) be nzyla mine (31 mg, 206 μπηοΙ) was then added and the mixture was stirred at room temperature for 20 hours. The solvent was then removed in vacuo and the residue was diluted with dichloromethane, washed with sodium hydrogen carbonate solution (20 mL) and brine (20 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a brown gum in 10% yield, 1 1 mg.
1H NMR (400MHz, CD3CI3): 0.17 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.08 (3H, m), 2.80-3.00 (10H, m), 3.47 ( H, m), 3.66 (2H, m), 4.23 (2H, m), 5.48 (ΪΗ, m). 6.66 (1H, d), 6.70-7.23 (10H, m), 7.97 (m), 8.27 (s); LRMS APCI m/z 504 [M+H]"
Preparations 28 to 29
The following compounds, of the general formula shown below were prepared from the product of preparation 26 and the appropriate amine, using a method
similar to that described for preparation 27. The reactions wer monitored by tic. analysis and were stirred at room temperature for 18-72hours.
Preparation 28: N-[4-(arrunomewyl)phenyQacetamide may be prepare as described in J. Med. Chem, 46, 31 6; 2003
Preparation 29: 4-(aminomethyl)benzamide may be prepared as described in WO 020B5860 p239
Preparation 30: [3-((2R)-2-{"{1R)-1 -Phenylethyl]amino>propyl)phenyl]acetic acid
Lithium hydroxide solution (1M in wafer, 90 mL, 90 mmol) was added to a solution of the product of preparation 19 ( 3.50 g, 43.5 mmol) in methanol (200 mL) and the mixture was stirred at room temperature for 18 hours. 1M Hydrochloric acid (90 mL) was then added to the reaction mixture and the methanol removed In vacuo. The resulting precipitate was filtered off and washed with water (20 mL) and a mixture of ethanol/diethyl ether, 20:80, to afford the title compound as a solid in 91 % yield , 11.8 g
O 2005/092840 PCT/IB20l>5/000<il9
1H NMR (400MHz, CD3OD) δ: 1.16 (3H, d), 1.62 (3H, d), 2.66-2.62 (1H, m),. .13- 3.26 {2H, m), 3.46 (2H, s), 4.48-4.56 (1H, q). 6.92 (1H, d), 7.19 (1 H, s), 7.18-7.22 (2H, m), 7.45-7.52 (5H, m); LRMS ESI m/z 298 [M+Hf
Preparation 31: W-1 -Adamantyl-2-[3-((2R)-2-{[(1R)-1-pheny1ethyl]am!no> propyl)phenyl]acetamide
1-Adamantylamine (5.44 g, 36.0 mmol) and triethylamine (15 ml_, 108 mmol) were added to a solution of the product of preparation 30 (10.7 g, 36.0 mmol) in dichloromethane ml_). 2-Chloro-1,3-dimethylimidazolidinum hexafluorophosphate (10.0 g, 36.0 mmol) was then added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and the organic solution was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5, afforded the product as a foam in quantitative yield, 17.6g.
1H NMR (400MHz, CD3OD) δ: 0.89 (3H, d), 1.35 (3H, d), 1.65-1.75 (6H, m), 1.98 (6H, m), 2.04 (3H, m), 2.37-2.42 (1H, dd), 2.65-2.74 (1H, m), 2.95-3.00 (1H, dd), 3.36 (2H, s), 3.98 (1H, q), 6.89 (1H, d), 6.98 (1 H, s), 7.09 (1H, d), 7.17 (1 H, t), 7.22-7.27 (1 H, m), 7.30-7.38 (4H, m); LRMS ESI m/z 431 [M+Hf
Preparation 32: W-1-Adamantyl-2-{3-[(2R)-2-aminopropyl]phenyl}r . acetamide. '
The title compound was prepared from preparation 31, using a similar method to that of preparation 20, as a solid in 92% yield.
1H NMR (400MHz, CD3OD) δ: 1.09 (3H, d), 1.66-1.72 (6H; m)i 2.00 (6H. m),. 2.03 (3Hf m)f 2.58-2.70 <2H, m), 3.10-3.16 (1H, q), 3.40 (2H, s), 7.06-7.28 (4H, m); LRM.S ESI m/z 327 [ +H]+
Preparation 33: 2-(3-{{2R)-2-[((2 ?).2-[3-(Acetylamino)-4-(benzyloxy)phenyl]-2-{[fert-butyl(dimethyl)silylloxy}ethyl)amlno]propyl>-pheny1)-W-1-adamantylacetamlde
A mixture of the products of preparation 12 (696 mg, 1.5 mmol) and preparation 32 (978 mg, 3.0 mmol) in dichloromethane (0.5 mL) was heated at 90 "C for 5 minutes allowing the dichloromethane to evaporate. The reaction mixture was then heated as a melt at 90 °C for 18 hours before cooling to room temperature. The crude product was then purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 98:2:0.2, to afford the title compound as a pale foam in 59% yield, 630 mg.
1H NMR (400MHz, CD3OD) δ: -0.18 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.05- 1.08 (d, 3H), 1.66-1.72 (6H, m), 2.00 (6H, m), 2.02 (3H, m), 2.52-2.71 (3H, m), 2.84-2.96 (2H, m), 3.36-3.41 (2H, m), 4.68-4.72 (1H, m), 5.20 (2H, s), 6.92-7.18 (6H, m), 7.30-7.50 (5H, m), 8.22 (m), 8.36 (s), 8.54 (s); LRMS ESI mVz 710 [M+Hf · . "
Preparation 34: N-Adamantan-1-yl-2-(3-{2-[(2R)-2-({(2/?)-2-(tert- butyldimethylsllanyloxy)-2-(3-formylamino-4- hydroxyphenyl)ethylaminoJpropyl}phenyl)acetarnide
PCT/IB2»)05/<M) (ili>
The title compound was prepared from the product of 33, using a similar method to that of preparation 20, as a clear foam in quantitative yield.
H N R (400MHz, CD3OD) δ: -0.17 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.04-1.06 (d, 3H), 1.69-1.70 (6H, m), 2.00 (6H, m), 2.03 (3H, m), 2.52-2.70 (3H, m), 2.88-2.94 (2H, m), 3.37-3.38 (2H, m), 4.64-4.69 (1H, m), 6.92-7.18 (6H, m), 8.00 (1H, d), 8.30 (s), 8.56 (s); LRMS ESI m z 620 [M+Hf
Preparation 35: -(3-Bromophenyl)-2-methylpropan-2-ol)
Methylmagnesium bromide (3M solution in diethyl ether, 51.6 mL, 155 mmol) was slowly added to a solution of 1-(3-bromo-phenyl)propan-2-one (15.0 g, 70 mmol) in dry diethyl ether (200 mL) at 0 °C and the mixture was stirred for 3 hours. The reaction mixture was then re-cooled to 0 °C and slowly quenched with saturated aqueous ammonium chloride solution. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residual yellow oil was then purified by column chromatography on silica gel eluting with dichloromethane:pentane:methanol, 90:5:5, to afford a pale yellow oil in 83% yield, 13.26 g.- 1H NMR (400MHz, CDCI3) δ: 1.22 (6H, s), 1.42 (1H, bs), 2.74 (2H, s), 7.15 (2H, m), 7.40" (2H, m)
Preparation W-[2-(3-Bromophenyl)-1 ,1 -dimethylethyl]-2- chloroacetamide
Chloroacetonitrile (6.63 mL, 105 mmol) was adqled to a stirred solution of the product of preparation 35 (12.0 g, 52.0 mmol) in acetic acid (25 mL) at room temperature. The resulting solution was cooled to 0 °C and concentrated sulfuric acid (25 mL) was added whilst the temperature was maintained below 10 °C. The resulting solution was left to stir for 1 hour and was then poured onto ice and basified by the addition of solid potassium carbonate. The product was extracted with ethyl acetate (2x 500 mL) and the combined organic solution was washed with water (50mL), dried over sodium sulfate and the concentrated ' in vacuo to afford the title compound as an orange solid in quantitative yield, 16.08 g.
1H NMR (400MHz, CDCb) δ: 1.37 (6H, s), 3.02 (2H, s), 3.94 (2H, s). 6.17 (1H, bs), 7.08-7.03 (1H, d), 7.10-7.13 (1H, t), 7.26 (1H, s), 7.39-7.32 (1H d,); LRMS ESI m z 306 [M+Hf ; Microanalysis: Ci2Hi5BrCINO requires: C 47.32; H 4.96; N 4.60; found C 47.26; H 4.87; N 4.65
Preparation 37: 2-(3-Bromophenyl)-1,1-dimethylethylamine
A solution of the product of preparation 36 (32.0 g, 105 rnmol), thiourea (9.60 g, 126 mmol) and acetic acid (50 mL) in ethanol (250 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, basified using aqueous sodium hydroxide solution (1M, 450 mL) and extracted with dichloromethane (2x 500 mL). The combined organic solution was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a black oil in 96% yield, 23 g.
1H NMR (400MHz, CDCI3) 5: 1.12 (6H, s), 1.84 (2H, bs). 2.62 (2H, s), 7.16-7.08 (2H, m), 7.36-7.32 (2H, m); LRMS ESI m/z 228 [M+Hf
WO 2(1(15/092840 PCT/lB2«05/ «n619
Preparation 38: [2^3-Bromopheny -1,1-dimethylethyl]car.bamlc acid fert-. butyl ester
The product of preparation 37 (5.0g, 22mmol) was treated with di-ferf-butyl dicarbonate (5.26g, 24mmol) in dichloromethane (50mL) and stirred for 20 hours. The reaction mixture was washed with water (50mL) and the combined organic solution was dried over sodium sulfate and concentrated in vacuo. The crude material was purified using a cation exchange column (methanol followed by 2M ammonia in methanol), followed by purification by flash column chromatography on silica gel eluting with dichloromethane to afford the title compound as a brown oil in quantitative yield, 7.23g.
1H NMR (400MHz, CDCI3) δ: 1.27 (6H, s) 1.50 <9H, s), 2.97 (2H, s), 4.24 (1H, bs), 7.05 (1H, d), 7.15-7.11 (1H, t), 7.30 (1H, s), 7.35 (1H, d); LRMS ESI m/z
Preparation 39: Benzyl 3-{2-{(tert-butoxycarbonyl)amino]-2 methylpropyl}benzoate
A solution of the product of preparation 38 (3.9 g, 12 mmol), [1,1 - ?/s(diphenylphosphino)ferrocene]dichtoropalladium(ll) (1.00 g, 1.3 mrnol) and triethylamine (3.3 mL, 24 mmol) in benzyl alcohol (60 mL) was heated to 100 °C under 100psi carbon monoxide for 5 hours. The cooled reaction mixture was . then filtered through Arbocel® and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with sodium hydrogen . carbonate solution (50 mL) and brine (2x 50 mL). The organic solution was then dried over sodium sulfate and concentrated in vacuo to give a dark oil. This oil was purified by column chromatography on silica gel, eluting with hexane:ethyl acetate 100:0 to 84:16, to afford the title compound as a pale yellow oil in 61% yield, 2.81 g.
<Η NMR (400MHz, CDCI3) 5: 1.25 (6H, s), 1.45 (9H, s), 3.05.(2H, s), 4.22 (1H,. bs), 5.35 (2H, s), 7.32-7.48 (7H, m), 7.86 (1 H, s), 7.93-7.97 (1 H, m) '
Preparation 40: Benzyl 3-(2-amlno-2*methylpropyl)ben2oate hydrochloride
The title compound was prepared from the product of preparation 39, using a method similar to that of preparation 24, as a white solid in 91% yield.
1H NMR (400MHz, CD3OD) δ: 1.33 (6H, s), 2.98 (2H, s), 5.37 (2H. s), 7.31-7.53 (7H, m), 7.93 (1H, s), 8.00-8.04 (1H. m); LRMS APCI m/z284 [ +H]+
Preparation 41: Benzyl 3-{2-[((2i¾)-2-[4"(benzyioxy)-3- (fonTiylamino)phenyl]-2- [ieri-butyl(dimethyl)silylloxy}€thyl)amino]-2- methy1propyl}benzoate
A mixture of the product of preparation 40 (1.81 g, 6.38 mmol), preparation 12 (2.96 g, 6.38 mmol) and potassium carbonate (1.76 g, 12.8 mmol) in dimethylsulfoxide (10 mL) was heated at 95 °C for 40 hours. The cooled reaction mixture was then diluted with water (250 mL) and extracted with ethyl acetate (3x 50 mL). The combined organic solution was washed with sodium · hydrogen carbonate solution (50 mL) and brine (2x 50 mL), dried over sodium sulfate and concentrated in vacuo to give an orange oil. This oil was purified by column chromatography on silica gel, eluting with dichloromethane:hexane, 50:50, followed by dichloromethane:methanol, 100:0 to 98:2. The appropriate fractions were evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel, eluting with
dichloromethane-.methanol, 100:0 to 98:2, to give a yellow gum-. The gum was. azeotroped with diethyl ether (x3) to afford the titfe compound as a yellow gum in 20% yield, 0.83 g.
1H NMR (400MHz, CDCl3): δ: -0.15 to -0.17 (3H, m), -0.03 (3H, s), 0.79-0.82 (9H, s), 1.01 (3H, s), 1.04 (3H, s), 2.62-2.86 (4H, m), 4.66-4.74 <1H, m), 5.06-5.07 (2H, m), 5.36 (2H, s), 6.88 (1H, d), 7.01-7.05 (1H, m), 7.27-7.50 (12H, m), 7.74 (1H, m), 7.87-7.96 (2H, m), 8.39 (s), 8.40 (s), 8.76 (s), 8.78 (s); LRMS APCI m/z 667 [ +H]"
Preparation 42: 3-[2-{{(2/?)-2-{[iert-Butyl(dimethyl)silyl]oxy}-2-[3-(formyIamino}-4- ydroxyphenyl]ethyl}arnino)-2-methylpropyl]benzoic acid
The title compound was prepared from the product of preparation 41 , using a method similar to that of 26. The crude product was then azeotroped with diethyl ether (x3) to afford the title compound as a pale yellow solid in 97% yield.
H NMR (400MHz, CD3OD): δ: -0.12 (3H, s). 0.05 (3H, s), 0.81 (9H, S), 1.24 (6H, s), 2.98 (2H, dd), 3.26-3.30 (2H, m), 4.91 (1H, t), 6.89 (1H, d), 7.02 (1H, m), 7.37-7.49 (2H, m), 7.85 (1H, bs), 7.93-7.96 (1H, d), 8.11 (s, 1H), 8.32 (s), 8.61 (s); LRMS ESI m/z 487 [M+H]"
Preparation 43: (4>Hydroxy-2f5-dimethylphenyi)acetonitrile
71
A solution of (4-methoxy-2,5-dimethylpheny()acetonitri(e (0.5 g, 2.9 mmol) in. dichloromethane (10 mL) was cooled to -80 °C and treated with borontribromide (1M in dichloromethane, 14.3 mL, 14.3 mmol). The reaction mixture was stirred at -80 °C for a further 30 minutes and then was allowed to warm to room temperature over a period of 2 hours. The reaction mixture was quenched with saturated sodium hydrogen carbonate solution (20 mL) and the organic layer was separated. The organic solution was washed with brine (20mL), dried over sodium sulfate and the concentrated in vacuo to afford a pale brown solid. Purification by column chromatography on silica gel, eluting with ethyl acetate:pentane 20:80 to 33:67, afforded the title compound as a colourless solid in 60% dispersion in mineral oil yield, 0.28 g.
1H NMR (400MHz, CD3OD) δ: 2.13 (3H. s), 2.23 (3H, s), 3.66 (2H. s), 6.60 (1 H, s), 6.98 (1 H, s); LRMS ESI m z 160 [M-H]"
Preparation 44: (4-Hydroxy-2,3-dimethyl-phenyl)acetonitriIe
The title compound was prepared from (4-methoxy-2,3-dimethyl-phenyl)acetonitrile using a similar method to that of preparation 43, as a colourless solid in 94% yield.
1H NMR (400MHz, CDCI3) δ: 2.20 (3H, s), 2.24 (3H, s), 3.62 (2H, s), 6.64 (1 H, d), 7.03 (1 H, d); LRMS APCI m/z 160 [M-HT
Preparation 45: (4-Hydroxy-3-methylphenyi)acetonitrile
The title compound was prepared from (4-methoxy-3-methylphenyl)acetonitrile using a similar method to that of preparation 43, as a pale yellow solid.
1H NMR (400MHz, CDCI3) δ: 2.25 (3H, s), 3.65 (2H, s), 4.98 (1 H, be), 6.76 (1 H . d).7.01 (1H; d), 7.07 (1H, s); LRMS ESI m/z 146 [M-H
72
Preparation 46: 4-(2-Aminoethy!)-2,5-dimethylphenol
A solution of the product of preparation 43 (0.28 g, 1.74 mmol) in ethanol (15 mL) was hydrogenated at 60psi over Raney Nickel® (0.1 g, 50% w/w) for 16 hours. The reaction mixture was then filtered and the solvent was removed in vacuo. The residue was purified using a cation exchange resin, eluting with methanol and then 1M ammonia in methanol to afford the title compound as a colourless oil.
1HNMR(400MHz, CD3OD) δ 2.11 (3H. s), 2.19 (3H, s), 2.63-2.67 (2H, m), 2.72-2.76 (2H, m), 6.54 (1H, s), 6.81 (1H, s); LRMS ESI m/z 166 [ +Hf
Preparation 47: 4-(2-Amlno-ethyl)-2t3-dimethyl-phenol
The title compound was prepared from the product of preparation 44 using a similar method to that of preparation 46, as a colourless solid in 95% yield.
1H NMR (400MHz, CDCI3) δ: 6.78 (1H, d), 6.55 (1H, d), 2.75-2.68 (4H, m), 2.19 (3H, s), 2.12 (3H, s); LRMS APCI m/z 66 fWI+Hf
Preparation 48: 4-(2-Aminoethyi)-2-methylphenol
The title compound was prepared from the product of preparation 45, using a similar method to that of preparation 46, as a colourless oil.
1HNMR(400MHz, CD3OD) 5: 2. 5 (3H, s), 2.60-2.64 (2H, m), 2.79-2.83 (2H, m), 6.66 (d, 1H), 6.82 (1H, d), 6.90 (1H, s); LRMS ESI m z 152 [M+H]+
Preparation 49: te/f-Butyl (3-iodobenzyl)carbarjiate
A suspension of 3-iodobenzylamine hydrochloride (4.95 g, 18.4 mrnol) in dichloromethane (100 mL) was treated with triekhylamine (3.1 mL, 22 mmoi) and di-ferf-buty) dicarbonate (4.40 g, 20 mmol) at¾d the resulting solution stirred at room temperature for 1.5 hours. The reaction [mixture was then washed with 2M hydrochloric acid (30 mL), water (30 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colourless solid in quantitative yield, 6.43 g.
1HNMR (400MHz, CDCl3) δ: 1.46 (9H, s), 4.21-4.30 (2H, m), 4.79-4.89 (1 H, bs), 7.06 (1H, dd), 7.25 (1H, d), 7.60 (1H, d), 7.63 (1H, s); LRMS ESI m/z 332 [M-H]*
Preparation 50: terf-Butyl [(4'"hydroxybiphenyl-3-yl)methyl]carbamate
A solution of the product of preparation 49 (0.75 g, 2.25 mmol), 4-hydroxy phenylboronic acid (0.62 g, 4.50 mmol) and 1.1'- b/s(diphenylphosphino)ferrocenyi palladium(ll)chloride (0.11 g, 0.14 mmol) in MW-dimethylformamide (14 mL) was treated with 2M aqueous sodium carbonate solution (4 mL) and the resulting mixture was heated at 80 °C"for 16 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate: pentane, 25:75, to afford the title compound as a pale pink crystalline solid in quantitative yield, . 0,73 g.
1H NMR (400MHz. CDCI3) 5: 1.47 (9H, s), 4.33-4.41 (2H, m), 4.87-4.94 (1H, bs), 6.89 (2H, d), 7.21 (1H, d), 7.37 (1H, dd), 7.43-7.45 (4H, m); LRMS ESI m/z 298 [M-H]*
Preparation 51: 3'-(AminomethyI)blphenyl-4-ot hydrochloride
The product of preparation 50 (0.73 g, 2.43 mmol) was treated with 4M hydrochloric acid in dioxan (6.1 mL, 24.3 mmol) and the resulting solution allowed to stir at room temperature for 3 hours. The reaction mixture was then concentrated in vacuo to afford the title compound as a colourless solid.
1H NMR (400MHz, CD3OD) 5: 4.17 (2H, sj, 6.87 (2H, d), 7.34 (1H, d), 7.45-7.50 (3H, m), 7.61 (1H, d), 7.65 (1h, s); LRMS ESI mfz 198 [M-H]"
Preparation 52: 2-Hydroxy-1 -naphthamide
A solution of 2-hydroxy-1-napthoic acid (5.0 g, 26.6 mmol), 1-(3-dimethylamlnopropyl>-3-ethylcarbodiimide hydrochloride (5.6 g, 29.2 mmol), and 1-hydroxybenzotriazole (3.95 g, 29.2 mmol) in tetrahydrofuran (70 mL) was stirred at room temperature for 30 minutes prior to the addition of 0.88 ammonia (6 mL). The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was then filtered, and the filtrate was diluted with water (80mL) and extracted with ethyl acetate (4x 80 mL). The combined organic extracts were washed with water (2x 50mL) and brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give a orange oil-. · Purification- of the1 oii by column chromatography on silica gel, eluting with
• dichloromethane:methanol:0.880 ammonia, 95:5:0.5, afforded the title compound as a pink solid in 37% yield, 1.83 g.
• 1HNMR (400MHz, CDCI3).5: 6.11-6.35 (2H, bs), 7.17 (1H, d), 7.36 (-1H, dd), 7.54 (1H, dd), 7.79 (1H, d), 7.84 (1H, d), 8.22 (1H, d), 11.70-11.88 (1H, bs);
LRMS ESI m/z 186 [M-H]"
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Preparation 53: 3,5-Dichloro«^ethyl-2-hydroxybenzamtde.
The title compound was prepared from 3,5-dichloro-2-hydnoxybenzoic acid and ethyiamine, using a similar method to that of preparation 52, to afford the title compound as a pale yellow solid.
^HNMR (400MHz, CDCI3) δ: 1.28 (3H, t), 3.47-3.54 (2H , m), 6.29-6.36 (1H, bs), 7.27 (1H, d), 7.48 (1 H, d); LRMS ESI m/z 232 [M-H]"
Preparation 54; 4-(Aminomethyl)-2,6-dimethylphenoI hydrochloride
A solution of borane in tetrahydrofuran (1M in tetrahydrofuran, 27.1 mL, 27.1 mmol) was added dropwise to a solution of 3,5-dimetfiyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol) in tetrahydrofuran (70 mL) and the resulting solution was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature, treated with 6N hydrochloric acid (20mL) and heated under reflux for a further 30 minutes. The reaction mixture was then cooled to room temperature and the solvent was removed in vacuo. he residue was purified using a strong cation exchange resin eiuting with methanol followed by 2M ammonia in methanol, to give an orange oil. This oil was then treated with 1M hydrogen chloride in methanol (20mL) and the reaction mixture was concentrated in vacuo to afford the title compound as a pale yellow solid in quantitative yield, 1.12 g.
'HNMR (400MHz, CDCI3) δ: 2.22 (6H, s), 3.75 (2H, s), 6.90 (2H, s).
Preparation 55: 2-(Aminomethyl)-4-chlorophenol hydrochloride
The title compound was prepared from 5-chloro-2-hydroxybenzonitrile, using a method similar to that described for preparation 54.
1HNMR (400MHz, CDCI3) δ: 4.08 (2H, s), 6.87 (1H, d), 7.27 (1H, d), 7.35 (1H, s); LR S APCI m/z 156 [ -Hf
Preparation 56: 4"-{Aminomethyl)bipheriyl-4-ol hydrochloride
The title compound was prepared from 4,-hydroxybiphenyl-4-carbonitrile, using a method similar to that of preparation 54.
1HNMR (400MHz, CD3OD) δ: 4.10 (s, 2H), 6.83 (d, 2H), 7.44-7.46 (m, 4H), 7.60 (d, 2H).
Preparation 57: 1-{Aminomethyl)-2-naphthol
A solution of borane in tetrahydrofuran ( 9.23 mL of a 1M solution, 19.23 mmol) was added dropwise to a solution of the amide from preparation 52 (0.90 g, 4.81 mmol) in tetrahydrofuran (10 mL) and the reaction was then heated under reflux for 2 hours. The solution was cooled, treated with 6 hydrochloric acid (10 mL) and heated under reflux for a further 2 hours. The resulting suspension was cooled to room temperature and the pH was adjusted to pH 9 . by addition of 0.88 ammonia and extracted with ethyl acetate (3x 50 mL). The combined organic solution was washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88
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ammonia, 95:5:0.5 to 90:10:1, afforded the title, compound .as a pink solid in. 23% yield, 0.19 g.
1H N R (400MHz, CD3OD) δ: 4.41 (2H, s)r 7.07 (1H, d), 7.23- (dd, 1H), 7.43 (1H, dd), 7.66 (1H, d), 7.72 (1H. d), 7.87 (1H, d); LRMS ESI m/z 174 [M+H]+
Preparation 58: 2,4-Dichloro-6-[(ethylamino)methyl]phenol
A solution . of the product of preparation 53 (0.77 g, 3.29 mmol) in tetrahydrofuran (10 mL) was cooled to 0 °C and treated with borane- tetrahydrofuran complex (1M in tetrahydrofuran, 9.9 mL, 9.9 mmol). The resulting solutio was allowed to warm to room temperature over 20 minutes and was then heated under reflux for 16 hours. The reaction mixture was cooled to 0 °C and quenched by addition of methanol. The r&sulting solution was allowed to warm to room temperature over 2 hours and was then concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL) and washed with water (2x 10 mL), brine (10 mL), dried over sodium sulfate and reduced in vacuo to give a colourless oil. Purification. of the oil by column chromatography on silica gel, eluting with methanol:dichloromQthane, 2:98 to 5:95 afforded the title compound as a colourless solid in 74% yield, 0.53 g. 1HNMR (400MHz, CDCl3) 5: 1.17 (3H, t), 2.72 (2H, q), 3.98 (2H, s), 6.86 (1H, d), 7.23 (1 H, d).
Preparations 59 to 68
The following compounds, of the genera) formula shown below were prepared from the product of preparation 42 and the appropriate amine, using a method similar to that described for preparation 27. The reactions were monitored by TLC analysis and were stirred at room temperature for 18-72 hours.
79
cartridge;, eluting with dichloromethane:methanol:0.88 ammonia, 96:4:0.3
Preparation 62: was further azeotroped with diethyl ether (x3) to afford the desired product
Preparation 68: 6-(aminomethyl)-2-naphthalenol may be prepared as described in US20040204455, p19
Preparation 69: 3^2-({(2/¾-2^iert-ButyI{dirhethyl)sllyl]oxy}-2-i3-(formyl amino)^-hydroxyphenyllethyl}amlno)-2-rnethylpropyll-.V-[2-(4-hydroxyphenyl)-2-methylpropyl]benzamide
4-(2-Amino-1 ,1-dimethyiethyl)phenol hydrochloride (Acta Chem. Scan . 8, 1203, 1207; 1954), (41 mg, 0.21 mmol) was added to a m cture of the product of preparation 42 (100 mg, 0.21 mmol), 0-(1H-benzotriazol-1-yl)-W,W>^N'-tetramethyluronlum hexafluorophosphate (78 mg, 0.21 mmol) and triethyiamine (35 jt L, 0.4 mmol) In N.N-dimethylformamide (3 mL) and the mixture was stirred for 18 hours at room temperature. The solvent was then removed in vacuo and the residue was taken up in ethyl acetate and. washed with saturated sodium hydrogen carbonate solution (3x 20 mL) and brine (3x 20 mL). The organic solution was then dried over sodium sulfate and concentrated in vacuo to afford the title compound as a brown foam in 54% yield.
LRMS APCI m/z 634 [M+Hf
Preparations 70 to 76
The following compounds, of the general formula shown below were prepared from the product of preparation 42 and the appropriate amine, using a method similar to that described for preparation 69. The reactions were monitored by TLC analysis and were stirred at room temperature for 18-72hours.
Preparation 77: Diethyl 2,2'-(1, 3 -phenylene)di acetate
Acetyl chloride (12.5 mL, 175 mmol) was added to a suspension of 2,2'-(1,3-phenylene)diacetic acid (50.0 g, 260 mmol) in ethanol (500 mL) and the resulting solution was heated under reflux for 16 hours. The reaction was then cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between saturated aqueous sodium hydrogen carbonate solution (300 mL) and ethyl acetate (500 mL). The organic phase was separated and washed with water (200 mL) and brine (300 mL), dried over sodium sulfate and the concentrated in vacuo to afford the title compound as a pale yellow oil in quantitative yield, 63.5 g.
1HNMR (CDCI3. 400MHz) δ: 1.31 (6H, t), 3.65 (4H, s), 4.20 (4H, q). 7.24-7.36 (4H, m); LRMS ESI m/z 251 [M+H]+
Preparation 78: [3-(2-Oxo-propyl)-phenyI]-acetic acid ethyl ester
A solution of the diester from preparation 77 (44.3 g, 1 7 mmol) and 2,2'-(1,3- phenylene)diacetic acid (59.2 g, 308 mmoi) in ethanol (24 mL) and dioxan (290mL) was treated dropwise with 12 hydrochloric acid (4.9 mL, 58.8 mmol). The reaction mixture was stirred under reflux for 8 hours, cooled to room temperature and concentrated in vacuo. The reaction mixture was then diluted with toluene (125 mL) and the resulting slurry was filtered. The filtrate was concentrated in vacuo and the residue was taken up in water and basified with sodium bicarbonate until pH neutral. The mixture was diluted with ethyl acetate (200 mL) and the organic layer was separated and washed with sodium hydrogen carbonate solution (5x 30 mL) and brine (50 mL). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with diethyl ether (3x 30 mL). The combined organic solution was dried over magnesium sulphate and concentrated in vacuo. Trituration of the residue with pentane afforded the title compound as a colourless solid in 27% yield, 0.8 g.
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1HNMR (CD3OD, 400MHz) δ: 1.25 (3H, t), 3.60 (2H, m), 3.63 (2H, m), 4.15 (2H,. q), 7.18-7.32 (4H, m); LRMS ESI: m/z 245 [M+Naf
Preparation 79: [3-(2-Hydroxy-2-methyl-propyl)-phenyi]-acetic acid
Methyl magnesium chloride (51 mL of a 3M solution in tetrahydrofuran, 153 mmol) was added dropwise to a stirred solution of the product of preparation 78 (11.6 g, 51 mmol) (International Journal of Peptide and Protein Research, 1987, 29(3), 331) in tetrahydrofuran (300 mL) at 0 °C. The reaction was then allowed to warm to room temperature overnight with the formation of a thick white precipitate and then water (50 mL) and 2N hydrochloric acid (80mL) were cautiously added. The aqueous layer was separated and extracted with ethyl acetate (2x 300 mL). The combined organic solution was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a golden oil in quantitative yield , 11.2 g.
1HN R (CDCI3..4OO MHz) δ: 1.22 (6H, s), 2.75 (2H, s), 3.63 (2H, s), 7.12-7.30 (4H, m); LRMS ESI m/z 209 fM+H]+
Preparation 80 : {3-[2-(2«"Chloro-acetylamino)-2-methyl-propyI]-phenyl}- acetic acid
2-Chloroacetonitrile (8.8 -mL, 140 mmol) was added to a solution of the product of preparation 79 (16.0 g, 70 mmol) In acetic acid (33 mL). The resulting ' solution Was cooled to 0 °C, treated with concentrated sulphuric acid (33 mL), and the reaction mixture allowed to warm gradually to room temperature. After 4 hours, the reaction mixture was poured onto ice and basified- with solid sodium carbonate. The solution was extracted with ethyl acetate (2x 500 mL) and the combined organic extract solution was dried over magnesium sulphate
84
and concentrated in vacuo to afford the title product as a- colourless solid in. 96% yield 19.0 g.
HN R (CDCI3, 400MHz) δ: 1.36 (6H, s), 3.02 (2H, s), 3.62 (2H, s), 3.95 (2H, s), 6.19 (1H, m), 7.06-7.31 (4H, m); LRMS ESI m/z 282 [M-H]"
Preparation 81: [3-(2-Amino-2-methyl'propyl)-phenyl]-acetic acid methyl ester
A solution of the product of preparation 80 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 mL) in ethanol (80 mL) was heated under reflux 16 hours. The reaction mixture was then allowed to cool to room temperature and was filtered. The filtrate was concentrated in vacuo and the residue was dissolved in methanol (150 mL) and saturated with hydrogen chloride gas. The resulting solution was heated to reflux for 16 hours. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (200 mL) and 5% aqueous sodium carbonate solution (200 mL). The organic phase was washed with brine (100mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by strong cation exchange resin, eluting with methanol followed by 2M solution of ammonia in methanol to afford the title compound as a yellow oil in 67% yield, 2.68 g.
1HNMR (CDCI3l 400MHz) δ: 1.14 (6H, s), 2.68 (2H. s), 3.62 (2Hf s), 3.69 (3H, s), 7.08-7.16 (3H, m), 7.23-7.27 (1H, m); LRMS ESI m/z 222 [M+H]+
Preparation 82: Methyl (3-{2-[(fert-butoxycarbony1)amino]-2 -methyl propyl}phenyl) acetate
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The title compound was prepared form the product of preparation .81 , using a. method similar to that of preparation 49, to afford the title compound as a colourless oil in 81% yield.
1HNMR (CQCfe, 400MHz) δ: 1.25 (6H, s), 1.45 (9H, s), 2.95 (2H, s), 3.60 (2H, s), 3.70 (3H, s), 4.25 (1H, bs), 7.02-7.06 (2H, m), 7.15 (1H, d), 7.25 (1H, m); LRMS ESI m/z 344 [M+Na]+
Preparation 83: (3-{2-[(ieri-Butoxycarbonyl)amino]-2-methylpropyr} phenyi)acetic acid
5M Sodium hydroxide solution (4.6 mL 23 mmol) was added to a solution of the product of preparation 82 (7.45 g, 23 mmol) in dioxan (30 mL) and water (8 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in water and acidified to pH3 with 2M hydrochloric acid. The mixture was then extracted with ethyl acetate (3x 30 mL) and the combined organic solution was washed with brine (3x 30 mL), dried over sodium sulfate and concentrated in vacuo to give an oil. This oil was then azeotroped with diethyl ether to afford the title compound as a colourless gum in 99% yield, 7.0 g.
1HNMR {CDCI3.400MHz) 8: 1.25 (6H, s), 1.50 (9H, s), 2.95 (2H, s), 3.55 (2H, s), 3.65 (s, 1H), 7.05 (2H, m), 7.10 (1H, d), 7.20 (1H, m), 7.25 (1H, m)
Preparation 84: ■ Benzyl (3-{2-[(ter -Butoxycarbonyl)amino]-z'- methylpropy1}phenyl)acetate
Caesium carbonate (6.03 g, 8.6 mmol) was added to a solution of the product of preparation 83 (5.7 g, 8.6 mmol) in N,N-dimethylformamide (40 mL) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was
then concentrated in vacuo and the residue was dissolved in. N.N-. dimethylformamide (80 mL), treated with benzylbromide (3.18 g, 1'8.6 mmol) and stirred for 3 hours at room temperature. The mixture was then filtered and concentrated in vacuo and the residue was dissolved in ethyl acetate (60 mL), washed with brine (60 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a pale yellow oil in 76% yield, 5.6 g.
1HNMR (CDCI3l 400MHz) δ: 1.25 (6H, s), 1.49 (9H, s). 2.98 (2H, s), 3.65 (2Hr s), 4.30 (s, 1H), 5.14 (2H, s), 7.06 -7.10 (2H, d), 7.15-7.20 (1H. m), 7.22-7.39 (6H, m); LRMS ESI m/z 396 [M+Q*
Preparation 85: Benzyl [3-(2-amlno-2-methylpropyl}phenyl]acetate
Trifluoroacetic acid (30 mL) was added to the product of preparation 84 (5.6 g, .1 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted with dichloromethane (100 mL) and basified with saturated sodium hydrogen carbonate solution (300 mL). The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow oil In 76 % yield.
1HNMR (CDCI3, 400MHz) 6: 1.10 (6H, s), 1.50 (9H, s), 2.64 (2H, s), 3.66 (2H, s), 5.13 (2H, s), 7.07 -7.12 (2H, d), 7.14-7.18 (1H, m), 7.22-7.38 (6H, m); LRMS ESI m z 298 [M+Hf
. Preparation 86: Benzyl (3-{2-[((2R)-2-[4-(benzyloxy)-3- (formylamino)phenyl]-2- iferi-butyI(dimethyl)silyl]oxy}ethyJ)amino]-2-. methylpropyl}phenyI) acetate
The title compound was prepared from the products of preparation 12 and preparation 85, using a similar method to that of preparation 13, in 55% yield. 1H NMR (400MHz, CDCfe) δ: -0.20 (3H, m), -0.06 (3H, s), 0.78 (9H, s), 0.92 (3H, s), 0.95 (3H, s), 2.53-2.77 (4H, m), 3.57 (2H, s), 4.61-4.68 (1H, m), 5.01-5.02 (2H, m), 5.06 (2H, s), 6.84-6.87 (1H, m), 6.97-7.36 (14H, m), 7.62-7.70 <1H, m), 8.33-8.35 (1H, m), 8.34 (s), 8.67 (s), 8.70 (s); LRMS ESI m/z 681 [Μ+ΗΓ
Preparation 87: {3-[2-({(2R)-2 [tert-Butyl(dime^
(formylamino)-4-hydroxyphenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid
The title compound was prepared from the product of preparation 86, using similar method to that of -preparation 26, In 93% yield.
1H NMR (400MHz, CDCI3) & -0.06 (3H, s), 0.O5 (3H, s), 0.88 (9H, s), 1.00 (3H. s), 1.04 "(3H, s), 2.58-2.88 (4H, m), 3.58 (2H, s), 4.64-4.67 (1H, rh), 6.88-6.90 (1H, m), 6 95-6.98 (1H. m), 7.07-7.27 (5H, m), 8.04-8.05 (d), 8.25 (s), 9.55 (bs); LRMS ESI m/z 501 [M+H]"
Preparation 88: 2-Chloro-W-ethyl-5-hydroxybenzamide
The title compound was prepared from 2-chloro-5-hydroxybenzoic acid and ethylamine, using a method similar to that used for preparation 52, as a colourless solid.
1HNMR (400MHz, CDCI3) δ: 1.22 (3H, t), 3.42-3.49 (2H, m), 6.48-6.52 (1 H, m), 6.80 (1H, dd), 7.13 (1H, d), 7.38 (1H, d); LRMS ESI m/z 2O0 [M+H]+
Preparation 89: -Ch1oro-3-[(et yIamino)methyl]phenol
The title compound was prepared from the product of preparation 88 using the method of preparation 57, as a colourless solid.
1HNMR (400MHz, CD3OD) δ: 1.15 (3H, t), 2.68 (2H, q), 3.79 (2H, s), 6.67-6.70 (1H, m), 6.84 (1 H, d), 7.16 (1 H, d).
Preparation 90: 4-{[ieri-Butyl(dimethyl)silyl]oxy}-2-chlorobenzaldehyde
A solution of 2~chloro-4-hydroxybenzaldehyde (5.0 g, 32 mmol)', fert- butyl(dimethyl)silyl chloride (5,3 g, 35 mmol), imidazole (2.9 g, 45 mmol) and /V,/V-dimethylaminopyridine (10 mg) in A/.W-dimethylformamide (40 mL) was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was partitioned between ethyi acetate (1O0mL) and water (100 mL). The organic phase was separated, washed with brine (50mL), dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel, eluting with pentane:ethyi acetate, 75:25 to 67:33, afforded the title compound as a colourless oil in 75% yield, 6.50 g.
'HNMR (400MHz, CDCI3) δ: 0.25 (6H, s), 0.97 (9H, s), 6.80 (1H, dd), 6.67 (1H, d), 7.84 (1H, d), 10.32 (1H, s)
Preparation 91 : A/-(4-{[ie/ -Butyl(dimethyl)silyI]oxy>-2-chloroben-zyl) prop- 2*en-1 -amine
A solution of the aldehyde from preparation 90 (6.50 g, 24.0 mmol) and ailylamine (1.51 g, 26.4 mmol) in dichloromethane (60 mL) was treated with sodium triacetoxyborohydride (7.6 g, 35.6 mmol) and the resulting suspension stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution {50 mL) was added and the organic layer separated. The organic solution was washed with b ne (50 mL), dried (sodium sulfate) and concentrated in vacuo to give a yellow oil. Purification of the oil by column chromatography on silica gel, eluting with pentane:ethy1 acetate 75:25 to 67:33, afforded the title compound as a colourless oil in 38% yield, 2.80 g.
1HNMR (400MHz, CDCI3) δ: 0.19 (6H, s), 0.97 (9H, s), 1.84 (1H, bs), 3.26 (2H, d), 3.81 (2H, s), 5.12 (1H, dd), 5.20 (1H, dd), 5.88-5.98 (1H, m), 6.71 (1H, dd), 6.85-6.86 (1 H, d), 7.24 (1 H, d); LRMS ESI m/z 312 [M+Hf
Preparation 92: (4-{[feri-Butyl(dimethy1)silyl]oxy}-2-chlorobenry1)amine
A solution of the product of preparation 91 (2.8 g, 9.0 mmol), dimethylbarbituric " acid (7.0 g, 45 mmol) and te.ra/r/s(triphenylphosphine)palladium(0) (0.10 g, 0.08mmol) in dichloromethane (80 mL) was heated under reflux for 4 hours. The cooled solution was then concentrated in vacuo and the residue was partitioned between ethyl acetate (50 mL) and 1N aqueous sodium hydroxide solution (50 mL). The organic layer was separated, washed with brine =(50mL), dried over sodium sulfate and concentrated In vacuo. Purification of the residue
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by column chromatography on silica gel, . eluting . with. dichloromethane:methanol:0.880 ammonia, 98:2:0 to 95:5:0.5, afforded the title compound as a colourless oil 70% yield, 1.70 g.
1HNMR (400MHz, CDCI3) δ: 0.19 (6H, s), 0.97 (9H, s), 1.89 (2H, s), 3.85 (2H. s), 6.70 (1 H, dd), 6.85-6.86 ( H, dd), 7.21 (1 H, d)
Preparations 93 to 95
The following compounds, of the general formula shown below were prepared from the product of preparation 87 and the appropriate amine, using a method similar to that described for preparation 27. The reactions were monitored by tic analysis and were stirred at room temperature for 18-72 hours.
No. Qi Data Yield
93 'H N R (400MHz, CD3OD) δ: -0.18 41%
(3H, s), -0.07 (3H, s), 0.75 (9H, s), 1.01
(3H, s), 1.04 (3H, s), 2.59-2.83 (4H, m).
3.56-3.58 (2H, m), 3.89 (3H, s), 4.41- 4.53 (2H, m), 4.63-4.66 (1H, m), 6.80- 6.82 (1H, m). 6.95-6.98 (1H, m), 7.03- 7.05 (1H, m), 7.09-7.11 (2H, m), 7.21- 7.26 (4H, m),7.93-7.69 (2H, d); LRMS
ESl m z648 [M+Hf
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Preparation 96: 2-{3-[2-({(2 ?)-2-{[ferjf-Butyl(dimethyl)slly1]oxy}-2-[3. (formyIamino)-4-hydroxyphenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-(2- chloro-4-hydroxybenzyI) acetamide
The title compound was prepared from the products of preparations .87 and 92 using a method similar to that of preparation 27 , as brown foam in 62% yield. 1H NMR (400MHz, CD3OD) 5: -0.19 (3H, s), -O.03 (3H, s), 0.79 (9H, s), 1.01- 1.10 (6H, m), 2.62-2.76 (3H, m), 2.85 (1H, m), 3.37-3.92 (2H, m), 4.34 (2H, s),
4.66 (ΙΗ, m), 6.62 (1H, m), 6.78-6.82 (2H, m), 6.91 (1H, m); 7.02-7.23 (5H, m)r 8.09-8.11 (1 H, m), 8.27 (s), 8.59 (s); LRMS APCI m/z .640 [ +Hf
Preparation 97: 2-(3-Bromophenyl)-Ar-(3,4-dimethylbenzy!)acetamide
The title compound was prepared from 3,4-dimethylbenzytemine and 3-bromophenylacetic acid, using a method similar to that of preparation 27, as a white solid in 93% yield.
1H NMR (400MHz, CDCI3) 5: 2.20 (6H, s), 3.50 (2H, s), 4.30 (2H, d), 5.80 (1H, brs), 7.60-7.80 (7H, m); LRMS ESI 332 [M]+
Preparation 98: N«(3,4-DlmethylbenzyI)-2-{3-[(E)-2«{1 ,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)vinyl]pheny1}acetamide
The product of preparation 97 (5.0 g, 15 mmol), N-vinylphthalimide (2.62 g, 5.1 mmol), tri-orffto-tolylphosphine (473 mg, 1.55 mmol), palladium(ll)acetate (98 mg, 0.4 mmol) and N,N-diisopropylethylamine (30 mL, 172 mmol) in acatonitrile (35 mL) was heated under reflux for 16 hours. The reaction mixture was then cooled to room temperature and the precipitate was filtered off. The solid was then dissolved in dichloromethane, activated charcoal was added, • and the -solution was filtered through Celite® The filtrate was concentrated in vacuo and the residue was re-crystallised from hot dichloromethane/methanol to afford the title compound as a yellow solid in 55% yield, 3.5 g.
1H NMR (400MHz, CDCI3) δ: 2.20 (6H, s), 3.80 (2H, s), 4.30 (2H, d), 6.0 (1H, brs), 6.90 (2H, m), 7.01 (1H, m). 7.18 (1H, m), 7.26-7.40 (4H, m), 7,56-7.61 (1 H, m), 7.75 (2H, m), 7.88 (2H, m)
Preparation 99: W-(3,4-Dimethylbenzyl)-2-{3-[2-(1 ,3-dioxo-1 ,3-dihydro-2W-isoindol-2-yl)ethyl]phenyl}acetamide
The product of preparation 98 (3.3 g, 7.7 mmol) and 10% palladium-on-carbon (1 g) were suspended in ethanol and the mixture was stirred under 50 psi of hydrogen gas, at room temperature for 16 hours. The reaction mixture was then filtered through Arbocef®, washing through with ethanol, and the filtrate was concentrated in vacuo to afford the title product as a yellow solid in 52% yield, 1.7 g.
1H NMR (400MHz, CDCI3) δ: 2.20 (6H, s), 2.95 (2H, t), 3.60 (2H, s), 3.90 (2H, t), 4.39 (2H, d), 5.95 (1H, brs), 6.90-7.20 (8H, m), 7.60-7.7Q (3H, m)
Preparation 100: 2-[3-(2-Amlnoethyl)pheny|]-A -(3,4-dimethylbenzyI}-acetamide
Hydrazine monohydrate (6 ml, 123.6 mmol) was added to a suspension of the product of preparation 99 (3.5 g, 8.2 mmol) in ethanol (125 ml) and the mixture was heated under reflux for 4 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eiuting with dichJoromethane:methanol:0.88 ammonia, 95:5:1 to afford the title compound the title compound in 57% yield, 1.4 g.
1H NMR (400MHz. CD3OD) δ: 2.18 (6H, s), 2.73 (2H, m), 2.86 (2H, m), 3.50 (2H, s), 4.25 (2H, s), 6.87-7.25 (7H, m); LRMS ESI 297 [IV!+Hf
Preparation 101 : 2-{3-{2-l((2R)-2-[4 Benzyloxy)-3-(formylamino)phenylJ-2-;
{[iert.butyl(dimethyl)silyJ]oxy}ethyl)arnino]ethyI}phenyl)-W-(3,4^
dimethylbenzyl)acetamide
The title compound was prepared from products of preparation 12 and preparation 100, using a method similar to that of preparation 33, as a yellow oil in 37% yield.
1H NMR (400MHz, CD3OD) δ: -0.18 (3H, s), -0.03 (3H, s), 0.80 (9H, s), 2.20 (6H, m), 2.80 (4H, m), 3.40 (2H, m), 3.50 (2H, s), 4.25 (2H, s), 4.76 (1H, m), 5.18 (2H, s), 6.85-7.45 (15H, m), 8.23 (s), 8.30 (s); LRMS ESI 680 [ +Hf
Preparation 102: 2-{3 2-{{(2^)-2-{[tert-butyl{dimethyl)silyI]oxy}-2.i:3- (formylamlno)-4-hydroxyphenyl]ethyl}arnlno)ethyl]phenyl}-N-(3,4- dimethylbenzyl)acetamide
The title compound was prepared from the product of preparation 101, using a ' method similar to that of preparation 20, as a white foam in 83% yield.
H NMR (400MHz, CD3OD) δ: -0.18 (3H, s), -0.05 (3H, s), 0.81 (9H, s), 2.18 (6H, m), 2.80 (4H, m), 3.29 (2H, m), 3.51 (2H, s), 4.25 (2H, s), 4.70 (1H, nn), 6.80 (1H, d), 6.91-7.20 (9H, m), 8.03 (s), 8.25 (s); LRMS ESI 590 [M+Hf
Preparations 103 to 110
The following compounds, of the general formula shown below were prepared from the product of preparation 87 and the appropriate amine, using a method similar to that described for preparation 27. The reactions were monitored by tic analysis and were stirred at room temperature for 18-72 hours.
No. Qi Data Yield
103 'H NMR (400MHz, CD3OD) 5: -0.25 66%
(3H, s), -0.08 (3H, s), 0.73 (9H, s),
0.97 (3H, s), 0.99 (3H, s), 2.37 (3H,
s), 2.56-2.83 (4H, m), 3.39-3.45 (2H,
m), 4.24 (2H, s), 4.60-4.63 (1H, m),
6.73-6.79 (1H, m), 6.85 (1H, dd). 6.97
(1H, d), 7.03 (1H, s). 6.97-7.16 (6H,
m), 8.04 (d), 8.21 (s), 8.53 (s); LRMS
ESI m/z 658 [M+HV
104 F nH NMR (400MHz, CDCI3) 5: -0.24 55%
(3H, s), -0.08 (3H, s), 0.74 (9H, s),
0.98 (3H, s), 1.00 (3H, s), 2.57-2.83
(4H, m), 3.48 (2H, m), 4.37 (2H, s),
4.60-4.63 (1H, m), 6.73 (1H, d), 6.85
(1H, dd), 6.99-7.17 (5H, m), 7.32 (2H,
d), 7.49 (2H, d), 8.04 (d), 8.22 (s),
8.52 (s); LRMS APCI m/z 658 [M+H]+
105 'H NMR (400MHz, CDCI3) δ: -0.17 19%
(3H. s), -0.06 (3H, s), 0.76 (9H, s), 1.01 (3H, s), 1.03 (3H, s), 2.59-2.83 (4H, m), 3.56-3.68 (2H, dd), 4.45-4.49 (2H, m), 4.64-4.67 (1H, m), 6.84-6.86 (1H, m), 6.95 (8H. m), 7.55-7.57 (2H.
m), 8.17 (d), 8.63 (s); LRMS ESI m/z 615 [M+Hf
106 1H NMR (400MHz, CDC!3) δ: -0.16 52%
(3H, s), -0.06 (3H, s), 0.77 (9H, s), 1.00 (3H, s), 1.04 (3H. s), 2.57-2.85 (4H, m), 2,53-3.67 (2H, dd), 4.40 (2H, m), 4.64-4.67 (1H, m), 6.80 (1H,m), 6.96 (1H, m), 7.02 (7H, m), 7.32-7.34 (2H, m), 8.17 (d), 8.74 (s); LRMS APCI m/z 674 [M+Hf
107 'H NMR (400MHz, CD3OD) δ: -0.26 72%
(3H, s), -0.10 (3H, s), 0.72 (9H, s), 0.93 (3H, s). 0.95 (3H, s), 2.49-2.79 (4H, m), 3.46-3.47 (2H, m), 4.33 (2H, s), 4.58-4.61 (1H, m), 6.72-7.48 (15H, m), 8.04 (1H, d), 8.21 (s), 8.52 (s) ;
LRMS APCI m/z 682 [M+H]+
108 Ή NMR (400MHz, CD3OD) δ: -.024 43%
(3H, s), -0.08 (3h, s), 0.74 (9H, s), 0.99 (3H, s), 1.02 (3H, s), 2.59-2.87 (4H, m), 3.47 (2Hf. m), 4.23 (2H, s), 4.62-4.65 (1H, m), 6.65 (1H, d), 6.74 (1 H. d), 6.90-6.95 (1H, m), 7.01-7.07 (3H, m), 7.10 (1H, s), 7.14-7.24 (2H, m), 8.05 (1H, d), 8.22 (s), 8.53 (s);
LRMS APCI m/z 640 [M+Hf
Preparations 111 to 119
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimlde hydrochloride (40 mg, 205 μιτιοΙ) was added to a solution of preparation 42 (100 mg, 206 mol), hydroxybenzotriazole hydrate (32 mg, 205 μπιοΙ) and triethylamine (0.55 μί, 412 μτηοΙ) in dichloromethane (2 mL) followed by the amine (205 μηιοΐ) and the mixture was stirred at room temperature for 18 hours. The solvent was then removed in vacuo and the residue was diluted with ethyl acetate, washed with , sodium hydrogencarbonate solution (20 mL) and brine (20 mL), dried (Na2S04) and concentrated in vacuo to leave a film which was suspended in diethyiether (x3) to afford a foam.
No. Qi Data Yield
111 LRMS ESI m/z 590 [M+H]* 81%
112 LRMS APCI m/z 582 [M+Hf 74%
113 LRMS APCI m/z 554 [M+H]* 94%
114 LRMS APCI m/z 658 [M+H]* 87%
115 LRMS APCI m z 604 [M+H]* 83%
116 LRMS APCI m/z 602 [M+Hf 89%
117 LRMS APCI m/z 591 [M+H]* 74%
118 LRMS APCI m/z 620 [M+H]* 90%
119 LRMS APCI m/z 669 [M+H]* 80%
120* LRMS APCI m/z 602 [M+H]* 92%
O 2D05/0928 PCT/IB2 500l)f»1
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* no evaporation from diethylether
Preparation 122 : WK5-[(2 ?)-2-{2-[3«(10-Aza-trlcyclo[6.3.1.0*2,7*]dodeca- 2(7),3,5-triene-10-carbonyl)phenyl]-1 ,1 -dimethy!ethylamino}-1 -(fert- butyldimethylsilanyloxy)etl yl]-2-hydroxyphenyl}formamide
The title compound was prepared with 10-aza-tricyclo[6.3.1.0*2,7*]dodeca -2(7)f3.5-triene, using a method similar to that of preparation 69.
LRMS APCl m/z 628 [M+Hf
Preparation 12 : 3^2-[{2R)-2-(feri-Butyldimethylsilanyloxy)-2-(3- formylamino-4-hydroxyphenyl)ethylamino]-2-methylpropyl}-W-[2-{5-chloro
2-hydroxyphenyl)ethyl]benzamide
The title compound was prepared with 2-(2-aminoethy1)-4-chlorophenol, using method similar to that of preparation 69.
LRMS APCl m/z 640 [M+H]
Preparations 124 to 128
The amine (412 μτηοΐ) was added to a mixture of preparation 42 (200 mg, 412 μιηοΙ), hydroxybenzotriazole hydrate (63 mg, 412 μΐηοΙ), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79 mg, 412 μίηοΙ) and triethylamine (0.11 mL, 824 μτηοΙ) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 18 hours. The solvent was then removed in vacuo and the residue was diluted with ethyl acetate, washed with sodium hydrogencarbonate solution (3x 20 mL) and brine (3x 20 mL), dried (MgS04). The crude material was purified by chromatography on silica gel, eluting with dichloromethane:0.88 ammonia, 99.7:0.3. The appropriate fractions were evaporated under reduced pressure and the residue and concentrated in vacuo, the resulting white foam was suspended in diethylether (x3) and evaporated.
No. Qi Data Yield
124 Ή NMR (400MHz, CDCI3) δ: -0.23 63%
(3H, s), -0.09 (3H, s), 0.69 (9H, s),
CHS 1.07 (3H, s), 1.08 (3H, s), 2.27 (3H,
s), 2.29 (3H, s), 2.60-2.82 (4H, m),
2.98 (2H, t), 3.64-3.73 (2H, m), 4.61- 4.65 (1H, m), 6.39 (1H, m), 6.84-7.42
(10H, m), 7.80 (1 H, s), 8.24 (1H, s),
9.70-9.80 (m); LRMS APCI m/z 619
[M+Hf
125 H NMR (400MHz, CDCI3) δ:. -0.23 70%
(3H, s), -0.09 (3H, s), 0.70 (9H, s),
CI 1.02 (3H, s), 1.04 (3H, s), 2.60-2.79
(4H, m), 3.09-3.12 (2H, t), 3.74-3.79 (2H, m), 4.58-4.60 (1H, m), 6.35-6.39 (1H, m), 6.88 (1H, d), 6.94 (1H, d), 7.10 (1 H, s), 7.20-7.34 (4H, m), 7.38- 7.42 (2H, m), 7.76 (1H, s), 8.24 (1H, s), 9.76 (1H, s); LRMS APCI m/z 624
[M+Hf
126 ΊΗ NMR (400MHz, CDCI3) δ: -0.22 96%
(3H, s), -0.09 (3H, s), 0.71 (9H, 5),
1.20 (3H, s), 1.22 (3H, s), 2.34 (6H, s), 2.61-2.78 (4H, m), 3.00 (2H, t), 3.56-3.60 (2H, m), 4.59-4.62 (1H, m), 6.39-6.43 (1H, m), 6.86 (1H, d), 6.96- 7.07 (3H, m), 7.16 (1H, s), 7.28-7.33 (2H, m). 7.42 (1H, d). 7.77 (1H, s), 8.24 (1 H, s), 9.65 (1 H, s); LRMS APCI m/z 618 [M+Hf
127 1H NMR (400MHz, CDCI3) 6: -0.23 73%
(3H, s), -0.09 (3H, s), 0.70 (9H, s), 1.04 (3H, s), 1.05 (3H, s), 2.33 (3H, s), 2.61-2.76 (4H, m), 2.88-2.92 (2H, t), 3.67-3.74 (2H, m), 4.57-4.60 (1 H, m), 6.25-6.29 (1H, m), 6.88 (1H, d), 6.98 (1H, d), 7.09-7.33 (7H, m), 7.75 (1H, s), 8.23 (1H, s), 9.82 (1H, s);
LRMS APCI m/z 604 [M+H]+
128 H NMR (400MHz, CDCI3) 5L -0.23 19%
(3H, s), -0.10 (3H, s), 0.68 (9H, s),
1.03 (3H, s), 1.04 (3H, s), 2.59-2.76
(4H, m), 3.42-3.48 (2H, m), 3.80-3.94
(2H, m), 4.58-4.61 (1H, m), 6.30-6.34
(1H, m), 6.89 (1H, d), 6.98 (1H, d),
7.10 (1H, s), 7.23-7.60 (6H, m), 7.75
(1H, s), 7.77 (1H, d), 8.15 (1H, d),
8.18 (1H, d), 9.77 (1 H, s); LRMS APCI
m/z 640 [M+H]+
Preparation 129 : 3-(2-Oxo-propyl)benzoic acid methyl ester
Tributyltin methoxide (80.3 mL, 279 mmol), methyl 3-bromobenzoate (53.5 g, 249 mmol), isopropenyl acetate (39.4 ml, 358 mmol), palladium(ll)acetate (2.6 g, 11.6 mmol) and tri-orfho-tolylphosphine (7.1 g, 23.2 mmol) were stirred together in toluene (350 mL) at 100 eC under nitrogen for 18 hours. After cooling, the reaction was treated with potassium fluoride solution (4M, 560 mi) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200 mL) and filtered through Celite ®, washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by chromatography eluting with ethylacetate:pentane 10-90 to 20:80 to give the title compound (45.3 g) as an orange oil. '
1H NMR" (400MHz, CDCfe) 5: 2.18 (3H, s), 3.75 (2H, s), 3.91 (3H, s), 7.43-7.37 (2H, m), 7.87 (1H, s), 7.95-7.93 (1H, d); LRMS ESI m/z 215 [M+Naf , 191 [M- H]\ ·
Preparation 130 : 3-[(2 )-2-((1R)-1-Phenylethylamino)propyl]benzoic acid methyl ester hydrochloride
The title compound was prepared with preparatidn 129, using a method similar to that of preparation 19, to give the title comppund (27.3 g) as a colourless crystalline solid.
H NMR (400MHz, CD3OD) δ: 1.17-1.16, (3H, d , 1.71-1.69 (3H, d), 2.71-2.65 (1H, dd), 3.25-3.19 (1H, m), 3.43-3.38 (1H, dd), 190 (3H, s), 4.68-4.63 (1H, q), 7.35-7.33 ( H, d), 7.45-7.42 (1H, dd), 7.55-7.49 (&H. m), 7.75 (1H, s), 7.92-7.90 (1H, d).
Preparation 131 : Methyl {3-[(2R)-2-aminopropyl]phenyl}acetate
The title compound was prepared with preparation 130, using a method similar to that of preparation 20, to give the title compound (8.48g) as a pale yellow oil. 1H NMR (400MHz, CDCI3) δ: 1.14-1.12 (3H, d), 2.64-2.59 (1H, dd). 2.78-2.73 (1Hr dd), 3.26-3.17 (1H, m), 3.90 (3H, s), 7.38-7.34 (2H, m), 7.90-7.87 (2H, m); LRMS ESI m/z 194 [M+Hf.
Preparation 132 : 3-((2/?)-2-rert-ButoxycarbonyIamlnopropyl)benzoic acid methyl ester
• A mixture of preparation 131 (5.00 g, 26.0 mmol), di-terf-butyldicarboxylate (6.22 g, 28.5 mmol) and sodium hydrogencarbonate (4.35 g, 52 mmol) were stirred in a mixture of 1,4-dioxane (100 mL) and water (10 mL) for 20 h. The solvent was removed and the material partitioned between ethyl acetate (200 mL) and hydrochloric acid (2M, 100 mL), the organics were washed with brine
(100 mL) and dried (MgS04). Removal of the solvent left a white solid (7.12 g,. 93 %).
1H F^ (400MHz, CD3OD) δ: 1.09 (3H, d), 1.35 (9H, s), 2.73-2.79 (2H, m), 3.76-3.83 (1H, m), 3.89 (3H, s), 6.54 (1H, d), 7.26-7.46 (2H, m), 7.84-7.87 (2H, m); LC S Rt 4.53 min m/z 294 [M+Hf
Preparation 133 : 3-((2/?)-2-fert-Butoxycarbonylaminopropyl)benzoic acid
A mixture of preparation 132 (7.10 g, 24.3 mmol) and lithium hydroxide (1.00 , 50.0 mL, 50.0 mmol) in tetrahydrofuran (100 mL) were stirred for 20 n. The reaction mixture was diluted with ethyl acetate (250 mL) and acidified to pH 2 with hydrochloric acid (2M). The aqueous phase was re-extracted with ethyl acetate ( 50 mL) and the combined organics washed with brine (300 mL) and dried (MgS04). Filtration and removal of the solvent gave 5.53 g (82 %) of the title compound.
1H NMR (400MHz, CD3OD) δ: 1.10 (3H, d), 1.36 (9H, s), 2.82-2.81 (2H, m), 3.77-3.84 (1H, m), 7.35-7.45 (2H, m), 7.84-7.89 (2H, m); LRMS APCI m z 278 [M-HT
Preparation 134 : 3-((2R)-2-ieri-Butoxycarbonylaminopropyl)benzoic acid benzyl ester
. Caesium carbonate (6.50 g, 19.8 mmol) in water (10 mL) was added to a solution of preparation 133 (5.50 g, 19.8 mmol) in Ν,Ν-dimethylformamide (50 . mL) and the resulting mixture stirred at room temperature for 1 h. Benzylbromide (3.42 g, 19.8 mmol) was then added and the mixture stirred for 20 h. Ethyl acetate (50 mL) was added and the suspension filtered, the filtrate was washed with saturated brine (100 mL) and dried (MgS04). Filtration and removal of the solvent left 7.20 g of the title compound.
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1H N R (400MHz, CD3OD) 5: 1.09 (3H, d), 1.32 (3H, s), 2.74 (2H, d), 2.7.5-2.83. (1H, m), 5.34 (2H, s), 7.29-7.40 (4H, m), 7.43-7.47 (3H, m), 7.85-7.90 (2H, m); LRMS APCI m/z 270 [M-BOC]+
Preparation 135 : 3-((2R)-2-Aminopropyl)benzoic acid benzyl ester
Preparation 134 (7.20 g, 9.0 mmol) was treated with trifluoroacetic acid (35 mL) and the mixture left to stir for 20 h. The trifluoroacetic acid was removed in vacuo and dichloromethane (175 mL) added. The mixture was basified with sat. sodium hydrogencarbonate (150 mL) and washed with sodium hydroxide (1M, 50 mL). The combined organics were washed with brine (150 mL) and dried (MgS04) to leave a brown oil (3.70 g, 72 %).
H NMR (400MHz, CD3OD) δ: 1.04 (3H, d), 2.66 (2H, d), 3.05 (1H, dt), 5.33 (2H, s), 7.28-7.44 (7H, m), 7.86-7.90 (2H, m); LRMS APCI m/z 270 [M+HJ+
Preparation 136 : 3- (2 )-2-[(2R)-2-{4-Benzyloxy-3-formylaminophenyl)-2- (terf-butyldimethylsilanyloxy)ethylamlno]propyl}benzoic acid benzyl ester
Preparation 135 (3.70 g, 13.8 mmol) and preparation 12 (3.20 g, 6.9 mmol) ■ were heated to 90 °C for 26 h. The mixture was allowed to cool and diluted ' with dichloromethane (100 mL). The organics were washed with sat. sodium hydrogencarbonate (200 mL) and concentrated In vacuo. The crude material ' was purified by chromatography (x2), eluting with ethyl acetate:heptahe 0: 00 to 40:60 to yield 2.0 g (52 %) of the title compound.
LRMS APCI m/z 270 [M+HJ*
Preparation 137 : 3-{(2R)-2-[(2R)-2-(tert-Butylc«methylsilariyloxy)-2-(3-. formyIamino-4-hydroxyphenyl)ethylamino]propyl}benzoic acid
Preparation 136 (2.0 g, 3.1 mmoi) and palladium-on-carbon (10 %, 205 mg) in methanol (100 mL) were hydrogenated at 60 psi/RT for 20 h. A solution of ammonia in methanol (2 , 50 mL) was added and the mixture allowed to stir for 2 min. The mixture was then filtered through a filter-aid, which was washed with the ammonia in methanol solution (2M, 250 mL), and the resulting organlcs concentrated to yield a dark green solid. The crude material was purified by chromatography, eluting with dichloromethane:methanol:0.88 ammonia 100:0:0 to 75:20:5 to yield the title compound as a dark green solid (131 mg).
1H NMR (400MHz, DMSO-d6) δ: -0.18 (3H, s), -0.06 (3H, s), 0.77 (9H, s), 0.89 (3H, d), 2.61-2.68 (2H, m), 2.65-2.73 (2H, m)r 2.80-2.86 (1H, m), 4.56-4.60 (1H, m), 6.75 (1H, d), 6.81 (1 H, dd), 7.83 (2H, d), 7.70-7.75 (2H, m), 8.00 (d), 8.25 (s), 9.53 (s); LRMS APCI m/z 473 [M+H]+
Preparation 138 : 3-{(2 )-2-[(2R)-2-(ferf-Butyldimethylsllanyioxy)-2-(3- formylamino-4-hydroxyphenyI)ethylamino]propyI}-/V-[2-(4-hydroxyphenyl)- 2-methylpropyl]benzamide
The title compound was prepared with 4-(2-amino-1 ,1-dimethylethyl)phenol hydrochloride (Acta Chem. Scand. 8, 1203, 1207; 1954), using a method similar to that of preparation 27.
1H NMR (400MHz, CD3OD) δ: ÷0.24 (3H, s), -0.08 (3H, s); 0.76 (9H, s), 0.99. (3H, d), 1.28 (6H, s), 2.54-2.92 (5H, m), 3.46 (2H, s), 4.60-1.63 (1H, m), 6.66-6.70 (3H, m). 6.77-6.80 (1H, dd), 7.20-7.34 (4H, m), 7.45 (1H, s), 7.50 (1 H, d), 7.92-7.93 (1H, d), 8.21 (s)r 8.55 (s); LRMS APCI m/z 620 [M+H]+
Preparation 139 : Methyl (2£)-3-[3-(2-oxopropyl)phenyl]acrylate
A solution of 3-br6mophenylacetone (50.0 g, 235 mmol), methyl acrylate (40.4 g, 469 mmol), palladium(H)acetate (7.9 g, 35.2 mmol), tri-orfno-tolylphosphine (21.4 g, 70.4 mmol) and triethylamine (82 mL) In acetonitrile (900 mL) was heated at reflux under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. Purification by flash column chromatography eluting with pentane:ethyl acetate 90:10 to 70:30 gave the title compound as an orange oil (54.3 g).
1H NMR (400MHz, CD3OD) δ: 2.15 (3H, s), 3.70 (2H, s), 3.77 (3H, s), 6.43-6.39 (1H, d), 7.20-7.18 (1H, d), 7.34-7.31 (2H, t), 7.41-7.39 (1H, d), 7.66-7.62 (1H, d); LRMS ESI : m z 241 [M+Naf, 217 [M-H]".
Preparation 140 : Methyl 3-[3-(2-oxopropyl)phenyl]propanoate
Prepared according to the procedure used for preparation 26 using preparation 39 to give the title compound as an orange oil.
1H NMR (400MHz, CD3OD) 5: 2.14 (3H, s), 2,64-2.60 (2H, t), 2.96-2.92 (2H, t), 3:66 (5H, s), 7.05-7.04 (2H, d), 7.11-7.09 (1H, d), 7.27-7.23 (1 H, q); LRMS ESI m/z 243 [M+Naf, 2 9 [M-H]".
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Preparation 141: Methyl . [3-((2R)-2-{[(1R)
ethyl]amino}propyl)phenyl]propanoate hydrochloride
Prepared according to the procedure used for preparation 19, using preparation 140 to give the -title compound as a white crystalline solid.
1H NMR (400MHz, CD3OD) δ: 1.18-1.16 (3H, d), 1.71-1.69 (3H, d), 2.62-2.56 (3H, m), 2.89-2.85 (2H, t), 3.20-3.12 (1H, m), 3.34-3.29 (1H, m), 3.61 (3H, s), 4.64-4.59 (1H, q), 6.92-6.91 (2H, d), 7.12-7.10 (1 H, d), 7.23-7.19 (1H, t), 7.54-7.47 (5H, m); LR S ESI m/z 326 [ +H]*.
Preparation 142 : 3-{3-[(2R)-2-((1/?)-i-Phenylethylamino)propyllphenyl}-propionic acid
Preparation 141 (3.25 g, 8.98 mmol) and sodium hydroxide (5M, 9.0 mL, 45.0 mmol) were stirred in 1 ,4-dioxane (40 mL) and water (40 mL) for 18 h. The solvent was removed in vacuo and the material dissolved in water, acidified to pH 6 with hydrochloric acid (2M) which solidified over 18 h. The solid was filtered off and dried in vacuo (1.0 g, 36 %). The filtrate was concentrated and tetrahydrofuran added and the mixture filtered. The filtrate was evaporated to leave a foam which was suspended in diethylether (x3) to yield a colourless foam (1.96 g, 70 %).
H NMR (400MHz, CD3OD) 6: 1.13 (3H, d), 1.62 (3H, d), 2.42 (2H, t), 2.55-2.64 (1H, m),-2.84 (2H, t), 3.08-3.42 (2H, m), 4.46-4.52 (1H, m), 6.86 (1H, d), 6.98 (1H, s), 7.11-7.22 (2H, m), 7.45-7.52 (5H, m); LC S APCI m/z 312 [M+Hf
Preparation 143: l-tS^-Dihydro-IH-isoquinolin^-y -S-iS-KaRJ-a-U RJ-l- phenylethylamino)propyl]phenyl}propan-1-one
Preparation 142 (1.95 g, 6.27 mmol), triethylamine (2.62 mL, 19.0 mmol) in dichloromethane (80 mLO were treated with 2-:chloro-1 f3-dimethylimidazoline hexafluorophosphate (1.75 g, 6.27 mmol) and the resulting solution left to stir for 3 h. The solvent was removed and the rescue taken up in ethyl acetate and washed with sat. sodium hydrogencarbonate (3x 20 mL), brine (3x 20 mL) and dried (Na2S04). After filtration and removal of the solvent the material was purified by chromatography, eluting with d|chloromethane:methanol:0.88 ammonia 99.7:0:0.3 to 96.7:3:0.3. The product was evaporated from diethylether (x3) to yield a semi-solid (2.3 g, 86 %).
1H N R (400MHz, CDCI3) δ: 0.88 (3H, d), 1.30 (3H, d), 2.42-2.50 (1H, m), 2.64- 2.98 (8H, m). 3.55-3.62 (1H, m), 3.78-3.96 (2Hf _m), 4.51 (1H, s), 4.72 (1H, s), 6.88-7.38 (13H, m); LCMS APCI m/z 427 [M+Hj
Preparation 144: 3-[3-((2/?)-2-Aminopropyl)phenyl]-1-(3,4-dihydro-1/ - isoquinolIn-2-yl)propan-1 -one
Preparation 143 (2.20 g, 5.16 mmol), ammonium formate (1.63 g, 26.0 mmol) and palladium hydroxide (500 mg) in ethanol (40 mL) were heated and stirred at 70 °C for 4 h. The mixture was filtered through a filter-aid and the solvent removed. The material was purified by chromatography, eluting with dichloromethane:methanol:0.88 ammohia 99.7:0:0.3 to 94.7:5:0.3 to yield a colourless oil which was evaporated from diethylether (x3) (1.26 g, 76 %).
' 1H NMR (400MHz, CDCI3) δ: rotamers 1.10/1.11 (3H, 2x d). 2.43-2.48 (1H, m), 2.62-2.76 (3H, m), 2J8-2.86 (2H, m), 2.96-3.02 (2H, m), 3.08-3.18 (1H, m), 3.58 (1H, t), 3.81 (1H, t), 4.53/4.73 (2H, 2x s), 6.98-7.24 (8H, m); LCMS APCI m z 323 [M+Hf
Preparation 145 : / -{Z-BenzyJoxy-S^KI^-l-iiert-butyldimethylsilanyloxy)- 2-((1 ?)-2-{3-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-3-oxo-propyl]phehyl>-1-methylethylamino)et yl]phenyl}formamide
The title compound w as prepared with preparation 144 and preparation 12, using a method similar to that of preparation 136 (216 mg, 67 %).
1H NMR (400MHz, CD3OD) δ: rotamers -0.19 (3H, s), -0.01 (3H, s), 0.82 (9H, s), 0.98-1.04 (3H, s), 2.48-2.96 ( 1H, m), 3.57-3.62/3.72-3.76 (2H, rn), 4.53-4.70 (3H. m), 5.18 (2H, m), 6.87-6.97 (3H, m), 6.99-7.18 (7H, m), 7.28-7.39 (3H, m), 7.45-7.60 (2H , m), 8.20 (d). 8.31 (d); LCMS APCI m/z 707 [Μ·ι-Η]+
Preparation 146 : N-{5-[(1R)-1-(iert-ButyldimethylsilanyIoxy)-2-(( R)-2- 3-[3- (3,4-dihydro-1H-lsoquinolin-2-yl)-3-oxo-propyl]phenyI}-1- methylethylamino)ethiyl]-2-hydroxyphenyl>formamide
Prepared using the amide from preparation 145 and the method described for preparation 15 to yield a brown foam (280 mg, 100 %).
1H NMR (400MHz, CD3OD) 5: rotamers -0.14 (3H, s), -0.03 (3H, s), 0.84 (9H, ' s), 1.08-1.12 (3H, m), 2.54-3.20 (11H, m), 3.60-3.65/3.74-3.77 (2H, 2>c t), 4.56- 4.66 (2H, 2x s), 4.78-4- .84 (1H, m), 6.80-7.24 (1H, m), 8.10 (s), 8.31 (s); LCMS APCI m z 617 [M+H]+
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Example 1 : W-Benzyl-2-(3-<2-t(2/?)-2-(3-formylamino-4-hydroxyphenyl)-2-. hydroxyethylamino]-2-methylpropyl}phenyl)acetamide
Preparation 15 (24 mg, 40 μτηοΙ), formic acid (0.5 mL), tetrahydrofuran (5 mL) and water (0.5 mL) were heated to 90 eC for 18 h. A further aliquot of formic acid (0.5 mL) and tetrahydrofuran (5 mL) were added and heating continued for a further 18 h. The solvent was removed and the product purified by chromatography (0-10 % methanol in dichloromethane + 0.3 % ammonia). The product was dissolved in methanol (x3) and evaporated (10 mg).
1HNMR (CD3OD 400 MHz) .8: 1.05-1.09 (6H, m), 2.69-2.78 (2H, m), 2.78-2.83 (1H, m), 2.87-2.93 (1H, m), 3.53 (2H, s), 4.35 (2H, s), 4.65 (1H, dd), 6.82-6.86 (1H, m), 6.99 (1 H, dd). 7.03-7.06 (1H, m), 7.13-7.28 (7H, m), 8.08 (d), 8.28 (s), 8.55 (s), 8.61 (s); MS (APCI) m/z 476 [M+HJ+; HRMS C2eH33N30 476.2544 [M+Hf found 476.2533.
Example 2 : N-(3,4-Dimethylbenzyl)-2-(3-(2-[(2R)-2-(3-formylamino-4- hydroxy-phenyl)-2-hydroxyethyIamino]-2-methylpropyl}phenyl)acetamide
Prepared using the amide from Preparation 16 and the method described for Example 1.
1HNMR (CD3OD 400 MHz) δ : 1.05-1.08 (6H, m), 2.18 (3H, s), 2.19 (3H, s), 2.67-2.94 (4H, m), 3.52 (2H, s), 4.27 (2H, s), 4.62 (1H, dd), 4.65 (1H, dd), 6.81- 7.06 (6H, m), 7.12-7.24 (3H, m), 8.07 (d), 8.27 (s). 8.55 (s), 8.61 (s).
MS (APCI) M/Z 504 [M+Hf; HRMS C30H37N3O4 504.2857 [M+HJ+ FOUND 504.2842.
Example 3: W<4-(dimethylamin )benzyl]-2-{3-[(2 ?)-2-{{(2f.)-2-[3- (formylamino)^-hydroxypheriyl]-2-hydroxyethyl}amino)propyl]phenyl} acetamide
A mixture of the product of preparation 27, (131 mg, 0.21 mmol) and triethylamine trihydrofluoride (16 μΐ, 0.10 mrnol) in tetrahydrofuran (2 mL) was stiYred at room temperature for 3 days. The mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1 to afford the title compound as a brown foam in 36% yield, 18 mg.
1H NMR (400MHz, CD3CI3) 8: 1.07 (3H, rn), 2.57 (1H, dd), 2.67-2.76 (2H, m), 2.85-2.99 (2H, m), 2.87 (6H, s), 3.47 (1H, m>, 4.23 (2H, s), 4.68 (1H, dd), 6.67-6.71 (2H, m), 6.77-6.79 (2H, d). 6.90 (1H, m), 6.97-7.70 (m, 6H), 7.97 (d), 8.27 (s), 8.35 (s); LRMS APCl m/z 619 [ +H]*
Examples 4 to 12
The following compounds, of the general formula shown below were prepared using a method similar to that described for example 3. The appropriate starting material . was treated with 1-1.1eq of triethylamine trihydrofluoride at room temperature for 18-72hours.
No. Qi Data Yield
re
I IS
purification by column chromatography on silica gel, - eluting. with. dichloromethane:methanol:0.88 ammonia 90:10:1*. This was followed by further azeotropes in methanol (x3) and diethyl ether (x3) to afford desired products as white solids
Examples 13 to 23
The following compounds, of the general formula shown below were prepared using a method similar to that described for example 3. The appropriate starting material was treated with 1-1.1eq of triethylafnine trihydrofluoride at room temperature for 18-72hours.
No. Qi Data Yield
13 Η NM (400MHz, CD3OD) δ: 1.09, 65%
1.10 (3H, 2xs), 1.14, 1.16 (3H, 2:xs),
2.76-3.04 (6H, m), 3.56 (2H, m),
4.67 (1H, dd), 6.84 (1H, d), Γ.02
(1H, m), 7.20-7.28 (4H, m), 7.33- 7.40 (2H, m), 7.60-7.67 (2H, m),
8.12 (1H, d), 8.29 (s), 8.64 (s);
LRMS ESI m/z 534 [M+Na]+
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Example 14: was azeotroped with 2M methanolic ammonia before puri ica on. * crude compounds were azeotroped with 2M methanolic ammonia before purification by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia 90: 0:1. This was followed by further azeotropes in methanol (x3) and diethyl ether (x3) to afford desired products as white solids
Examples 24 to 27
The following compounds, of the general formula shown below were prepared using a method similar to that described for example 3. The appropriate starting material was treated with 1-1. eq of triethylamine trihydrofiuoride at room temperature for 18-72 hours.
, No. Qi Data Yield
24 1H NMR (400MHz, CD3OD) 5: 1.01 75%
(3H, s), 1.03 (3H, s), 2.63-2.87 (4H, m), 3.52 (2H, s), 3.84 (3H, s), 4.38 (2H, s), 4.56-4.60 (1H, m), 6.78-6.80 (1H, m), 6.94-6.97 (1H. m), 7.00-7.02 (1H, m), 7.11-7.20 (4H, m), 7.26-7.29 (2H, m), 7.87-7.89 (2H, d), 7.98-7.99 (d), 8.21 (s), 8.54 (s); LRMS ESI m z 534 [M+HJ*
TH NMR (400MHz, CDCI3) 6: 0.96- 41%
1.04 (9H, m), 2.60-2.88 (4H, m), 3.16- 3.33 (2H, m), 3.66, 3.79 (2H, 2xs), 4.61, 4.66 (2H, 2xs), 4.64, 4.79 (1H, m), 6.56 (1H, m), 6.73-6.79 (2H, m), 6.92-7.19 (6H, m), 7.98 (1H, m), 8.23 (s), 8.65 (s); LRMS APCI m/z 554
[M+Hf
26 nH NMR (400MHz, CDCI3) δ: 0.98 (3H, 93% s), 1.00 (3H, s), 2.61-2.84 (4H, m), 3.48 (2H, s), 4.30 (2H, s), 4.54-4.57 (1H, m), 6.75-6.77 (3H, m), 6.91-6.94 (1H, m), 6.96-6.99 (1H, m), 7.08-7.18 (6H, m), 7.33-7.40 (4H, m), 7.98 (s), 8.21 (s), 8.56 (s); LRMS ESI m/z 568
[M+Hf
Example 28: W-1-Adamantyl-2 3-[(2/?)-2-({(2 ?)-2-[3-(formylamino)phenyl]- 2-hydroxyethyI}amino)propyl]phenyl}acetamide
A mixture of the product of preparation 34 (500 mg, 0.81 mmol) and ammonium fluoride (200 mg, 5.4 mmol) in methanol (5 mL) and water (1.5 mL) was heated at 40 °C for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 90:10:0.1 , to afford the title compound as a foam in 84% yield, 347 mg.
1H NMR (400MHz, CD3OD) 5: 1.05-1.10 (m, 3H), 1.64-1.74 (6H, m), 1.98-2.03 (9H, m), 2.36-2.98 (5H, m), 3.36 (2H, s), 4.46-4.60 (1H, m), 6.46-7.20 (6H, m), 7.96 (1H, s), 8.28 (s), 8.56 (s); LRMS ESI m/z 506 [M+H]+
Example 29; Af-(3.4-Dimethylberayl)-2-^
hydroxy phenyl]-2-hydroxyethyl}amino)ethyl]phenyl}acetamide
The title compound was prepared from the product of preparation 102, using a si milar method to that of examples 4-12, as solid.
1H NMR (400MHz, CD3OD) 2.20 (6H, m), 3.00 (2k m), 3.18 (2H, m), 3.28 (2H, m), 3.56 (2Hr s), 4.28 (2H, s), 4.81 (1H, m), 6.81 (1H. d), 6.98(2H, m), 7.05 (2H, m), 7.20 (4H, m), 7.30 (1 H, t), 8.10 (s), 8.30 (s); LRMS ESI 476 [M+Hf
Examples 30 to 37
The following compounds, of the general formula shown below were prepared using a method similar to that described for example 3. The appropriate starting material was treated with 1-1.1eq of trlethylamine trihydrofluoride at room temperature for 18-72hours.
No. Qv Data Yield
nH NMR (400MHz, CD3OD) δ: 0.94 26%
(3H, s), 0.97 (3H, s), 2.33 (3H, s),
2.56-2.81 (4H, m), 3.43 (2H, s), 4.21
(2H, s), 4.52-4.55 (1H, m), 6.73 (1H, m), 6.89-6.95 (2H, m), 7.03-7.13 (7H, m), 7.98 (d), 8.19 (s), 8.52 (s); LRMS
ESI m/z 522 [M+Hr
31 NMR (400MHz, CD3OD) & 0.99 27% (3H, s), 1.01 (3H, s), 2.60-2.85 (4H, m), 3.49 (2H, s), 4.36 (2H, s), 4.54- 4.59 (1H, m), 6.75 (1H. d), 6.92 (1H, dd), 6.98 (1H, d), 7.08-7.18 (3H, m), 7.31 (2H, d), 7.48 (2H, d), 8.00 (d), 8.22 (s), 8.64 (s); LRMS APCI m/z
544 [M+Hf
32 1H NMR (400MHz, CD3OD) δ: 0.97 38%
(3H, s), 1.00 (3H, s). 2.59-2.86 (4H, m). 3.48 (2H, s), 4.34 (2H, s), 4.53- 4.56 (1H, m), 6.74 (1H, d), 6.92 (1H, d), 6.98 (1H, bd), 7.08-7.17 (3H. m), 7.29 (2H, d), 7.55 (2H, d), 8.00 (1H, d), 8.22 (s), 8.64 (s); LRMS ESI m z 501 [M+Hf
33 'H NMR (400MHz, CD3OD) 5: 1.00 49%
(3H, s), 1.02 (3H, s), 2.62-2.86 (4H, m), 3.47 (2H, s), 4.30 (2H, s), 4.55- 4.58 (1 H, m), 6.82 (1H, d), 6.99 (1 H, dd), 7.04 (1H, d), 7.14-7.23 (5H, m), 7.29 (1H, s), 7.31 (1H, s), 8.07 (1H, dO, 8.29 (s), 8.64 (s); LRMS APCI m/z 560 [M+Hf
34 'H NMR (400MHz, CD3OD) δ: 0.93 82 %
(3H, s), 0.96 (3H, s), 2.51-2.83 (4H, m), 3.47 (2H, s), 4.34 (2H, s), 4.52- 4.55 (1H, m), 6.73-6.76 (3H, m), 6.90- 6.97 (2H, m), 7.04-7.06 (2H, m), 7.12- 7.14 (2H, m), 7.20-7.33 (5H, m), 7.99 (1H, bs), 8.21 (s), 8.54 (s); LRMS APCI m z 568 [M+H]+
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Examples 38 to 46
The appropriate amides, triethylamine trihydrofluoride (1 equivalent) in tetrahydrofuran (5 mL) was stirred at room temperature for 2 days. The mixture was then concentrated in vacuo and the residue treated with methanoiic ammonia and evaporated (x3) to leave a foam which was taken up in dichloromethane:methanol:0.88 ammonia, 90:10:1 filtered, then purified by column chromatography on silica gel, eluting with
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dichtoromethane:methanol:0.88 ammonia, 90:10:1 to afford- the title compound, as a film which was dissolved in methanol and evaporated (x3), then suspended in diethylether and evaporated (x3) to yield a white solid.
No. Qi Data Yield .
38 NM (400MHz, CD3OD) δ: 1.07 52%
(3H, s), 1.14 (3H, s). 2.73-3.00 (6H,
m). 3.57-3.62 (2H, m). 4.65-4.70 (1H,
m), 6.83 (1H, d), 7.01-7.05 (1H, m),
7.16-7.40 (7H, m), 7.61-7.67 (2H, m),
8.09 (1H, d), 8.29 (s), 8.63 (s); LR S
APC! m z 476 [M+Hf
39 ΊΗ NMR (400MHz, CD3OD) δ: 0.94- 65%
1.34 (11H, m), 1.58-1.80 (6H, m),
2.74-3.00 (4H, m), 3.14-3.30 (2H, m),
4.65-4.69 (1H, m), 6.83 (1H, d), 7.02- 7.06 (1H, m). 7.32-7.31 (2H, m), 7.37- 7.73 (2H, m), 8.07 (1H, d), 8.30 (s),
8.63 (s); LRMS APCI m/z 468 [M+Hf
40 ΊΗ NMR (400MHz, CD3OD) δ: 1.09 69%
(3H, s), 1.11 (3H, s), 1.46-1.80 (6H, m), 2.76-2.95 (4H, m), 3.35 (2H, bs),
3.69 (2H, bs), 4.62-4.65 (1H. m), 6.82
(1H, d), 6.99-7.02 (1H, m), 7.18-7.30
(3H, m), 7.33-7.37 (1H, m), 8.04 (1H.
s), 8.29 (s), 8.63 (s); LRMS APCI m/z
438 [M+Hf
325
41 1H NMR (400MHz, CD3OD) & 1.04 52%
(3H, s), 1.11 (3H, s), 2.69-3.03 (6H,
F F m), 3.47-3.67 (2H, m), 4.63-4.67 (1H,
m), 6.82 (1H, d), 7.00-7.06 (1H. m), 7.30-7.64 (8H, m), 8.08 (1H, s), 8.29 (s), 8.63 (s); LRMS APCI m/z 542
[M+Hf
42 1H NMR (400MHz, CD3OD) 5: 1.05 59%
(3H, s), 1.13 (3H, s), 1.88-1.98 (2H, m), 2.64-2.80 (4H, m), 2.89-3.00 (2H, m), 3.38-3.46 (2H, m), 4.63-4.67 (1H, m), 6.81 (1H, d), 6.98-7.08 (1 H, m), 7.10-7.30 (5H, m), 7.30-7.40 (2H, m), 7.62-7.70 (2H, m), 8.08 (1H, s), 8.27 (s), 8.61 (s); LRMS APCI m z 488
[M+Hf
43 1H NMR (400MHz, CD3OD) 8: 1.06 56%
(3H, s), 1.13 (3H, s), 2.71-3.04 (8H, s), 4.50-4.80 (2H, m), 6.80 (1 H, d), 6.96-7.06 (1H, m). 7.11-7.20 (4H, m), 7.31-7.42 (2H, m), 7.68-7.71 (2H, m).
8.06 (1H, d), 8.27 (s), 8.61 (s); LRMS APCI m/z 488 [M+H]+
44 1H NMR (400MHz, CD3OD) δ: 1.04 62%
(3H, s), i.11 (3H, s), 2.70-2.97 (4H, m), 3.06 (2H, t), 3.71 (2H, t), 4.64- 4.68 (1H, m), 6.82-6.86 (1H, m), 7.00- 7.06 (1H, m), 7.19-7.38 (4H, m), 7.61- 7.64 (2H, m), 7.72 (1H, t), 8.08 (1H, s), 8.28 (s), 8.45 (1H, d), 8.63 (s);
LRMS APCI m/z 477 [M+Hf
45 NMR (400MHz, CD3OD) & 1.05 28% (3H, s), 1.12 (3H, s), 2.70-3.00 (6H, m), 3.50-3.60 (2H, m), 3.74 (3H, s), 4.63-4.66 (1 H, m), 6.80-6.86 (3H, m), 7.00-7.06 (1 H, m), 7.12 (2H, d), 7.30- 7.39 (2H, m), 7.60-7.65 (2H, m), 8.09 (1H, s), 8.29 (s), 8.63 (s); L MS APCI m/z 506 [M+Hf
46 Η NMR (400MHz, CD3OD) δ: 1.13 27%
(3H, s), 1.18 (3H, s), 2.75-3.06 (6H, m). 3.62 (2H, t), 4.68-4.75 (1H, m), 6.85 (1H, d), 7.03 (1H. d), 7.37-7.45 (4H, m), 7.62-7.70 (2H, m), 7.80 (2H, d)r 8.12 (1H, s). 8.30 (s), 8.64 (s);
LRMS APCI m/z 555 [M+Hf
47 'H NMR (400MHz, CD3OD) δ: 1.14- 57%
1.24 (6H, m), 2.80-3.06 (7H, m), 3.80- 3.84 (1H, bs). 3.93-3.97 (1H, bs), 4.55-4.59 (1 H, bs), 4.68-4.73 (1H, m), 6.87 (1H, dd), 7.00-7.15 (3H, m), 7.20-7.30 (2H, m), 7.82-7.87 (1H, m).
8.09 (1H, s), 8.28 (s), 8.63 (s); LRMS APCI m/z 488 [M+H]+
48 'H NMR (400MHz, CD3OD) δ: 1.14 8%
(3H, s), 1.19 (3H, s), 1.74 (6H, s), 2.07 (3H, s), 2.15 (6H, s), 2.76-3.10 (4H, m), 4.56 (1H, bs), 4.64-4.72 (1H, m), 6.84 (1H, d), 7.03 (1H, d), 7.31- 7.39 (2H, m), 7.58-7.62 (2H, m), 8.11 ( H, s), 8.30 (s), 8.63 (s); LRMS APCI m z 506 [M+-Hf
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Examples 51 to 55
The following compounds, of the general formula shown below were prepared using a method similar to that described for example 3. The appropriate starting material was treated with 1-1. eq of triethylamine trihydrofluonde at room temperature for 18-72hours.
No. Qi Data yield
51 1H NMR (400MHz, CD3OD) & 1.04 81%
XX (3H, s), 1.12 (3H, s), 2.24 (6H, s),
2.69-3.01 (6H, m), 3.52-3.55 (2H, m), 4.62-4.66 (1H, m), 6.82-6.84 (1H, m), 6.95-7.10 (4H, m), 7.31-7.37 (2H, m), 7.60-7.70 (2H, m), 8.09 (1H, s), 8.28 (s), 8.63 (s); LRMS APCI m/z 504
[M+Hf
52 ηΗ NMR (400MHz, CD3OD) δ: 1.04 79%
(3H, s), 1.11 (3H, s), 2.69-2.96 (4H,
CI m). 3.01-3.08 (2H, m), 3.61-3.66 (2H,
m), 4.62-4.65 (1H, m), 6.82 (1H, d), 7.00-7.03 (1H, m), 7.16-7.21 (2H, m),
7.28-7.40 (4H, m), 7.61-7.65 (2H, m), 8.08 (1H, s), 8.28 (s), 8.63 (s); LRMS APCI m/z 510 [M+Hf
53 1H NMR (400MHz, CD3OD) δ: 1.05 96%
(3H, s), 1.13 (3H, s), 2.34 (6H, s), 2.71-2.79 (2H, m), 2.95-3.01 <4h, m),
3.43-3.49 (2H, m), 4.64-4.67 91 H, m),
6.83 (1H, d), 6.95-6.97 (3H, m), 7.02- 7.08 (1H, m), 7.33-7.41 (2H, m), 7.67- 7.73 (2H, m), 8.12 (1H, s), 8.29 (s), 8.63 (s); LRMS APCI m/z 504 [M+Hf
54 NMR (400MHz, CD3OD) 5: 1.04 86%
(3H, s), 1.11 (3H, s), 2.27 (3H, s), 2.69-2.98 (6H, m), 3.54-3.60 (2H, m), 4.62-4.65 (1H, m), 6.82 (1H, d), 7.00- 7.14 (5H, m), 7.30-7.38 (2H, m), 7.59- 7.67 (2H. m), 8.08 (1H, s), 8.29 (s), 8.62 (s); LRMS APCI m z 504 [M+Hf
129
Example 56: 3-{(2R)-2-I(2R)-2-(3-Formylam!no«4-hydroxyphenyl)-2- hydroxyethylamino]propyl}-W-[2-(4-hydroxyphenyl)-2- methylpropyl]benzamide
The title compound was prepared from the product of preparation 138, using a method similar to that of examples 38-50, as a brown glass (35 mg, 31 %) H NMR (400MHz, CD3OD) δ: 1.03 (3H, d), 1.27 (6H, s), 2.56-2.90 (4H, m), 3.45 (2H, s), 4.55-4.58 (1H, m), 6.67-6.72 (3H, m), 6.85-6.87 (1H, m), 7.19-7.26 (5H, m), 7.38 (1 H, s), 7.43 (1H, d), 7.91 (d), 8.21 (s), 8.51 (s); LRMS APCI m/z 506 [M+H]+
Example 57: Af 5-[(1A?)-2.((1R)-2-{3-I3-(3,4-Dihydro-1W-isoqulnolin-2-yl)-3- oxopropyl]phenyl}-1 -methylethylamino)-1 -hydroxyethyl]-2- hydroxyphenyl}formamide
The title compound was prepared from the product of preparation 138, using a method similar to that of examples 38-50, as a brown glass (35 mg, 31 %)
130
1H N R (400MHz, CD3OD) 8: 1.00-1.05 (3K, m)r 2.48-2.92 <11H, ra), 3.59 (1Hr t), 3.73 (1H, t), 4.5 4.65 (3H, m), 6.75-7.18 (10H, m), 7.97 (s), 8 '8 (d), 8.56 (d); LRMS APCI m/z 502 [ +H]+
The ability of the compounds of the formula (1) to act as potent β2 agonists therefore mediating smooth muscle relaxation may be determined by the measure of the effect of beta-2 adrenergic receptor stimulation oh electrical field stimulated-contraction of guinea pig trachea strips.
Guinea-pig trachea
Male, Dunkin-Hartley guinea pigs (475-525g) are kilted by C02 asphyxiation and exsanguination from the femoral artery and the trachea is isolated. Four preparations are obtained from each animal, starting the dissection immediately below the larynx and taking 2.5 cm length of trachea. The piece of trachea is opened by cutting the cartilage opposite the trachealis muscle, then transverse sections, 3-4 cartilage rings wide, are cut. The resulting strip preparations are suspended in 5 ml organ baths using cotton threads tied through the upper and lower cartilage bands. The strips are equilibrated, un-tensioned, for 20 minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 μΜ !ndomethacin (Sigma I7378), 10 μΜ Guanethidine (Sigma G8520) and 10 μΜ Atenolol (Sigma A7655), heated at 37°C and gassed with 95% 02/5% C02, before applying an initial tension of 1 g. The preparations are allowed to equilibrate for a further 30- 45 minutes, during which time they are re-tensioned (to 1 g) twice at 15-minute intervals. Changes in tension are recorded and monitored via standard isometric transducers coupled to a data-collection system (custom-designed at Pfizer). Following the tensioning equilibration, the tissues are subjected to . electrical field stimulation (EFS) using the following parameters : 10 s trains every 2 minutes, 0.1 ms pulse width, 0 Hz and just-maximal voltage (25 Volts) . continuously throughout the length of the experiment EFS of post-ganglionic cholinergic nerves in the trachea results in monophasic contractions of the smooth muscle and twitch height is recorded. The organ baths are constantly perfused with the above-described Krebs Ringer buffer by means of a peristaltic pump system (pump flow rate 7.5 ml / minute) throughout the
experiment, with the exception of when a beta-2 agonist . according to the. present invention is added, the pump is then stopped for the time of the cumulative dosing to the bath and started again after maximal response is reached for the wash-out period.
Experimental protocol for assessment of potency and efficacy
Following equilibration to EFS, the peristaltic pump is stopped and the preparations 'primed' with a single dose of 300 nM isoprenaline (Sigma 15627) to establish a maximal response in terms of inhibition of the contractile EFS response. The isoprenaline is then washed out over a period of 40 minutes. Following the priming and wash-out recovery, a standard curve to isoprenaline is carried out on all tissues (Isoprenaline Curve 1) by means of cumulative, bolus addition to the bath using half log increments in concentration. The concentration range used is 1e"9 to I Z 6 M. At the end of the isoprenaline curve the preparations are washed again for 40 minutes before commencing a second curve, either to isoprenaline (as internal control) or a beta-2 agonist according to the present invention. Beta-2 agonist responses are expressed as percentage inhibition of the EFS response. Data for beta-2 agonist are normalised by expressing inhibition as a percentage of the maximal inhibition induced by isoprenaline in Curve 1. The EC50 value for beta-2 agonist according to the present invention refers to the concentration of compound required to produce half maximal effect Data for beta-2 agonists according to the present invention are then expressed as relative potency to isoprenaline defined by the ratio (EC50 beta-2 agonist) (EC50 Isoprenaline).
Confirmation of beta-2 mediated functional activity
Beta-2 agonist activity of test compounds is confirmed using the protocol above, however, prior to constructing the curve to beta-2 agonist according to the present invention, the preparations are pre-incubated (for a minimum of 45 minutes) with 300 nM IC1 118551 (a selective p2 antagonist) which results in the case of a beta-2 mediated effect in a rightward-shift of the test compound dose response curve.
WO 2005/092840 PCT IB2005/(MK»f.l9
132
According to another alternative, the agonist potency- for the β2 receptor, of the compounds of the formula (1) may also be determined by the measure of the concentration of compound according to the present invention required to produce half maximal effect (EC50) for the β2 receptor.
Compound Preparation
m /100% DMSO (dimethylsulfoxide) stock of compound is diluted to required top dose in 4 % DMSO. This top dose is used to construct a 10-point semWog dilution curve, all in 4 % DMSO. Isoprenaline (Sigma, I-5627) was used as a standard in every experiment and for control wells on each plate. Data was expressed as % isoprenaline response.
Cell Culture
CHO (Chinese Hamster Ovary) cells recombtnantly expressing the human β2 adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et al., Mol Pharmacol 33: 133-139 1988 ΟΗΟηβ2) were grown in Dulbeccos MEM/ NUT MIX F12 (Gibco, 21331-020) supplemented with 10 % foetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 pg/ml geneticin (Sigma, G7034) and 10 pg/ml puromycin (Sigma, P8833). Cells were seeded to give about 90 % confluency for testing.
Assay Method
μΙ / well each dose of compound was transferred into a cAMP- Flashplate® (NEN, SMP004B), with 1% DMSO as basal controls and 100 nM Isoprenaline as max controls. This was diluted 1:2 by the addition of 25 μΙ / well PBS. Cells were trypsimsed (0.25% Sigma, T4049), washed with PBS (Gibco, 14040- 74)
. and resuspended in stimulation buffer (NEN, SMP004B) to give 1x10e cells / ml CHOhB2. Compounds were incubated with 50 μΙ / well cells for 1 hour. Cells
• were then lysed by the addition of 100 μΙ / well detection buffer (NEN, SMP004B) containing 0.18 pCi / ml 1z5l-cAMP (NEN, NEX-130) and plates were incubated at room temperature for a further 2 hours. The amount of ^l-cAMP bound to the Flashplate® was quantified using a Topcount NXT (Packard),
normal counting efficiency for 1 minute. Dose-response data was expressed as % Isoprenaline activity and fitted using a four parameter sigmoid fit.
It has thus been found that the compounds of formula (1) according to the present invention that are illustrated in examples 1 to 57 above show a β2 cAMP EC50 below 5nM.
134
Claims (1)
- CLAIMS A compound of general formula wherein the group is in the meta or para and R2 are independently selected from H and n is or is a group selected wherein p is 1 or 2 and q is 1 or said group being optionally bridged by carbon and a group wherein Q2 is a is H or alkyl and A is said cycioalkyl being optionally bridged by O J35 one or more carbon or a group and R7 are the same or different and are selected from NHCOR10 and phenyl optionally substituted with 1 to 3 groups selected from halo and R9 and are the same or different and are selected from H or and the represent the attachment point to the if their pharmaceutically acceptable salts solvates or isotopic variations A compound according to claim 1 wherein is a group wherein A is or A compound according to claim 1 wherein Q is a group wherein A is a group wherein R6 and R7 are the same or different and are selected from NHCOR10 and phenyl optionally substituted O 136 1 to 3 groups selected halo and provided at least 2 of R3 to R7 are equal to wherein R9 and are the same or different and are selected from H or A compound according to claim 3 wherein is a group wherein A is a group wherein and R7 are the same or different and are selected from and phenyl optionally substituted with A compound according to claim 1 wherein A is a group wherein one of R3to R7 is OH or phenyl substituted with A compound according to claim 1 wherein A is naphthyl optionally susbstituted with A compound according to any one of claims 1 to 6 wherein Q2 or A compound according to claim 7 wherein Q2 is WO 137 A compound according to claim 1 wherein is wherein and are A compound according to any one of claims 1 to 9 wherein R is H or and R2 Is A compound according to claim 10 wherein is or and R2 is H or A compound according to claim 1 to 11 wherein n is 0 or The of a compound according to any one of claims 1 to A compound according to any one of claim 1 to 13 wherein the group is in the meta A compound according to claim 1 selected from the group consisting of me 3 2 R O 139 3 acid methyl hydroxyphenyl me WO 141 5 A pharmaceutical composition comprising at least an effective amount of a compound of the formula as described in arty one of claims 1 to 15 or a pharmaceutically acceptable salt or derived form A compound of the formula as described in any one of claims 1 to 15 or a pharmaceutically acceptable derived form or composition for use as a medicament The use of a compound of the formula as described in any one of claims of a pharmaceutically acceptable derived form or composition for the manufacture of a drug for the treatment of and conditions selected from the group consisting asthma of whatever or in asthma that is a member selected from the consisting of atopic allergic atopic bronchial bronchial essential true intrinsic asthma caused by pathophysiologic extrinsic asthma caused by environmental essential asthma of unknown or inapparent bronchitic emphysematous allergen induced cold air induced occupational infective asthma caused by or viral Incipient wheezy infant syndrome and chronic or acute chronic small airways and obstructive or inflammatory airways diseases of whatever or in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic chronic obstructive pulmonary disease COPD that includes chronic pulmonary emphysema or dyspnea associated or not associated with COPD that is characterized by progressive airways adult respiratory distress syndrome exacerbation of airways reactivity consequent to other drug therapy and airways disease that is associated with pulmonary bronchitis of whatever or in particular bronchitis that is a member selected from the group consisting of acute acute laryngotracheal arachidic catarrhal croupus dry infectious asthmatic productive staphylococcus or streptococcal bronchitis and vesicular acute lung bronchiectasis of whatever or in bronchiectasis that is a member selected from the group consisting of cyttndric sacculated fusiform capillary cystic dry bronchiectasis and follicular Combination of a compound according to any of claims 1 to 15 with other therapeutic selected inhibitors or activating protein Leukotriene antagonists including antagonists of Histamine receptor antagonists including H1 and H3 and agonist vasoconstrictor sympathomimetic agents for decongestant muscarinic M3 receptor antagonists or anticholinergic PDE PDE4 and PDE5 Sodium COX inhibitors both and selective or inhibitors Oral and inhaled Monoclonal antibodies active against endogenous inflammatory necrosis factor molecule inhibitors including and B2 Immunosuppressive Inhibitors of matrix Tachykinin NK2 and NK3 receptor Elastase Adenosine A2a receptor Inhibitors of Compounds that act on dopamine D2 Modulators of the IKK modulators of cytokine signalling pathyways such as p38 MAP kinase or syk Agents that can be classed as mucolytics or HDAC PI3 kinase or a pharmaceutically acceptable salt or solvate or a pharmaceutically acceptable salt or solvate or a pharmaceutically acceptable salt or solvate or a pharmaceutically acceptable salt or solvate or a pharmaceutically acceptable salt or solvate LUZZATTO LUZZATTO insufficientOCRQuality
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