Sulfonamide derivatives for the treatment of diseases

专利摘要:

公开号:AU2005214154A1
申请号:U2005214154
申请日:2005-01-12
公开日:2005-09-01
发明作者:Alan Daniel Brown；Kim James；Charlotte Alice Louise Lane；Ian Brian Moses；Nicholas Murray Thomson
申请人:Pfizer Inc；
IPC主号:C07C311-08

专利说明:
WO 2005/080324 PCT/IB2005/000112 I SULFONAMIDE DERIVATIVES FOR THE TREATMENT OF DISEASES This invention relates to P2 agonists of general formula: OH H N HO
R
1
R
2
(CH
2 )n 01 (1)
NHSO
2
CH
3 0 in which R1, R 2, n and Q have the meanings indicated below, 5 and to processes for the preparation of, compositions containing and the uses of such derivatives. Adrenoceptors are members of the large G-protein coupled receptor super-family. The adrenoceptor subfamily is itself divided into the a and P subfamilies with the P sub-family being composed of at least 3 receptor sub 10 types: p1, P2 and P3. These receptors exhibit differential expression patterns in tissues of various systems and organs of mammals. P2 adrenergic (P2) receptors are mainly expressed in smooth muscle cells (e.g. vascular, bronchial, uterine or intestinal smooth muscles), whereas P3 adrenergic receptors are mainly expressed in fat tissues (therefore P3 agonists could 15 potentially be useful in the treatment of obesity and diabetes) and P1 adrenergic receptors are mainly expressed in cardiac tissues (therefore P1 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, 20 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 provide some background information.
WO 2005/080324 PCT/IB2005/000112 2 Glucocorticosteroids, anti-leukotrienes, theophylline, cromones, anti cholinergics and P2 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 5 include both short and long acting inhaled P2 agonists. Short acting, rapid onset P2 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 P2 adrenoceptor expressed on airway smooth muscle cells, which. results in relaxation and 10 hence bronchodilation. Thus, as functional antagonists, P2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins. Because P2 receptors are so widely distributed in the airway, p2 agonists may also affect other types of cells that play a role in asthma. For 15 example, it has been reported that P2 agonists may stabilize mast cells. The inhibition of the release of bronchoconstrictor substances may be how P2 agonists block the bronchoconstriction induced by allergens, exercise and cold air. Furthermore, P2 agonists inhibit cholinergic neurotransmission in the human airway, which can result in reduced cholinergic-reflex bronchoconstriction. 20 In addition to the airways, it has also been established that P2 adrenoceptors are also expressed in other organs and tissues and thus P2 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, 25 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 p2 agonists are limited in their use due to their low selectivity or adverse side-effects driven by high systemic exposure and mainly 30 mediated through action at P2 adrenoreceptors expressed outside the airways WO 2005/080324 PCT/IB2005/000112 3 (muscle tremor, tachycardia, palpitations, restlessness). Therefore there is a need for improved agents in this class. Accordingly, there is still a need for novel P2 agonists that would have an appropriate pharmacological profile, for example in terms of potency, 5 pharmacokinetics, or duration of action. In this context, the present invention relates to novel P2 agonists. Various Sulfonamide derivatives have already been disclosed. For example, W002066250 discloses compounds active as p3 agonist, selective over p2, of formula : OH H R N 10 (R1)m B R4 ) 10 0) wherein m may be 2, R 1 may be H, OH or NR 5
SO
2
R
5
(R
5 being H or C-C 6 alkyl), Z may be a bond, R 2 may be H or C-C 6 alkyl, R 4 may be C-C 6 alkyl, B may be phenyl, Y is C-C 6 alkyl and A may be phenyl. W0021000622 discloses selective P3 agonists of formula: O. 15 wherein R' may be phenyl substituted with hydroxy and alkylsulfonylamino, X 1 may be a bond, R 2 may be hydrogen, R 3 is hydrogen or hydroxyalkyl, X 2 may be CH 2 , X 3 is a bond, 0 or NH and R4 is cyclic group.
WO 2005/080324 PCT/IB2005/000112 4 Other sulfonamide derivatives are also disclosed in US5,776,983 as p3 agonists They are more specifically of formula: OH - R 5 H N A
R
5 '
R
6 R3 R 4 R2
NHSO
2 R1 5 wherein R 1 may be CH 3 , R 2 may be OH, R 6 may be H, R 3 may be H or alkyl, R 4 may be H, alkyl, R 5 may be H, R 5 ' may be C(O)NR6 R wherein R and R6' may be H or lower alkyl. However, none of the above sulfonamide derivatives have shown a selective P2 agonist activity, allowing them to be used as efficient drugs in the 10 treatment of the p2-mediated diseases and/or conditions, in particular allergic and non-allergic airways diseases or other diseases such as those previously cited. The invention relates to the compounds of general formula (1): OH H N I (CH2)n Q I HO
R
1
R
2 (1
NHSO
2
CH
3 0 15 wherein the (CH 2 )n-C(=O)Ql group is in the meta or para position, R1 and R 2 are independently selected from H and C1-C4 alkyl, n is 0, 1 or 2 and Q1 is a group selected from, WO 2005/080324 PCT/IB2005/000112 5 R3 R4
R
3 R11 R4,
(CH
2 )p R 5 *kN R5 */R6 R6 and a group *-NRIQ 2 -A, wherein p is 1 or 2, Q 2 is a C1-C4 alkylene, R 1 1 is H or C1-C4 alkyl and A is pyridyl, C3-C10 cycloalkyl, said cycloalkyl being optionally bridged by one or more, preferably 1, 2, 3 or 4, carbon atoms, 5 tetrahydropyranyl, piperidinyl optionally substituted with benzyl, tetrahydrothiopyranyl or a group R3 R4 R3 R4 R
R
5 or R 7
R
6 wherein R3, R4, R , R and R are the same or different and are selected from H, C1C4 alkyl, OR', SR', halo, CN, CF 3 , OCF 3 , COOR', SO 2 NR R" 10 CONRR", NR 9
R
10 , NHCOR1 0 and phenyl; wherein R is Cr1C4 alkyl and R9 and R10 are the same or different and are selected from H or C1C4 alkyl and the * represent the attachment point to the carbonyl group; or, if appropriate, their pharmaceutically acceptable salts and/or isomers, 15 tautomers, solvates or isotopic variations thereof. The compounds of formula (1) are agonists of the P2 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.
WO 2005/080324 PCT/IB2005/000112 6 In the here above general formula (1), C1C4 alkyl and C1C4 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-(C-C 4 )alkyl radicals, S-(C-C 4 )alkyl radicals etc... . 5 Examples of suitable (C-C 4 )alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl.... Examples of suitable O-CrC4 alkyl radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy.... 10 The C3-C cycloalkyl 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, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane. Preferred cycloalkyl groups are cyclohexyl and adamantyl. 15 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, 20 means that the phenyl can be substituted in the meta or para position. The compounds of the formula (1) WO 2005/080324 PCT/IB2005/000112 7 OH H HO (CH2
NHSO
2 Me 0 can be prepared using conventional procedures such as by the following 1 2 1 illustrative methods in which R1, R , Q1, and n are as previously defined for the compounds of the formula (1) unless otherwise stated. 5 The amide derivatives of the formula (1) may be prepared by coupling an acid of formula (2) or a salt thereof: OH H N (2)
(CH
2 ), OH HO
R
1
R
2 0
NHSO
2 Me with an amine of formula NHR -Q2 -A (3),
R
3 R1 R2 R 3 R N
R
3 H HN R5
R
4 (3') or R 6 (3" 10 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, N'-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. I-hydroxybenzotriazole hydrate or 1-hydroxy-7 azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g. 15 N-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may be undertaken in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofu ran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10"C and 40'C (room temperature) for a period of 1-24 hours.
WO 2005/080324 PCT/IB2005/000112 8 Said amine (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. 5 The acid of formula (2) may be prepared from the corresponding ester of formula (4) : OH H N (4)
(CH
2 )n ORa HO R1 R2
NHSO
2 Me wherein Ra is a suitable acid protecting group, preferably a (C-C 4 )alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method 10 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, propionitrile, 1,4-dioxan, 15 tetrahydrofuran/water), at a temperature comprised between 20'C and 1000C, for a period of 1 to 40 hours. The ester of formula (4) may be prepared by reaction of an amine of formula (5): H2N
(CH
2 )n ORa (5) Re Ra2 0 20 wherein Ra and n are as previously defined, with a bromide of formula (6): WO 2005/080324 PCT/IB2005/000112 9 OH Br (6) HO
NHSO
2 Me 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. dimethyl sulphoxide, toluene, N, N-dimethylformamide, propionitrile, 5 acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, potassium hydrogen carbonate) at a temperature comprised between 80'C and 1200C, for 12 to 48 hours. The bromide of formula (6) may be prepared according to the method of WO 02/06258 (pg. 36, example 14a). 10 The amine of formula (5), where R 1 is Me and R 2 is H, may be prepared as either the (R) or (S) enantiomer from the corresponding protected amine of formula (7): Rc RbN (CH2)n ORa (7)
R
1
R
2 --f O wherein Ra and n are as previously defined and Rb and Rc represent any 15 suitable substituents so that HNRbRc is a chiral amine (for example, Rb may be hydrogen and Rc may be a-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 T.W. GREENE, Protective Groups in Organic 20 Synthesis , A. Wiley-Interscience Publication, 1981.
WO 2005/080324 PCT/IB2005/000112 10 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): H3C (CH 2 )n ORa (8) 0 wherein Ra, Rb, Rc and n are as previously defined. 5 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 NaCNBH 3 or sodium triacetoxyborohydride of formula Na(OAc) 3 BH) optionally in the presence of a drying agent (e.g. molecular sieves, magnesium sulfate) 10 and optionally in the presence of an acid catalyst (e.g. acetic acid) 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 salt and selectively crystallised from a 15 suitable solvent or mixture of solvents (e.g. isopropanol, 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): Hal ORa (9) 20 0 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.
WO 2005/080324 PCT/IB2005/000112 11 In a typical procedure, the aryl halide of formula (9) is reacted with a tin enolate generated in-situ by treatment of isoprenyl acetate with tri-n-butyltin methoxide of formula Bu 3 SnOMe in the presence of a suitable palladium catalyst (palladium acetate/ tri-ortho-tolylphosphine of formula Pd(OAc) 2 /P(o 5 Tol) 3 ) in a non-polar solvent (e.g. toluene, benzene, hexane). Preferably, the reaction is carried out at a temperature comprised between 800C and 110*C for 6 to 16 hours. The aryl halide of formula (9) may be obtained by esterification of the corresponding acid of formula (10): Hal OH (10) 10 0 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 15 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 400C (room temperature) for 8 to 16 hours. The acid of formula (10) is a commercial product. The amine of formula (5), where R' = R 2 = alkyl, may be prepared 20 according to the following scheme: Scheme 1 WO 2005/080324 PCT/IB2005/000112 12 0 O HO RaO ( OH R(CH 2 )n OH I (GHA 2 ) OH R' R 2 Al 0 (11) (12) O H2NR (CH 2 )n ORa
R
1
R
2 (5) wherein R1, R2 and Ra are as previously defined. In a typical procedure, the ester of formula (11) is reacted with an "activated" alkyl (organometallic alkyl such as R 2MgBr, R 2MgCI or R 2Li) to give 5 the corresponding tertiary alcohol of formula (12) using the method described above. Said tertiary alcohol of formula (12) is then treated with an alkyl nitrile (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 10 standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks. The resulting aminoacid is then esterified using the method described herein to give the amine of formula (5). Alternatively, the amine of formula (5), where R1 = R2 = C 1
-C
4 alkyl and n=O, may be prepared according to the following scheme: 15 Scheme 2 WO 2005/080324 PCT/IB2005/000112 13 RaO Br -H Br 0
R
1
R
2 (13) (14)
H
2 NR H 2 N 0 Br R
R
1
R
2
R'R
2 ORa (15) (5) wherein R 1 , R 2 and Ra are as previously defined. In a typical procedure, the ester of formula (13) is reacted with an "activated" alkyl (organometallic alkyl such as R 2 MgBr, R 2 MgC or R 2 Li) to give 5 the corresponding tertiary alcohol of formula (14) using the method described above. Said tertiary alcohol of formula (14) is then treated with an alkyl nitrile (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 10 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(diphenylphophino)ferrocene]dichloropalladium(1)) under an atmosphere of carbon monoxide using RaOH as solvent (e.g. MeOH, EtOH) 15 at elevated temperature (100 0 C) and pressure (100psi) to give the ester of formula (5). The ketone of formula (8) where n=2 may be prepared by reduction of an alkene of formula (16): 0 ORa WO 2005/080324 PCT/IB2005/000112 14 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 stirred under an atmosphere of hydrogen, optionally at elevated pressure (e.g. 60 psi), at temperature between 5 room temperature and 600C 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):
H
3C -a 03 H a l (1 7 ) 10 In a typical procedure, the aryl halide (17) is coupled with a vinyl ester (e.g. methyl acrylate) in the presence of a suitable palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium(0) of formula Pd(PPh 3
)
4 , palladium acetate/tri-ortho-tolylphosphine of formula Pd(OAc) 2 /P(o-tol)3 or (diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdC 2 ) in a 15 sutiable solvent (e.g. acetonitrile, N, 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 (17) is a commercial product. The amine of formula (5), where R 1 and R 2 are both H, may be prepared 20 according to the following scheme: Scheme 3 WO 2005/080324 PCT/IB2005/000112 15 HO 0 HO
(CH
2 )n ORa HO(CH 2 ) ORa (18) 0 H2N (CH 2 ORa wherein R', R2 and Ra are as previously defined. In a typical procedure, the acid of formula (18) is preferentially reduced 5 to the corresponding alcohol (19) 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 (19) is then converted into a leaving 10 group such as mesylate, tosylate, bromide or iodide and displaced with appropriate amine nucleophile. The preferred nucleophile is azide ion which can then be reduced to the primary amine via hydrogenation or triphenylphosphine. Alternative nucleophiles could include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the 15 alkyl group to furnish the amine. In a typical procedure, the compounds of formula (I) wherein R 1 and R 2 are both methyl and n is 1, may be prepared by reacting a compound of formula (21) OH H N X c0 2 - X+ HO c NHSO2Me (21) WO 2005/080324 PCT/IB2005/000112 16 where X is H, Li, K or Na and an organic amine base or other metal salt, with a suitable amine of formula NHR -Q 2 -A (3)
R
3 R4R 3 Ra R N (CH2P
R
5 H R5 HN
R
6 (3'), or R (3") in the presence of a conventional coupling agent such as 1-(3 5 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent such as pyridine dimethylformamide and dimethylacetamide, optionally in the presence of an organic base (such as Hunig's base) and an additive (such as 1 hydroxybenzotriazole) in order to obtain a compound of formula (1): OH H N HO R' R 2 I
(CH
2 )n Y (1) 10
NHSO
2
CH
3 0 wherein R1 and R 2 are methyl and n is 1. Said compound of formula (21) may be obtained by hydrogenation of a compound of formula (22) OH H I / ~ C 2 -X N 0
NHSO
2 Me 2 (22) 15 wherein X is H, Na, Li or K and an potentially an organic amine or other metal salts in the presence of a suitable solvent such as methanol, IPA, THF and water and in the presence of a suitable catalyst such as palladium hydroxide on carbon or palladium on carbon.
WO 2005/080324 PCT/IB2005/000112 17 Said compound of formula (22) may be obtained by reacting a compound of formula (23) OH H N . C0 2
-C-C
4 alkyl
NHSO
2 Me (23) with M-OH wherein M is selected from Li, Na or K, optionally in the presence of 5 a suitable solvent such as propionitrile, tetrahydrofunan or dioxane, preferably propionitrile. Said compound of formula (23) may be obtained by deprotecting a compound of formula (24) OTBDMS H N c0 2 -cl-C 4 alkyl ONHSO2Me 10 2 ,(24) using a deprotecting agent such as tetrabutylammonium fluoride, HF, or triethylamine trihydrofluoride in the presence of a suitable solvent such as propionitrile. 15 Said compound of formula (24) may be obtained by reacting a compound of formula
H
2 N 0- c -c 4 alkyl with a compound of formula WO 2005/080324 PCT/IB2005/000112 18 OTBDMS Br 0 HN
,..CH
3 0 0 in the presence of a suitable solvent such as propionitrile, THF, toluene, ethyl acetate, acetonitrile, propionitrile, dioxane, DMF, DMSO, and optionally in the presence of a base such as sodium hydrogen carbonate, potassium hydrogen 5 carbonate, Hunig's base or triethylamine, at a temperature between 50*C and 150*C for 12 to 36 hours. 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 10 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 (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. 15 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 20 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.
WO 2005/080324 PCT/IB2005/000112 19 Preferably Q 1 is a group *-NH-Q 2 -A, wherein Q 2 is CH 2 and A is cyclohexyl, tetrahydrothiopyranyl, piperidinyl optionally substituted with benzyl, or naphthyl. Preferably, Q 1 is
R
3 R4 H
R
6 ,wherein R 3 , R 4 , R 5 and R6 are H. 5 Preferably, Q 1 is a group *-NH-Q 2 -A, wherein Q 2 is a C1-C4 alkylene and A is a group
R
3 R4 R5
R
7 RB wherein R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are selected from H, C1-C4 alkyl, OR", SR 9 , CN, halo, CF 3 , OCF 3 , S0 2
NR
9
R
10 , CONR 9
R
1 0 , 10 NR'R4, NHCOR0 and phenyl provided at least 2 of R 3 to R 7 are equal to H; wherein R 8 is C1-C4 alkyl and R 9 and R1 0 are the same or different and are selected from H or C1-C4 alkyl; More preferably, Q 1 is a group *-NH-Q 2 -A, wherein Q2 is a -CH 2 -, -(CH 2
)
2 -, (CH 2
)
3 -, preferably -CH 2 -, and A is a group R3 R4
R
5 15
R
7
R
WO 2005/080324 PCT/IB2005/000112 20 3 4 5 6 7 wherein R , R4, R5, R6 and R are the same or different and are selected from H, CH 3 , OCH 2
-CH
3 , SCH 3 , halo, CF 3 , OCF 3 , phenyl, dimethylamino, CN, tert butyl, provided at least 2 of R 3 to R are equal to H. More preferably, Q 1 is a group *-NH-Q 2 -A, wherein Q 2 is a -CH 2 -, -(CH 2
)
2 -, 5 (CH 2
)
3 -, preferably -CH 2 -, and A is a group R3 R4 R5 R7 R6 wherein R 3 , R 4 , R 5 , R3 and R are the same or different and are selected from H, CH 3 , Cl, F, CF 3 provided at least 2 of R 3 to R 7 are equal to H. In the above groups of compounds, the following substituents are particularly 10 preferred:
R
1 is H or C1C4 alkyl and R 2 is C1-C4 alkyl. More preferably, R' is H or CH 3 and R2 is CH 3 . n is 1, 2 or 3. More preferably n is 1.
R
1 is H and R2 is CH 3 and n is 1. 15 R 1 is CH 3 , R 2 is CH 3 and n is 1. Particularly preferred are the compounds of the formula (1) as described in the Examples section hereafter, i.e. : N-Benzyl-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, 20 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl) amino]-2-methylpropyl}phenyl)-N-(4-methoxybenzyl)acetamide 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino]-2-methylpropyl}phenyl)-N-(2-methoxybenzyl)acetamide, WO 2005/080324 PCT/1B200510001 12 21 N-(2-Ethoxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hyd roxy-3-[(methylsulfonyl) amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hyd roxy-3-[(methylsu Ifonyl)aminojphenyl} ethyl)amino]-2-methyl propyl}phenyl)-N-(3-methoxybenzyl)acetamid e, 5 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hyd roxy-3-[(methylsulfonyl)a mino]phenyl} ethyl )am ino]-2-methyl pro pyllphenyl)-N-(4-methylbe nzyl)aceta mide, 2-(3-{2-[((2 R)-2-Hyd roxy-2-{4-hyd roxy-3-[(m ethyl s ulfonyl)a mi no]phe nyl}ethyl) amino]-2-methylpropyllphenyl )-N-(2-methyl benzyl )acetamide, 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hyd roxy-3-[(methylsulfonyl)amino]phenyl~ethyl) 10 am in o]-2-methyl propyl}ph enyl)-N-(3-m ethyl benzyl)aceta mid e, N-(3,4-Dimethoxybenzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methylsulfonyl)aminolphenyl~ethyl)amino]-2-methylpropyl}phenyl)acetamide, N-(2,4-Dimethoxybenzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}pheny!)acetamide, 15 N-(3,5-Dimethoxybenzyl )-2-(3-{2-[((2R)-2-hydroxy-2-{4-hyd roxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyi)acetamide, N-(4-C hlo robe nzyl)-2-(3-{2-[((2 R)-2-hyd roxy-2-{4-hydl roxy-3-[(methyl s ulfonyl) aminolphenyllethyl)aminol-2-methylpropyl}phenyl)acetamide, N-(2-Chlorobenzyl )-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3-[(methylsulfo nyl) 20 amino] phenyl}ethyl)amino]-2-methylpropyllphenyl)acetamnide, N-(3-Ch lo robenzyl )-2-(3-{2-[((2 R)-2-hyd roxy-2-{4-hyd roxy-3-[(m ethyl sulIfo nyl) amino]phenyl}ethyI)amino]-2-methylpropyl}phenyi)acetamide, N-(4-Fluorobenzyl )-2-(3-{2-[((2P)-2-hyd roxy-2-{4-hyd roxy-3-[(methyl su Ifonyl) amino]phenyi}ethyl)amino]-2-methylpropyllphenyl)acetamide, 25 N-(2,4-Diohiorobenzyl)-2-(3-{2-[((2P)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyllethyl)aminoj-2-methylpropyllphenyl)acetamide, N-(3 ,4-Dichlorobenzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(m ethyls uIfo nyl)am ino] phenyl~ethyI)a m inoI-2-m ethyl pro pyllph en yl)aceta mid e, N-(4-tert-B utyl benzyl )-2-(3-{2-[((2R)-2-hydroxy-2-{4-hyd roxy-3-[(methylsu Ifonyl) 30 amino]phenyllethyl)amino]-2-methylpropytlphenyl)acetamide, N-(2-Chloro-6--fluorobenzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4--hydroxy-3 [(m ethyls ulfo nyl)am ino] phenyl}ethyl)a m ino]-2-m ethyl pro pyllph en yl)aceta mid e, WO 2005/080324 PCT/IB2005/000112 22 N-(2,3-Dimethylbenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenylethyl)amino]-2-methylpropyl}phenyl)acetamide, N-(3,5-Dichlorobenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, 5 N-[3,5-bis(Trifluoromethyl)benzyl]-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, N-(3,4-Dimethylbenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, N-(2,5-Dichlorobenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 10 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)aceta mide, 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)aminolphenyl} ethyl)a mino]-2-methylpropyl}phenyl)-N-(2-phenylethyl)acetamide, 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl) amino]-2-methylpropyl}phenyl)-N-(3-phenylpropyl)acetamide, 15 N-(2,3-Dichlorobenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, N-(2,4-Dichloro-6-methylbenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, N-(Cyclohexylmethyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 20 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, N-(2-Chloro-6-methylbenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, N-(2-Ethoxybenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)aminolpropyl}phenyl)acetamide, 25 N-(3,4-Dimethylbenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)aminolphenyl}ethyl)amino]propyl}phenyl)acetamide, N-(3,4-Dichlorobenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, 2-(3-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl) 30 ethyl)amino]propyl}phenyl)-N-(3-phenylpropyl)acetamide, N-(Cyclohexylmethyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, WO 2005/080324 PCT/1B200510001 12 23 N-(2-Ch loro-6-flu orobe nzyl)-2-(3-(2R)-2-I((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amiloIpropyllpheflyl)acetamide, N-(2-Chloro-4-fiuorobenzyl)-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methylsulfonyl)amino]phenyl}ethy)amino]propyl}phel)acetamide, 5 N-(3 ,5-Dichlorobenzy)-2-(3-{(2R)-2-I((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methylsulIfo nyl)am ino] phenyl~ethyl)a i no]p ropylp h efyl)aceta mid e, 2-(3-{(2R)-2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsulfo nyl)amino]pheny} ethyl)aminopropylphenyl)-N-14-(trifluorolethyl)bel~lacetamide N-(2 ,5-Dichlo robe nzyl )-2-(3-{(2 R)-2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 10 [(methyl su lfonyl)a mi no] phe nyllethyl)a mi no] pro py}ph eyl)acetalmid e, N-[4-Fluoro-2-(trifluoromethyl )benzyll-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4 hyd roxy-3-[(methyl su Ifony)amino] phelyl}ethyl)a mifno]propyl}pheflyl)aceta mid e, N-[4-Fluoro-3-(triflu oromethyl )benzyl]-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4 hyd roxy-3-[(methyl su lfon yl)a mi nolp henyllethyl)a minol pro pyllph enyl)acetam ide, 15 N-[2-Fluoro-4-(triflu oromethyl )benzyl]-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4 hyd roxy-3-[(m ethyl su lfonyl)am ino]p h eyl~ethyl)a r ilo] pro pyIlph efyl)aCetalhid e, N-(2 ,4-Dichloro-6-methylbenzyl )-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methyl sulIfonyl)a mi no] phenyllethya minol pro pyI}ph efnl)aceta mid e, N-[4-Ch lo ro-3-(trifi u oro methyl) be nzyll-2-(3-(2 R)-2-[((2R)-2-hYd roxy-2-{4 20 hydroxy-3-[(methylsulfonyl)amino]phenyethyl)amio]propy}phelyI)acetamlide, N-[2-Ch Ioro-5-(trifluo romethyl )benzyl]-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4 hyd roxy-3-[(meth yls ulfo nyl)am ino] ph enyleth yIa m ino] pro pyllph efl)a ceta mide, N-[3,5-bis(Trifluoro methyl)benzyl]-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methylsulfonyl)aminolphenyl}ethyl)amino]propyllphenyl)acetamide, 25 N-[3-Fluoro-5-(trifluoromethyl)benzyll-2-(3-{(2 R)-2-[((2R)-2-hyd roxy-2-(4 hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)aminolpropyl}phenyl)acetamide, N-(3 ,4-D ich Iorobenzyt)-2-(4-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methylsulfonyl)amino]phenyl}ethyl)aminol.-2-methylpropyl}phenyl)acetamide, N-[2-Ch Ioro-5-(trifl uoro methyl )benzyll-2-(4-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3 30 [(rnethylsulfonyl)amino]phenyl~ethyl )amino]-2-methylpropyllphenyl)acetamide, N-[4-Chloro-3-(trifl uoro methyl )benzyll-2-(4-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3 1(methylsu lfonyl)ami no] phenyllethyl)ami nol-2-methylpropyllphenyl)acetamid e, WO 2005/080324 PCT/IB2005/000112 24 N-[3,5-bis(Trifluoromethyl)benzyl]-2-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)ami no]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, N-[3-Fluoro-5-(trifluoromethyl)benzyl]-2-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, 5 N-[2-Fluoro-5-(trifluoromethyl)benzyl]-2-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, N-[4-Fluoro-2-(trifluoromethyl)benzyl]-2-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, N-[4-Fluoro-3-(trifluoromethyl)benzyl]-2-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 10 [(methylsulfonyl)amino]phenyl}ethyl)am ino]-2-methylpropyl}phenyl)acetamide, 2-(4-{(2R)-2-[((2R)-2-Hydroxy-2-(4-hydroxy-3-[(methylsulfonyl)aminolphenyl} ethyl)amino] propyl}phenyl)-N-(2-methoxybenzyl)acetamid e, N-(2-Ethoxybenzyl)-2-(4-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, 15 N-Benzyl-2-(4-{(2R)-2-1((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] phenyl}ethyl)amino]propyl}phenyl)acetamide, 2-(4-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino]propyl}phenyl)-N-(3-phenylpropyl)acetamide, N-(2,3-Dihydro-1 H-inden-2-yl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 20 [(methylsulfonyl)amino]phenyl}ethyl)aminopropyl}phenyl)acetamide, 2-(3-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino]propyl}phenyl)-N-(2-methoxybenzyl)acetamide, N-Benzyl-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl) amino]phenyl}ethyl)amino]propyl}phenyl)aceta mide, 25 2-(3-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino] propyl}phenyl)-N-(2-phenylethyl)acetamide, 2-(3-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino]propyl}phenyl)-N-(mesitymethy)acetamide, 2-(3-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)aminolphenyl} 30 ethyl)amino]propyl}phenyl)-N-(2,3,6-trichlorobenzyl)acetamide, 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl) amino]-2-methylpropyl}phenyl)-N-[3-(trifluoromethyl)benzyl]acetamide, WO 2005/080324 PCT/IB2005/000112 25 N-(2,3-Dichlorobenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, N-(3-Chloro-4-methylbenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)aminojpropyl}phenyl)acetamide, 5 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hyd roxy-3-[(methylsulfonyl)amino]phenyl}ethyl) amino]-2-methylpropyl}phenyl)-N-[2-(methylthio)benzyl]acetamide, 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino]-2-methylpropyl}phenyl)-N-[4-(methylthio)benzyl]acetamide, 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hyd roxy-3-[(methylsulfonyl)amino]phenyl} 10 ethyl)amino]-2-methylpropyl}phenyl)-N-(tetrahydro-2H-thiopyran-4-yl)acetamide, N-(Biphenyl-2-ylmethyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, 2-(3-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino]propyl}phenyl)-N-(1 -naphthylmethyl)acetamide, 15 2-(3-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino]propyl}phenyl)-N-(pyridin-2-ylmethyl)acetamide, 2-(3-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino]propyl}phenyl)-N-[4-(trifluoromethoxy)benzyl]acetamide, N-(4-Cyanobenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 20 [(methylsulfonyl)amino] phenyl}ethyl)amino]propyl}phenyl)acetamide, N-[4-(Dimethylamino)benzyl]-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, 2-(3-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino]propyl}phenyl)-N-phenylacetamide, 25 N-(I -Benzylpiperid in-4-yl)-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide and, 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl) amino]-2-methylpropyl}phenyl)-N-(mesitylmethyl)acetamide. 30 According to one aspect of the present invention, the compounds of formula (1) wherein the (CH 2 )n-C(=O)Q group is in the meta are generally preferred.
WO 2005/080324 PCT/IB2005/000112 26 Pharmaceutically acceptable salts of the compounds of formula (1) include the acid addition and base salts thereof. 5 Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, 10 hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate trifluoroacetate and xinafoate salts. 15 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. 20 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, 25 Germany, 2002). Pharmaceutically acceptable salts of compounds of formula (1) may be prepared by one or more of three methods: 30 (i) by reacting the compound of formula (1) with the desired acid or base; WO 2005/080324 PCT/IB2005/000112 27 (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 5 (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. 10 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 ionisation in the resulting salt may vary from completely ionised to almost non-ionised. 15 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. 20 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 25 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). 30 Hereinafter all references to compounds of formula (1) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
WO 2005/080324 PCT/IB2005/000112 28 The compounds of the invention include compounds of formula (1) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric 5 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 10 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 15 Symposium Series (T. Higuchi and W. Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E. B Roche, American Pharmaceutical Association). Prodrugs in accordance with the invention can, for example, be produced by 20 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). 25 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 30 replaced by (C-C 8 )alkyl; WO 2005/080324 PCT/IB2005/000112 29 (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
(C-C
6 )alkanoyloxymethyl; and 5 (iii) where the compound of formula (1) contains a primary or secondary amino functionality (-NH 2 or -NHR where R #H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (1) 10 is/are replaced by (C-C 10 )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. 15 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. 20 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 (-CH 3 -> -CH 2 OH): 25 (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 (-NR 1
R
2 +_ -NHR or -NHR 2 ); 30 (iv) where the compound of formula (1) contains a secondary amino group, a primary derivative thereof (-NHR -+ -NH 2
);
WO 2005/080324 PCT/IB2005/000112 30 (v) where the compound of formula (1) contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and 5 (vi) where the compound of formula (1) contains an amide group, a carboxylic acid derivative thereof (-CONH 2 -> 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) 10 contains an alkenyl or alkenylene group, geometric cis/trans (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 of proton tautomerism in compounds of formula (1) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds 15 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), 20 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, d-lactate or lysine, or racemic, for example, d/-tartrate or di-arginine. 25 Cisltrans 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 30 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).
WO 2005/080324 PCT/IB2005/000112 31 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 5 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 enantiomer(s) by means well known to a skilled person. 10 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 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an 15 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 20 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 R 1 is hydrogen and R 2 is C-C 4 alkyl, preferably methyl, and n and Q1 are as defined above, is generally preferred: OH H N
(CH
2 )n 01 HO /' R 1
R
2 HO( 25
NHSO
2
CH
3 0 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 WO 2005/080324 PCT/IB2005/000112 32 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 5 include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as "C, 1C and 14 C, chlorine, such as 3 6 Cl, fluorine, such as 18 F, iodine, such as 1231 and 1251, nitrogen, such as 3N and 1N, oxygen, such as 10, 0 and 10, phosphorus, such as 32 P, and sulphur, such as 3S. 10 Certain isotopically-labelled compounds of formula (1), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 4C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. 15 2 Substitution with heavier isotopes such as deuterium, i.e. H, 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. 20 Substitution with positron emitting isotopes, such as 1C, "F, "0 and "N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. 25 Isotopically-labeled compounds of formula (1) 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. 30 WO 2005/080324 PCT/IB2005/000112 33 Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g.
D
2 0, de-acetone, de-DMSO. The compounds of formula (1), their pharmaceutically acceptable salts 5 and/or derived forms, are valuable pharmaceutically active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the P2 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 10 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 15 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. 20 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 25 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. 30 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 WO 2005/080324 PCT/IB2005/000112 34 may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995). The compounds of the invention may also be administered directly into the 5 blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion 10 techniques. Parenteral formulations are typically aqueous solutions which may contain excipients 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 15 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 20 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. 25 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, semi-solid, or 30 thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug coated stents and poly(dl-lactic-coglycolic)acid (PGLA).microspheres.
WO 2005/080324 PCT/IB2005/000112 35 The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting 5 powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. 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 Sci, 88 (10), 955-958 by Finnin 10 and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, Bioject T M , etc.) injection. 15 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. 20 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, 25 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-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. 30 The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for WO 2005/080324 PCT/IB2005/000112 36 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. 5 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 10 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 15 such as lactose or starch and a performance modifier such as I-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. 20 A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1pg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1pl to 100pl. A typical formulation may comprise a compound of formula (1), propylene glycol, sterile water, ethanol and sodium chloride. Alternative 25 solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the 30 invention intended for inhaled/intranasal administration.
WO 2005/080324 PCT/IB2005/000112 37 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. 5 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 0.001mg to 10mg of the compound of formula (1). The overall 10 daily dose will typically be in the range 0.001mg 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 15 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 20 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. 25 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 30 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 polyacrylic acid, polyvinylalcohol, hyaluronic WO 2005/080324 PCT/IB2005/000112 38 acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, 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 5 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. 10 The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of 15 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, 20 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 98155148. 25 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 the 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 30 coad ministration of the compositions.
WO 2005/080324 PCT/IB2005/000112 39 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 5 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 10 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 15 the invention is typically in the range 0.001mg to 5000mg depending, of course, on the mode of administration. For example, an intravenous daily dose may only require from 0.001mg to 40mg. The total daily dose may be administered in single or divided dosesand may, at the physician's discretion, fall outside of the typical range given herein. 20 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. 25 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 30 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-relevant disease processes including, but not limited to (i) WO 2005/080324 PCT/IB2005/000112 40 bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as breathlessness, cough. 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 5 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 10 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 15 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 20 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 25 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 WO 2005/080324 PCT/IB2005/000112 41 sequential 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 in a controlled manner whereupon they are 5 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 10 acceptable salts, derived forms or compositions thereof, include, but are by no means limited to: (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (b) Leukotriene antagonists (LTRAs) including antagonists of LTB 4 , LTC 4 , LTD 4 , 15 and LTE 4 , (c) Histamine receptor antagonists including H1 and H3 antagonists, (d) oc- and cc 2 -adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use, (e) muscarinic M3 receptor antagonists or anticholinergic agents, 20 (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), 25 (j) Oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor) (k) Monoclonal antibodies active against endogenous inflammatory entities, (1) Anti-tumor necrosis factor (anti-TNF-ax) agents, (m)Adhesion molecule inhibitors including VLA-4 antagonists, 30 (n) Kinin-B 1 - and B 2 -receptor antagonists, (o) Immunosuppressive agents, WO 2005/080324 PCT/IB2005/000112 42 (p) Inhibitors of matrix metalloproteases (MMPs), (q) Tachykinin NK 1 , NK 2 and NK 3 receptor antagonists, (r) Elastase inhibitors, (s) Adenosine A2a receptor agonists, 5 (t) Inhibitors of urokinase, (u) Compounds that act on dopamine receptors, e.g. D2 agonists, (v) Modulators of the NFKp pathway, e.g. IKK inhibitors, (w) modulators of cytokine signalling pathways such as p38 MAP kinase, syk kinase or JAK kinase inhibitor, 10 (x) Agents that can be classed as mucolytics or anti-tussive, and (y) Antibiotics. According to the present invention, combination of the compounds of formula (1) with : - H3 antagonists, 15 - Muscarinic M3 receptor antagonists, - PDE4 inhibitors, - glucocorticosteroids, - Adenosine A2a receptor agonists, - Modulators of cytokine signalling pathyways such as p38 MAP kinase or syk 20 kinase, or, - Leukotriene antagonists (LTRAs) including antagonists of LTB 4 , LTC 4 , LTD 4 , and LTE 4 , are further preferred. According to the present invention, combination of the compounds of 25 formula (1) with : - glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone 30 furoate, or WO 2005/080324 PCT/IB2005/000112 43 - 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, 5 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. 10 The compounds of formula (1) have the ability to interact with the P2 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role which the P2 receptor plays in the physiology of all mammals. Therefore, a further aspect of the present invention relates to the 15 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 P2 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 20 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 25 asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced WO 2005/080324 PCT/IB2005/000112 44 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 5 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), 10 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 (ARDS), exacerbation of airways hyper reactivity consequent to other drug therapy and airways disease that is 15 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 20 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 25 cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.
WO 2005/080324 PCT/IB2005/000112 45 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 P2 agonist activity. In particular, the present inventions concerns the use of the 5 compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug for the treatment of p2 mediated diseases and/or conditions, in particular the diseases and/or conditions listed above. As a consequence, the present invention provides a particularly 10 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 15 being, in particular the diseases and/or conditions listed above, comprising admidministering 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): 20 Preparation 1 : Methyl [3-(2-oxopropyl)phenyl]acetate
H
3 C
OCH
3 00 Tributyltin methoxide (28.3ml, 98mmol), methyl (3-bromophenyl)acetate (WO 95/27692, pg. 16, e.g. Sa) (15.0g, 65.Ommol), isopropenyl acetate (10.8ml, 98.Ommol), palladium(II)acetate (750mg, 3.30mmol) and tri-ortho 25 tolylphosphine (2.0g, 6.5mmol) were stirred together in toluene (75ml) at 1000C under nitrogen for 5 hours. After cooling the reaction was diluted with ethyl acetate (150ml) and 4M aqueous potassium fluoride solution (90ml) and stirred WO 2005/080324 PCT/IB2005/000112 46 for 15 minutes. The mixture was filtered through Arbocel@ and the organic phase separated and concentrated in vacuo. The residue was purified column chromatography on silica gel eluting with diethyl ether:pentane (0:100 to 25:75 and then changing to dichloromethane), to yield the title compound as a pale 5 yellow oil, 12.6g. 'HNMR(CDCI, 400MHz) 8: 2.15 (s, 3H), 3.61 (s, 2H), 3.69 (s, 5H), 7.10-7.13 (m, 2H), 7.19 (d, IH), 7.30 (t, 1H) ppm. MS (electrospray): m/z 229 [MNa]* 10 Preparation 2 Methyl [3-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl) phenyl]acetate hydrochloride H N
OCH
3 CH CH CH3 CH3 0 A solution of the ketone of preparation 1 (8.5g, 41.2mmol), (R)-a-methyl 15 benzylamine (4.8ml, 37.2mmol), sodium triacetoxyborohydride (11 .6g, 56mmol) and acetic acid (2.2ml, 38mmol) in dichloromethane (400ml) was stirred at room temperature for 48 hours. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (200ml) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous 20 phase extracted with dichloromethane (100ml). The combined organic extracts were dried (magnesium sulphate) and concentrated in vacuo. Purification by column chromatography on silica gel eluting with dichloromethane:methanol:0.880 ammonia (99:1:0.1 changing to 95:5:0.5) gave a 4:1 mixture of diastereomers (R,R major) as a pale yellow oil (8.71g). 25 Treatment with a I M solution of hydrogen chloride in methanol (40ml, 40mmol), followed by three crystallisations from a diisopropylether:methanol mixture gave the title compound as a colourless crystalline solid, 5.68g.
WO 2005/080324 PCT/IB2005/000112 47 Preparation 3: Methyl {3-[(2R)-2-aminopropyl]phenyl}acetate
H
2 N O0CH 3
OH
3 0 A solution of the amine of preparation 2 (7.69g, 22mmol) and ammonium 5 formate (6.94g, 11 Ommol) in methanol (50ml) was heated to 750C in the presence of 20% palladium hydroxide-on-charcoal (2.00g). 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 (100ml) and 0.880 ammonia (100ml) and the organic phase 10 separated. The aqueous phase was extracted with dichloromethane (100ml) and the combined organic extracts dried (magnesium sulphate) and concentrated in vacuo to give the title compound as a colourless oil, 4.78g. 'HNMR (CD 3 0D, 400MHz) : 1.06 (d, 3H), 2.57-2.67 (m, 2H), 3.05-3.12 (m, IH), 3.63 (s, 2H), 3.67 (s, 3H), 7.09-7.13 (m, 3H), 7.23-7.27 (t, 1H) ppm. 15 MS (electrospray): m/z 208 [M+H]+ Preparation 4 : N-{2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl] phenyl} methanesulfonamide OH Br 0 HNI CH. o 0 20 A solution of (1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-bromoethanol (Org. Process Research and Development, 1998, 2, 96) (30.8g, 95.6mmol) in dichloromethane (300mi) was treated with pyridine (9.3ml, 115mmol). The resulting solution was cooled to 50C and a solution of methanesulfonyl chloride (7.8ml, 100.7mmol) in dichloromethane (10ml) added dropwise. The mixture 25 was stirred at 5oC for a further 30 minutes and then allowed to warm gradually WO 2005/080324 PCT/IB2005/000112 48 to room temperature over a period of 16 hours. The reaction mixture was washed with 2N hydrochloric acid (110ml) and the organic phase separated, dried (magnesium sulfate) and the solvent removed in vacuo to give an orange oil. The residue was crystallized from hot toluene (100ml) to give the title 5 compound as a pale pink solid (33.7g). 1 HNMR (DMSOde, 400MHz) 6: 2.93 (s, 3H), 3.52-3.66 (m, 2H), 4.74 (m, 1H), 5.19 (s, 2H), 7.11 (d, 1H), 7.19-7.22 (m, 1H), 7.33-7.36 (m, 2H), 7.40-7.43 (m, 2H), 7.56 (d, 2H), 8.95 (s, IH) ppm. MS (electrospray) : m/z 398 / 400 [M-H] 10 Preparation 5: N-[2-(benzyloxy)-5-((1 R)-2-bromo-1 -{[tert-butyl(dimethyl) silyl]oxy}ethyl)phenyl]methanesulfonamide OTBDMS Br 0 HN CH 3 o 0 15 A solution of the bromide of preparation 4 (21.5g, 53.7mmol) in N,N dimethylformamide (125ml) was treated with imidazole (4.16g, 75.2mmol) and tert-butyl(dimethyl)silylchloride (9.73g, 64.5mmol) and the resulting solution left to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (200mi) and washed with water (2 x I 00ml). The aqueous phases 20 were combined and extracted with ethyl acetate (100mi). The combined organic extracts were washed with 2N hydrochloric acid (1I00ml), dried (magnesium sulphate) and reduced in vacuo. The residue was suspended in pentane :ethyl acetate (200m, 1:1 by volume) and the solvent evaporated. The residue was triturated with further pentane:ethyl acetate (200ml, 1:1 by volume) and the 25 resulting solid filtered off and dried in vacuo to give the title compound as a colourless solid (23.7g). 1 HNMR (CDCl3, 400MHz) 8: -0.07 (s, 3H), 0.11 (s, 3H), 0.89 (s, 9H), 2.91 (s, WO 2005/080324 PCT/IB2005/000112 49 3H0, 4.80-4.83 (m, 1H), 6.80 (bs, 1H), 6.98 (d, 1H), 7.12 (d, 1H), 7.36-7.44 (M, 5H), 7.52-7.54 (m, I H) ppm. Alternative process for the preparation of preparation 5: 5 A solution of the bromide of preparation 4 (10g, 24.98mmol) was dissolved in DCM (20mi, 2ml/g) and then imidazole (4.58g, 37.47mmol, 1.5eq) was added followed by TBDMSiCI (5.27g, 34.97mmol, 1.4eq). The reaction mixture was heated to reflux for 1 hour and then allowed to cool to 304C. The mixture was diluted with isopropyl acetate (80ml, 8ml/g) and then quenched with 2M HCI 10 (50, 5ml/g) and stirred vigorously for 10 minutes. The phases were separated and the organic phase was washed with water (50ml, 5ml/g). The organic phase was then reduced in volume under reduced pressure at 450C to 25-30ml. The solution was then cooled to room temperature and a suspension quickly formed and was stirred at room temperature for 30 minutes. Heptane (20ml, 15 2m/g) was then added over 10 minutes and the suspension was cooled to 5 10"C and stirred for 1 hour. The suspension was then filtered and washed on the filter paper with heptane (2 X 10mli). The resulting filter cake was dried in a vacuum oven at 50"C for 12 hours to give the title compound as a white solid (11.05g, 86% yield). 20 1 HNMR (CDCla, 400MHz) 5: -0.07 (s, 3H), 0.11 (s, 3H), 0.89 (s, 9H), 2.91 (s, 3HO, 4.80-4.83 (m, 1H), 6.80 (bs, 1H), 6.98 (d, IH), 7.12 (d, 1H), 7.36-7.44 (m, 5H), 7.52-7.54 (m, 1H) ppm.
WO 2005/080324 PCT/IB2005/000112 50 Preparation 6 : Methyl (3-{(2R)-2-[((2R)-2-{4-(benzyloxy)-3 [(methylsulfonyl)amino]phenyl}-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl) amino]propyl}phenyl)acetate OTBDMS H ON
OCH
3 rCH 3 0 HNS
,...CH
3 5 0 0 The amine of preparation 3 (4.2g, 20.2mmol) was dissolved in dichloromethane (20ml), treated with the bromide of preparation 5 (8.0g, 15.6mmol) and the reaction mixture heated to 90 0 C for 16 hours (solvent allowed to evaporate). The reaction mixture was diluted with ethyl acetate (200ml), washed with IM 10 aqueous sodium hydroxide (30ml), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate:pentane (1:1 changing to 3:2) to yield the title product (5.8g). 'HNMR (CD 3 0D, 400MHz) 6: -0.18 (s, 3H), -0.01 (s, 3H), 0.82 (s, 9H), 1.05 (d, 15 3H), 2.54-2.66 (m, 3H), 2.83 (s, 3H), 2.85-2.93 (m, 2H), 3.59 (s, 2H), 3.66 (s, 3H), 7.69-4.72 (m, IH), 5.18 (s, 2H), 6.97-7.07 (m, 5H), 7.14-7.18 (m, IH), 7.30-7.40 (m, 4H), 7.48 (d, 2H) ppm. MS (electrospray): m/z 641 [M+H]* 20 Preparation 7: Methyl [4-((2R)-2-{[(1 R)-1 -phenylethyl]amino}propyl) phenylacetate hydrochloride H N cH 3 cH 3
~C
3 0 WO 2005/080324 PCT/IB2005/000112 51 The title compound was prepared by a method similar to that described for preparation 2 using methyl 4-(oxopropyl)-phenyl acetate (WO 97/24331, pg. 68, e.g. 24D). 1 HNMR (CD 3 0D, 400MHz) 5: 1.18 (d, 3H), 1.70 (d, 3H), 2.62 (dd, 1H), 3.18 (m, 5 1H), 3.30 (m, 1H), 3.62 (s, 2H), 3.66 (s, 3H), 4.61 (q, IH), 7.06 (d, 2H), 7.21 (d, 2H), 7.53 (m, 5H) ppm. MS (electrospray): m/z 312 [M+H]* Preparation 8 : Methyl {4-[(2R)-2-aminopropyl]phenyl}acetate
H
2 N 0 10
OH
3 0OH1 3 The title compound was prepared by a method similar to that described for preparation 3 using the amine of preparation 7. 'HNMR (CDC 3 , 400MHz) 8: 1.14 (d, 3H), 2.79 (m, 2H), 3.39 (q, 1H), 3.60 (s, 2H), 3.68 (s, 3H), 7.17 (d, 2H), 7.22 (d, 2H) ppm. 15 MS (electrospray) : m/z 208 [M+H]+ Preparation 9 Methyl (4-{(2R)-2-[((2R)-2-{4-(benzyloxy)-3 [(methylsulfonyl)amino]phenyl}-2-{([tert-butyl(dimethyl)silyl]oxy}ethyl) amino]propyl}phenyl)acetate OTBDMS H N 20 0 The bromide of preparation 5 (2.0g, 4.11mmol), the amine of preparation 6 (852mg, 4.11mmol) and N-ethyldiisopropylamine (531mg, 4.11mmol) were dissolved in dimethyl sulphoxide (6ml) and the reaction mixture heated to 900C for 16 hours. The reaction mixture was diluted with ethyl acetate (100ml) and 25 washed with sat. aq. sodium chloride (4x50ml), dried (magnesium sulphate) WO 2005/080324 PCT/IB2005/000112 52 and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (100:0 changing to 95:5) to yield the title product, 520mg. 'HNMR (CDCI,, 400MHz) 8: -0.16 (s, 3H), -0.04 (s, 3H), 0.83 (s, 9H), 1.07 (s, 5 3H), 2.51 (m, 1H), 2.75 (m, 2H), 2.88 (s, 3H), 2.96 (m, 2H), 3.18 (s, 2H), 3.67 (s, 3H), 4.73 (m, 1H), 5.09 (s, 2H), 6.77 (m, 1H), 6.93 (d, 1H), 7.04 (dd, 2H), 7.10 (m, 2H), 7.16 (m, 2H), 7.35-7.43 (m, 5H), 7.50 (d, 1H) ppm. MS (electrospray): m/z 641 [M+H]* 10 Preparation 10 : Diethyl 2,2'-(1,4-phenylene)diacetate H 3C 0 0 0
CH
3 2,2'-(1,4-phenylene)diacetic acid (10.0g, 51mmol) was dissolved in ethanol (100ml) and the solution treated dropwise with catalytic acetyl chloride (2.5ml). The reaction mixture was stirred at reflux for 18 hours before being allowed to 15 cool and concentrated in vacuo. The residue was taken up in ethyl acetate (100ml) and extracted with sodium bicarbonate solution (3x50ml) and brine (3x50ml). The organic phase was then dried (magnesium sulphate) and concentrated in vacuo. The residue was triturated with pentane to yield the title product, 11.8g. 20 1HNMR (CDCl 3 , 400MHz) 5: 1.26 (t, 6H), 3.57 (s, 4H), 4.12 (q, 4H), 7.21 (m, 4H) MS (electrospray) : m/z 273 [M+H]+ Preparation 11 : [4-(2-ethoxy-2-oxoethyl)phenyl]acetic acid HO 00 25 0 CH 3 A solution of the diester from preparation 9 (11.8g, 47.Ommol) and 2,2'-(1,4 phenylene)diacetic acid (15.73g, 81.Ommol) in ethanol (6.14ml) and dioxan (75ml) was treated dropwise with 12M hydrochloric acid (1.57ml, 18.8mmol).
WO 2005/080324 PCT/IB2005/000112 53 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 (125ml) and the resulting slurry filtered. The filtrate was concentrated in vacuo and the residue taken up in water and basified with sodium bicarbonate 5 until pH neutral. The mixture was diluted with ethyl acetate (200ml) and the organic layer was separated and washed with sodium bicarbonate solution (5x30ml) and sat. aq. sodium chloride (50ml). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with ether (3x30ml). The organics were combined, dried (magnesium sulphate) and 10 concentrated in vacuo. The residue was triturated with pentane giving the title compound as a colourless solid 10.8g. 1HNMR (CD 3 0D, 400MHz) 8: 1.23 (t, 3H), 3.56 (m, 2H), 3.60 (m, 2H), 4.10 (q, 2H), 7.22 (m, 4H) ppm. MS (electrospray): m/z 245 [MNa]+ 15 Preparation 12 : [4-(2-Hydroxy-2-methylpropyl)phenyl]acetic acid HO OH Y H 3 C CH 3 OH The carboxylic acid of preparation 11 (18.26g, 82.Ommol) was dissolved in tetrahydrofuran (450ml) and the solution cooled to 0 0 C and treated dropwise 20 with a solution of methylmagnesium chloride in tetrahydrofuran (82ml, 246mmol). The reaction mixture was allowed to warm to room temperature and left to stand for 18 hours. The reaction mixture was slowly diluted with water (80ml) followed by 2M hydrochloric acid (120ml, 240mmol). The mixture was extracted with ethyl acetate (3xlOOml) and the organic extracts combined and 25 washed with brine (3x50ml). The ethyl acetate phase was dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol:acetic acid (99.6:0:0.4 changing to 94.6:5:0.4) to yield the title product as a colourless solid.
WO 2005/080324 PCT/IB2005/000112 54 1HNMR (CDCl 3 , 400MHz) 5: 1.15 (s, 6H), 2.70 (s, 2H), 3.55 (s, 2H), 7.18 (s, 4H) MS (electrospray) : m/z 207 [M-H] 5 Preparation 13 : (4-{2-[(Chloroacetyl)amino]-2-methylpropyl}phenyl) acetic acid HO C1 H The title product was prepared by a method similar to that described for preparation 19 using the alcohol of preparation 12. 10 1HNMR (CD 3 0D, 400MHz) 5: 1.30 (s, 6H), 3.02 (s, 2H), 3.55 (s, 2H), 3.90 (s, 2H), 7.10 (d, 2H), 7.20 (d, 2H), 7.55 (m, IH) ppm. MS (electrospray) : m/z 282 [M-H] Preparation 14 [4-(2-Amino-2-methyl-propyl)-phenyl]-acetic acid methyl 15 ester H3 HC CH 3 0
NH
2 The amide of preparation 13 (500mg, 1.77mmol) was dissolved in acetic acid (10ml) and the solution treated with thiourea (160mg, 2.10mmol) and stirred at 950C for 2 hours. The reaction mixture was allowed to cool to room temperature 20 and concentrated in vacuo. The residue was taken up in methanol (40ml), treated with methanolic hydrochloric acid (10ml) and heated to reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was taken up in water and extracted with ether (3x20ml). The aqueous was basified to pH 11 with sodium carbonate 25 solution and extracted with ethyl acetate (3x30ml). The combined ethyl acetate extracts were dried (magnesium sulphate) and concentrated in vacuo. Then resultant oil was evaporated from ether (x5) to yield the title product, 280mg.
WO 2005/080324 PCT/IB2005/000112 55 1HNMR (CDCl 3 , 400MHz) 8: 1.10 (s, 6H), 2.60 (s, 2H), 3.60 (s, 2H), 3.70 (s, 3H), 7.12 (d, 2H), 7.20 (d, 2H) ppm. MS (electrospray) : m/z 222 [M+H]+ 5 Preparation 15 : Methyl (4-{2-[((2R)-2-{4-(benzyloxy)-3-[(methylsulfonyl) amino] phenyl}-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)am ino]-2-methyl propyl}phenyl)acetate OTBDMS H N0
H
3 C OH 3 O CH 3 0 0 3 O\ NH HGC The bromide of preparation 5 (2.00g, 3.90mmol) and the amine of preparation 10 12 were heated together as a melt at 950C under nitrogen for 44 hours and then allowed to cool to room temperature. The reaction mixture was suspended in dichloromethane:0.880 ammonia 99.8:0.2 and purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.880 ammonia 99.8:0:0.2 to 97.8:2:0.2 to 80:20:5. The crude product was 15 evaporated from ether (x3) to yield the title product, 1.76g. 1HNMR (CDCl 3 , 400MHz) 8: -0.09 (s, 3H), 0.00 (s, 3H), 0.90 (s, 9H), 1.00 (s, 3H), 1.05 (s, 3H), 2.55-2.70 (m, 3H), 2.80-2.85 (m, 1H), 2.85 (s, 3H), 3.60 (s, 2H), 3.70 (s, 3H), 4.71 (m, IH), 5.10 (s, 2H), 6.70-6.90 (m, 1H), 6.90-7.15 (m, 6H), 7.35-7.45 (m, 5H), 7.55 (d, 1H) ppm. 20 MS (APCI) : m/z 655 [M+H]+ Preparation 16 : Diethyl 2,2'-(1,3-phenylene)diacetate H 3C O O CH 3 0 0 2,2'-(1,3-phenylene)diacetic acid (10.0g, 51mmol) was dissolved in ethanol 25 (100ml) and the solution treated dropwise with catalytic acetyl chloride (2.5ml).
WO 2005/080324 PCT/IB2005/000112 56 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 (100ml) and extracted with sodium bicarbonate solution (3x50ml) and brine (3x50ml). The organic phase was then dried (magnesium sulphate) and 5 concentrated in vacuo. The residue was triturated with pentane to yield the title product, 11.8g. 1 HNMR (CDCl 3 , 400MHz) 5: 1.31 (t, 6H), 3.65 (s, 4H), 4.20 (q, 4H), 7.24-7.36 (m, 4H) ppm. MS (electrospray) : m/z 251 [M+H]+ 10 Preparation 17 : [3-(2-ethoxy-2-oxoethyl)phenyl]acetic acid HO O _CH 3 0 0 A solution of the diester from preparation 16 (44.3g, 177mmol) and 2,2'-(1,3 phenylene)diacetic acid (59.2, 308mmol) in ethanol (24ml) and dioxan (290ml) 15 was treated dropwise with 12M hydrochloric acid (4.9mi, 58.8mmol). 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 (125ml) 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 20 neutral. The mixture was diluted with ethyl acetate (200ml) and the organic layer was separated and washed with sodium bicarbonate solution (5x30ml) and brine (50mi). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with ether (3x30ml). The organics were combined, dried (magnesium sulphate) and concentrated in vacuo. The residue 25 was triturated with pentane giving the title compound as a colourless solid 10.8g. IHNMR (CD 3 0D, 400MHz) 5: 1.25 (t, 3H), 3.60 (m, 2H), 3.63 (m, 2H), 4.15 (q, 2H), 7.18-7.32 (m, 4H) ppm. MS (electrospray): m/z 245 [MNa]+ 30 WO 2005/080324 PCT/IB2005/000112 57 Preparation 18 : [3-(2-Hydroxy-2-methylpropyl)phenyl]acetic acid HO COH 0 H 3 C 3 C CH 3 Methyl magnesium chloride (51ml of a 3M solution in tetrahydrofuran, 153mmol) was added dropwise to a stirred solution of the preparation 17 5 (11.6g, 51mmol) (International Journal of Peptide and Protein Research, 1987, 29(3), 331) in tetrahydrofuran (300ml) at 00C under nitrogen. The reaction was allowed to warm to room temperature overnight with the formation of a thick white precipitate and then water (50ml) and 2N hydrochloric acid (80ml) were cautiously added. The aqueous was extracted with ethyl acetate (2x300ml) and 10 the combined organics washed with brine (50ml), dried (sodium sulfate), and the solvent removed in vacuo to furnish the title compound as a golden oil (11.2g). 'HNMR (CDCl 3 , 400 MHz) & 1.22 (6H, s), 2.75 (2H, s), 3.63 (2H, s), 7.12-7.30 (4H, m). 15 MS (ESI): m/z 209 [M+H]* Preparation 19 (3-{2-[(Chloroacetyl)amino]-2-methylpropyl}phenyl) acetic acid H HO N O0 ~ H 3 C CH 3 0 20 2-Chloroacetonitrile (8.8ml, 140mmol) was added to a solution of the alcohol from preparation 18 (16.Og, 70mmol), in acetic acid (33ml). The resulting solution was cooled to OC, treated with concentrated sulphuric acid (33ml), 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 25 carbonate. The solution was extracted with ethyl acetate (2x500ml) and the combined organic extracts dried (magnesium sulphate) and concentrated in vacuo to give the title product as a colourless solid, 19.0g.
WO 2005/080324 PCT/IB2005/000112 58 'HNMR (CDC3, 400MHz) 6: 1.36 (s, 6H), 3.02 (s, 2H), 3.62 (s, 2H), 3.95 (s, 2H), 6.19 (m, 1H), 7.06-7.31 (m, 4H) ppm. MS (electrospray): m/z 282 [M-H]~ 5 Preparation 20 [3-(2-Amino-2-methyl-propyl)-phenyl]-acetic acid methyl ester
H
2 N O CHa HC CH 3 ' A solution of the amide from preparation 19 (5.1g, 18mmol), thiourea (1.6g, 21mmol) and acetic acid (18ml) in ethanol (80ml) was heated to reflux under a 10 nitrogen atmosphere for 16 hours. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo, the residue dissolved in ethanol (150ml), saturated with hydrogen chloride gas and the resulting solution heated to reflux for 16 hours. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate 15 (200ml) and 5% aqueous sodium carbonate solution (200ml). The organic phase was washed with brine(100ml), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by strong cation exchange resin, eluting with methanol and then a 2M solution of ammonia in methanol, to elute the product. The eluent was concentrated in vacuo giving the title 20 compound as a yellow oil, 2.68g. 'HNMR (CDCl 3 ,400MHz) 8: 1.14 (s, 6H), 2.68 (s, 2H), 3.62 (s, 2H), 3.69 (s, 2H), 7.08-7.16 (m, 3H), 7.23-7.27 (m, 1H) ppm. MS (electrospray): m/z 222 [M+H]* 25 Preparation 21 (3-{2-[(2R)-2-(4-Benzyloxy-3-methanesulfonylamino phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-2-methyl-propyl} phenyl)-acetic acid methyl ester WO 2005/080324 PCT/IB2005/000112 59 OTBDMS H J -- N I 'Z CH 3 H3C GCCH1 3 HNs
,CH
3 O 0 The bromide of preparation 5 (36.Og, 70.8mmol) and the amine of preparation 20 (36.Og, 153mmol) were heated at 85 0 C for 72 hours. The reaction mixture was cooled to room temperature and purified by column chromatography on 5 silica gel eluting with pentane:ethyl acetate (50:50 by volume) to yield the title product as a pale yellow oil (37.2g). 1HNMR (CDCI 3 , 400MHz) 5: -0.15 (s, 3H), 0.00 (s, 3H), 0.83 (s, 9H), 1.01 (s, 3H), 1.04 (s, 3H), 2.57-2.97 (m, 7H), 3.59 (s, 2H), 3.68 (s, 3H), 4.68-4.72 (m, 1H), 5.09 (s, 2H), 6.79 (bs,1H), 6.95 (d, 1H), 7.04-7.21 (m, 7H), 7.37-7.44 (m, 10 5H), 7.56 (d, IH) ppm. MS (APCI) : m/z 655 [M+H]+ Preparation 22 : Methyl (4-((2R)-2-[((2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2 {4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl} 15 phenyl)acetate OTBDMS H N HO NoCH3 0 0 \ ~NH H3CO 0 The benzyl protected product of preparation 9 (520mg, 0.813mmol) was added to a solution of 10% Pd/C (100mg) in methanol (25ml) and the reaction mixture stirred at room temperature under 60psi of hydrogen for 8 hours. The reaction 20 mixture was filtered through Arbocel@ and the filtrate concentrated in vacuo to yield the title product.
WO 2005/080324 PCT/IB2005/000112 60 1HNMR(CDCl 3 , 400MHz) 5: -0.16 (s, 3H), -0.01 (s, 3H), 0.80 (s, 9H), 1.25 (d, 3H), 2.77-2.87 (m, 3H), 2.91 (s, 3H), 3.08-3.19 (m, 2H), 3.61 (s, 2H), 3.74 (s, 3H), 4.84 (m, 1H), 6.65 (d, 1H), 6.80 (d, 1H), 7.08 (d, 2H), 7.16 (d, 2H), 7.18 (m, IH) 5 MS (electrospray) m/z 551 [M+H]+ Preparation 23 : (4-{(2R)-2-[((2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-{4 hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl) acetic acid OTBDMS H N HO CH,' OH 0 \ NH 10H 3 C 0 10 The ester of preparation 22 (844mg, 1.53mmol) was added to a solution of lithium hydroxide (71mg, 1.69mmol) in tetrahydrofuran:water 10:1 (11ml) and the reaction mixture stirred at room temperature for 4 hours. Additional lithium hydroxide (142mg, 3.38mmol) was added and the reaction mixture stirred at 15 room temperature for a further 18 hours. The reaction mixture was diluted with a 4M solution of hydrochloric acid in dioxane (1.27ml, 5.Ommol) and concentrated in vacuo. The residue was taken up in water (20ml) and ethyl acetate (20ml), the organic layer was separated, dried (magnesium sulphate) and concentrated in vacuo to yield the title product, 748mg. 20 IHNMR(CD 3 0D, 400MHz) 8: -0.19 (s, 3H), -0.01 (s, 3H), 0.79 (s, 9H), 1.13 (d, 3H), 2.66 (m, IH), 2.82 (m, 1H), 2.84 (s, 3H), 3.00 (m, IH), 3.17 (m, 1H), 3.32 (m, 1H), 3.42 (s, 2H), 4.86 (m, 1H), 6.80 (d, 1H), 6.95 (d, 1H), 7.00 (d, 2H), 7.17 (d, 2H), 7.31 (d, IH) ppm. MS (electrospray) : m/z 537 [M+H]+ 25 WO 2005/080324 PCT/IB2005/000112 61 Preparation 24 : Methyl (4-{2-[((2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-{4 hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl} phenyl)acetate OTBDMS H N
HCH
3 CH 0O \ NH 5 The benzyl protected alcohol of preparation 15 (1.72g, 2.60mmol) was dissolved in methanol (40ml) and the solution treated with 10% Pd/C (200mg) and placed under 60psi of hydrogen at room temperature for 18 hours. The reaction mixture was filtered through Arbocel@ and the filtrated concentrated to low volume in vacuo. The solution was treated with 10%Pd/C (250mg) and 10 placed under 60psi of hydrogen at room temperature for 72 hours. The reaction mixture was filtered through Arbocel@ and the filtrated concentrated in vacuo. The oil produced was evaporated from ether (x3) to yield the title product, 1.43g. 1HNMR (CD 3 0D, 400MHz) 8: -0.08 (s, 3H), 0.00 (s, 3H), 0.80 (s, 9H), 1.12 (d, 15 6H), 2.65-3.00 (m, 7H), 3.60 (s, 2H), 3.70 (s, 3H), 4.70 (m, 1H), 6.85 (d, 1H), 7.00-7.20 (m, 5H), 7.35 (d, IH) ppm. MS (APCI): m/z 565 [M+H]+ Preparation 25 : (4-{2-[((2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-{4-hydroxy 20 3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl} phenyl)acetic acid OTBDMS H
H
3 C cH 3 HO H3 OH H S
H
3 C \ 0 WO 2005/080324 PCT/IB2005/000112 62 The ester of preparation 24 (1.41g, 2.50mmol) was dissolved in dioxan (16mi) and water (2ml) and the solution treated dropwise with 5M sodium hydroxide solution (3.49m, 17.5mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was 5 taken up in water and chilled before being treated with 2M hydrochloric acid (8.78ml, 17.6mmol). The solution was diluted with ethyl acetate and concentrated in vacuo due to lack of separation. The residue was evaporated from ethyl acetate (x3) to yield the title product, 1.67g. 1HNMR (DMSO-D6, 400MHz) 8: -0.08 (s, 3H), 0.00 (s, 3H), 0.85 (s, 9H), 0.90 10 (s, 3H), 0.95 (s, 3H), 2.50-2.80 (m, 4H), 2.85 (s, 3H), 2.90 (s, 2H), 4.60 (m, IH), 6.75-7.30 (m, IOH) ppm. MS (APCI): m/z 551 [M+H]+ Preparation 26 (3-{(2R)-2-[((2R)-2-{4-(Benzyloxy)-3-[(methylsulfonyl) 15 amino]phenyl}-2-{[tert-butyl(dimethyl)siyl]oxy}ethyl)amino] propyl) phenyl)acetic acid OTBDMS N OH N ~N..CH 3 0 HN cH 3 S 0 0 The ester of preparation 6 (2.90g, 4.5mmol) was dissolved in a solution of lithium hydroxide (216mg, 9.Ommol) in water (30ml) and tetrahydrofuran (60ml) 20 and the reaction mixture stirred at room temperature for 48 hours. The reaction mixture was acidified to pH 6 with 2M hydrochloric acid and concentrated to low volume in vacuo. The mixture was extracted with ethyl acetate (x2) and the organics combined and washed with brine, dried (magnesium sulphate) and concentrated in vacuo to yield the title product. 25 1HNMR(CDCl 3 , 400MHz) 8: -0.21 (s, 3H), 0.01 (s, 3H), 0.80 (s, 9H), 1.09 (d, 3H), 2.54-2.61 (m, 1H), 2.84-2.98 (m, 2H), 3.15-3.20 (m, 1H), 3.52 (s, 2H), WO 2005/080324 PCT/IB2005/000112 63 4.91-4.94 (m, 1 H), 5.08 (s, 2H), 6.59 (bs, 3H), 6.90-6.93 (m, 2H), 7.04-7.17 (m, 4H), 7.35-7.42 (m, 5H), 7.49 (s, 1 H) ppm. MS (electrospray): m/z 627 [M+H]+ 5 Preparation 27 : (3-{(2R)-2-[((2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-{4 hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl) acetic acid OTBDMS H O N OH HO
H
3 0 HN s CH 3 0 0 The benzyl protected product of preparation 26 (250mg, 0.40mmol) was added 10 to a mixture of 20% Pd/C (30mg) and ammonium formate (126mg, 2.Ommol) in ethanol (15ml) and the reaction mixture heated at reflux for 3 hours. The reaction mixture was allowed to stand at room temperature for 18 hours and was then concentrated in vacuo. The residue, containing catalyst, was purified by column chromatography on silica gel eluting with 15 dichloromethane:methanol:0.880ammonia 95:5:0.5 to 90:10:1 to 80:20:5 to yield the title product. 1HNMR(CD 3 ,OD, 400MHz) 8: -0.07 (s, 3H), 0.12 (s, 3H), 0.90 (s, 9H), 1.25 (d, 3H), 2.73-2.79 (m, IH), 2.95-3.05 (m, 4H), 3.14-3.49 (m, 3H), 3.53 (s, 2HO, 5.00-5.03 (m, 1H), 6.96 (d, IH), 7.06-7.17 (m, 3H), 7.23-7.30 (m, 2H), 7.45 (m, 20 1H) ppm. MS (electrospray) : m/z 537 [M+H]*, 559 [M+Na]* Preparation 28 : Methyl (3-{2-[((2R)-2-{4-(benzyloxy)-3-[(methylsulfonyl) amino]phenyl}-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methyl 25 propyl}phenyl)acetate WO 2005/080324 PCT/IB2005/000112 64 OTBDMS H N
OCH
3
IH
3 C OH 1 0 HO 0 \ NH 3C 0 A solution of the benzyl protected alcohol of preparation 21 (36.8g, 56mmol) in ethanol (550ml) was treated with ammonium formate (16.0g, 254mmol) and 20% palladium hydroxide on carbon (1.5g). The resulting suspension heated to 5 850C for 2 hours. After 2 hours further 20% palladium hydroxide on carbon (1.0g) was added and heating continued for 1 hour. The reaction mixture was cooled to room temperature, filtered and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (500ml) and 2N aqueous ammonia (100ml). The organic phase was separated, dried (magnesium 10 sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane : methanol : 0.88 ammonia (95:5:0.5 by volume) to yield the title product as a pale yellow oil (20.6g). 'HNMR(400MHz, CDCl 3 )S: -0.17 (s, 3H), -0.05 (s, 3H), 0.80 (s, 9H), 1.07 (s, 15 3H), 1.09 (s, 3H), 2.66-2.91 (m, 7H), 3.62 (d, 2H), 3.69 (s, 3H), 4.71-4.74 (m, 1H), 6.58 (d, 1H), 6.88 (dd, 1H), 7.05-7.14 (m, 3H), 7.21-7.25 (m, 1H), 7.30 (s, 1H) ppm. MS (electrospray): m/z 565 [M+H]* 20 Preparation 29 : (3-{2-[((2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-{4-hydroxy 3-[(methylsulfonyl)amino]phe nyl}ethyl)amin o]-2-methylpropyl} phenyl)acetic acid WO 2005/080324 PCT/IB2005/000112 65 OTBDMS H3C OH H 3 C CH 3 1 0 HO HN --
CH
3 0 0 The ester of preparation 28 (20.6, 36mmol) was dissolved in tetrahydrofuran (150ml) and the solution treated dropwise with IM aqueous lithium hydroxide (72ml, 72mmol). The reaction mixture was stirred at room temperature for 72 5 hours. The reaction mixture was neutralised by addition of 1 M hydrochloric acid (72ml, 72mmol) and concentrated to low volume. The aqueous phase was decanted and the residue washed with water (2x50ml). The residue was redicolved in tetrahydrofuran (50mI) and toluene (50ml) and the solvent removed in vacuo to give the title compound as a pale brown foam (20.17g). 10 1 HNMR (400MHz, CD 3 0D): -0.14 (s, 3H), 0.07 (s, 3H), 0.83 (s, 9H), 0.91 (m, 1H), 1.32 (m, 6H), 2.93 (m, 5H), 3.23 (m, 2H), 3.54 (m, 2H), 4.94 (m, 1H), 6.91 (d, 1H), 7.03-7.16 (m, 3H), 7.26 (m, 2H), 7.60 (m, 1H). MS (APCI): m/z 551 [M+H]+ 15 Preparation 20a : [3-(2-amino-2-methyl-propyl)-phenyl]-acetic acid ethyl ester
H
2 N0
H
3 C><CH, A mixture of the aide from preparation 19 (151.4g, 534mmol), thiourea (48.7g, 20 640mmol) and acetic acid (303ml) in ethanol (1.5L) was heated to reflux under a nitrogen atmosphere for 5 hours. The reaction mixture was allowed to cool to room temperature and the suspension concentrated in vacuo. The residues were azeotroped with toluene (2 x 900mL) then treated with ethanol (1.5L) and stirred for 1 hour. The solid precipitate was removed by filtration, and the 25 filtrate cooled in an ice bath, treated with 98% sulphuric acid (227mL) and WO 2005/080324 PCT/IB2005/000112 66 stirred for 1 hour at ambient temperature. The solution was concentrated in vacuo to remove most of the ethanol and adjusted to pH9 using aqueous sodium bicarbonate. The solid precipitate was removed by filtration and washed with water (300mL) then ethyl acetate (1.OL). The layers of the 5 combined biphasic filtrate and washes were separated and the aqueous layer re-extracted with ethyl acetate (1.OL + 500mL). The combined ethyl acetate extracts were dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a brown oil (89.5g). 'H NMR (de-DMSO, 400MHz) 6: 0.99 (s, 6H), 1.16 (t, 3H), 2.59 (s, 2H), 3.61 (s, 10 2H), 4.06 (q, 2H), 7.06 (m, 3H), 7.21 (m, 1H) Preparation 20b : [3-(2-amino-2-methyl-propyl)-phenyl]-acetic acid ethyl ester, di-p-toluoyl-L-tartrate
H
3 N4- I _ 0 C~ H 3
CO
2 H C H 3 IHC 0 'No H a0 O C O 15 H c C020 A solution of the amine from preparation 20a (1 24.9g, 531 mmol) in acetonitrile (1.OL) was treated with a solution of di-p-toluoyl-L-tartaric acid (194.8g, 504mmol) in acetonitrile (750mL). The resulting slurry was stirred for 3 hours and the solid precipitate isolated by filtration and washed with acetonitrile (2 x 20 250mL) to give the title compound as an off-white solid (210g). 1 H NMR (d 6 -DMSO, 400MHz) 8: 1.13 (s, 6H), 1.17 (t, 3H), 2.34 (s, 6H), 2.78 (s, 2H), 3.63 (s, 2H), 4.06 (q, 2H), 5.61 (s, 2H), 7.02 (d, 2H), 7.15 (d, 1H), 7.25 (m, 5H), 7.80 (d, 4H) 25 Preparation 20c: [3-(2-Ami no-2-methyl-propyl)-phenyl]-acetic acid ethyl ester
H
2 N 0OCH H 3 O H I WO 2005/080324 PCT/IB2005/000112 67 A solution of potassium carbonate (37.90g, 274.22mmol) in water (213ml) was added to a suspension of preparation 20b (42.62g, 68.56mmol) in propionitrile (213ml) and stirred until all solid had dissolved. The phases were then separated and the propionitrile phase washed with water (107ml). The solution 5 was reduced in volume under reduced pressure to approximately 30ml to give the title compound as a propionitrile solution. A sample was removed and concentrated to dryness to obtain a weight weight assay and yield was shown to be 81%. 1 H NMR (d 6 -DMSO, 400MHz) 8: 0.99 (s, 6H), 1.16 (t, 3H), 2.59 (s, 2H), 3.61 (s, 10 2H), 4.06 (q, 2H), 7.06 (m, 3H), 7.21 (m, 1H) Preparation 21a : Ethyl (3-(2-[((2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-{4-benzyloxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl} 15 phenyl)acetate OTBDMS H N cO 2 Et O NHSO 2 Me N-[2-(benzyloxy)-5-((1 R)-2-bromo-1 -{[tert-butyl(dimethyl) silyl]oxy}ethyl)phenyll methanesulfonamide (14.34g, 27.88mmol) was added to the solution of 20 preparation 20c (13.12g, 55.75mmol) in propionitrile (15ml). The mixture was then heated at reflux for 3 days. The solution was diluted with propionitrile (55ml) and cooled to 20-250C. The solution was washed with I M HCI(aq) (70ml) then water (35ml) and the solution carried directly into the next step assuming 100% yield. 25 WO 2005/080324 PCT/IB2005/000112 68 Preparation 28a: Ethyl (R)-2-(3-{2-[2-hydroxy-2-(4-benzyloxy-3-methanesulfonamidophenyl) ethylamino] -2-methyl propyl}phenyl)acetate OH H N CO 2 Et oI NHSO 2 Me 5 Triethylamine trihydrofluoride (9.1ml, 8.99g, 55.76mmol) was added to the solution of preparation 21a (18.64g, 27.88mmol) in propionitrile (72ml). The solution was stirred at 20-25*C for 3 hours. The solution was then quenched with 5M NH3(aq) (72ml) stirred for 10 minutes and the phases separated. The 10 propionitrile solution was then washed with water (72ml) and the solution carried directly into the next step assuming 100% yield. Preparation 29a: (R)-2-(3-{2-[2-hydroxy-2-(4-benzyloxy-3-methanesulfonamidophenyl) 15 ethylamino]-2-methylpropyl}phenyl)acetic acid OH H NCO 2H
NHSO
2 Me A solution of sodium hydroxide (6.69g, 167.28mmol) in water (72ml) was added to the solution of preparation 28a (15.47g, 27.88mmol) in propionitrile (72ml). 20 The two phase mixture was then stirred vigorously for 3 hours. The phases were allowed to separate and the aqueous phase washed with fresh propionitrile (72m[), then diluted with 1,4-dioxane (72ml). The pH of the solution was then adjusted to pH 6-7 by the addition of 37% w/w HCI(aq) and the resulting suspension was stirred for one hour. The suspension was then WO 2005/080324 PCT/IB2005/000112 69 filtered and washed on the filter paper with water then dried giving the title compound as an off white solid (13.55g, 92% over 3 steps). 1 HNMR(400MHz, CD 3 0D) 8 : 1.33 (s, 3H), 1.35 (s, 3H), 2.89 (s, 3H), 2.96 (s, 2H), 3.06-3.19 (m, 2H), 3.50 (s, 2H), 4.50 (m, 1H), 5.22 (s, 2H), 7.08 (d, IH), 5 7.13 (d, 1H), 7.19 (s, 1H), 7.24 (t, 2H), 7.27 (d, IH), 7.31 (d, 1H), 7.38 (t, 2H), 7.48 (d, 2H), 7.49 (s, 1H) ppm. Preparation 29b: (R)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-methanesulfonamidophenyl) 10 ethylamino]-2-methylpropyl}phenyl)acetic acid sodium salt OH H HON OCo-Na+ HO9)
NHSO
2 Me A solution of sodium hydroxide (1.40g, 35.05mmol) in water (1 00ml) was added to a suspension of preparation 29a (18.46g, 35.05mmol) in methanol (600ml). 15 The mixture was hydrogenated over 20wt% Palladium hydroxide on carbon at 150psi and 60 0 C for 5 hours. The mixture was filtered to remove catalyst residues and then reduced in volume at reduced pressure to 100ml. The mixture was distilled and replaced at reduced pressure to acetonitrile at constant volume. The resulting suspension was filtered and washed on the 20 paper with acetonitrile then dried to provide the title compound as an off white solid (15.34g, 95%). 'HNMR(400MHz, CD 3 0D) 8 : 1.07 (s, 3H), 1.09 (s, 3H), 2.70 (s, 2H), 2.73-2.81 (m, 2H), 2.87 (s, 3H), 3.44 (s, 2H), 4.60-4.63 (m, 1H), 6.84 (d, 1H), 6.92 (d, 1H), 7.04 (d, 1H), 7.11 (s, IH), 7.14 (d, 1H), 7.15 (t, IH), 7.34 (s, IH) 25 ppm. Said compounds of formula 29b can then be reacted with a suitable amine of formula NHR8-0 2 -A (3) WO 2005/080324 PCT/IB2005/000112 70
R
3 R3 R4R84
R
8 R N
(CH
2 )p / R 5 H :3 -7R 5 HNC
R
6 (3'), or
R
6 (3') in the presence of a conventional coupling agent such as 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent such as pyridine, 5 dimethylformamide or dimethylacetamide. in order to obtain a compound of formula (1): OH H N HO I (CH2)n Q1 (1) HO ' R1 R2
NHSO
2
CH
3 0 wherein R' and R 2 are methyl and n is 1. 10 Preparations 30 - 106 The appropriate carboxylic acid from preparation 23, 25, 27 or 29 (0.15mmol) was dissolved in a solution of 1-hydroxybenzotriazole hydrate (22mg, 15 0.1 6mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34mg, 0.18mmol) and N-ethyldiisopropylamine (130pL, 0.73mmol) in N,N dimethylformamide (2ml). The solution was treated with the appropriate amine (0.23mmol) and the reaction mixture shaken at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned 20 between dichloromethane (3ml) and water (1ml). The phases were separated and the organic layer washed with brine (1ml), dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on WO 2005/080324 PCT/IB2005/000112 71 silica gel eluting with dichloromethane:methano:0.88 ammonia 98:2:0 to 96:4:0.5 to 94:6:0.5 to yield the desired product. Altenatively, the following process can be used for the synthesis of preparations 5 30 to 106: A solution of the appropriate acid from preparation 23, 25, 27 or 29 (36mmol) in N,N-dimethylformamide (200ml) is treated with 1-hydroxybenzotriazole hydrate (5.26g, 39mmol), the appropriate amine (43mmol) and 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.5g, 39mmol). The 10 resulting suspension is left to stir at room temperature for 18 hours. The solvent is removed in vacuo and the residue partitioned between dichloromethane (400ml) and water (100ml). The organic phase is separated, washed with saturated aqueous sodium chloride (100ml), dried (magnesium sulfate) and the solvent removed in vacuo. The residue is purified by column 15 chromatography on silica gel eluting with dichloromethane : methanol : ethyl acetate : 0.88 ammonia (95:5:0:0.5 changing to 0:5:95:0) by volume) to yield the desired product.
WO 2005/080324 PCT/IB2005/000112 72 Preparations 30 to 65 OTBDMS H
H
3 0H 3 x 0 HN H O// CH No Q Data 30 'HNMR (CDCl 3 , 400MHz) 6: -0.17 (s, 3H), 0.06 (s, 3H), 0.79 (s, 9H), 1.07 (m, 6H), 2.63-2.87 (m, 7H), 3.61 (m, 2H), 4.42 (m, 2H), 4.73 (m, 1H), 6.21 (m, 1H), 6.63 (m, 1H), 6.86 (d, IH), 7.03-7.28 (m, 9H), 7.35 (m, 1H) ppm. MS (electrospray) m/z 640 [M+H]* 31 'HNMR (CDCl 3 , 400MHz) 8: -0.17 (s, 3H), 0.05 (s, 3H), 0.80 (s, 9H), 1.07 (m, 6H), 2.62-2.88 (m, 7H), 3.56 (q, 2H), 3.75 (s, H CH3H), 4.33 (m, 2H), 4.71 (m, 1H), 6.11 (m, 0 1H), 6.67 (m, 1H), 6.81 (m, 2H), 6.88 (m, 1H), 7.02-7.14 (m, 5H), 7.22 (m, IH), 7.36 (m, 1H) ppm. MS (electrospray) m/z 670 [M+H]* WO 2005/080324 PCT/IB2005/000112 73 32 1 HNMR (CDC 3 , 400MHz) 8: -0.17 (s, 3H), 0.05 (s, 3H), 0.80 (s, 9H), 1.07 (m, 6H), 2.62-2.88 (m, 7H), 3.56 (q, 2H), 3.75 (s, 3H), 4.33 (m, 2H), 4.71 (m, IH), 6.11 (m, H IH), 6.67 (m, 1H), 6.81 (m, 2H), 6.88 (m, IH), 7.02-7.14 (m, 5H), 7.22 (m, 1H), 7.36 (m, IH) ppm. MS (electrospray) m/z 670 [M+H]f 33 'HNMR (CDCl 3 , 400MHz) 8: -0.16 (s, 3H), 0.03 (s, 3H), 0.82 (s, 9H), 1.01 (s, 3H), 1.04 (s, 3H), 1.22 (t, 3H), 2.65 (m, 2H), 2.71-2.90 (m 5H), 3.50 (m, 2H), 3.91 (q, 2H), 4.41 (d, H 2H), 4.68 (m, 1H), 6.20 (m, IH), 6.72-6.93 (m, 5H), 7.06 (m, 2H), 7.16 (m, 3H), 7.36 (m, IH) ppm. MS (APCI) m/z 684 [M+H]* 34 -THNMR (CDCla, 400MHz) 8: -0.17 (s, 3H), 0.05 (s, 3H), 0.80 (s, 9H), 1.07 (m, 6H), CH, 2.62-2.88 (m, 7H), 3.56 (q, 2H), 3.75 (s, N 3H), 4.33 (m, 2H), 4.71 (m, 1H), 6.22 (m, IH), 6.61 (m, 1H), 6.77 (m, 3H), 6.83 (m, IH), 7.07 (m, 2H), 7.18 (m, 3H), 7.34 (m, 1H) ppm. MS (electrospray) m/z 670 [M+H]* 35 1 HNMR (CDClq, 400MHz) 5: -0.17 (s, 3H), 0.05 (s, 3H), 0.80 (s, 9H), 1.04 (s, 3H), 1.07 (s, 3H), 2.10 (s, 3H), 2.62-2.88 (m, 7H), 2.60 (m, 2H), 4.38 (m, 2H), 4.71 (m, IH), CHa 6,13 (m, 1H), 6.64 (m, 1H), 6.86 (d, IH), 7.01-7.17 (m, 7H), 7.26 (m, IH), 7.35 (m, 1 H) MS (APCI) m/z 654 [M+H]* WO 2005/080324 PCT/IB2005/000112 74 36 'HNMR (CDC13, 400MHz) 8: -0.17 (s, 3H), 0.05 (s, 3H), 0.80 (s, 9H), 1.04 (s, 3H), 1.07 CH (s, 3H), 2.10 (s, 3H), 2.62-2.88 (m, 7H), 2.60 (m, 2H), 4.38 (m, 2H), 4.71 (m, 1H), H 5.93 (m, IH), 6.62 (d, IH), 6.86 (m, IH), 7.01-7.17 (m, 7H), 7.24 (m, IH), 7.33 (m, 1H) ppm. MS (APCI) m/z 654 [M+H]* 37 'HNMR (CDCl 3 , 400MHz) 6: -0.17 (s, 3H), 0.05 (s, 3H), 0.80 (s, 9H), 1.04 (s, 3H), 1.07 (s, 3H), 2.10 (s, 3H), 2.62-2.88 (m, 7H),
CH
3 (n N C2.60 (m, 2H), 4.38 (m, 2H), 4.71 (m, .IH), H 6.13 (m, IH), 6.62 (m, 1H), 6.84 (m, 1H), 7.00 (m, 2H), 7.07 (m, 3H), 7.16 (m, 2H), 7.23 (m, IH), 7.35 (m, 1H) ppm. MS (APCI) m/z 654 [M+H] 38 7HNMR (CDCl 3 , 400MHz) 3: -0.17 (s, 3H), 0.06 (s, 3H), 0.77 (s, 9H), 1.04 (s, 3H), 1.08 CHq (s, 3H), 2.64-2.87 (m, 7H), 3.60 (m, 2H), 3.72 (s, 6H), 4.35 (m, 2H), 4.67 (m, 1H), o 6.12 (m, IH), 6.62 (m, IH), 6.73 (m, 3H),
CH
3 6.82 (m, 1H), 7.07 (m, 2H), 7.14 (m, 1H), 7.22 (m, 1H), 7.34 (m, 1H) ppm. MS (APCI) m/z 700 [M+H]* 39 'HNMR (CDC13, 400MHz) 8: -0.17 (s, 3H), 0.06 (s, 3H), 0.77 (s, 9H), 1.04 (s, 3H), 1.08 O "CH (s, 3H), 2.64-2.87 (m, 7H), 3.60 (m, 2H), 3.72 (s, 6H), 4.35 (m, 2H), 4.67 (m, IH), 6.11 (m, 1H), 6.38 (m, 2H), 6.73 (m, 1H), cH 3 6.91 (m, 2H), 7.05 (m, 3H), 7.21 (m, 1H), 7.36 (m, 1 H) ppm. MS (APCI) m/z 700 [M+H]* WO 2005/080324 PCT/IB2005/000112 75 40 1 HNMR (CDCl 3 , 400MHz) 8: -0.17 (s, 3H), 0.06 (s, 3H), 0.77 (s, 9H), 1.04 (s, 3H), 1.07
CH
3 2.428 7H, (n H2 (s, 3H), 2.64-2.87 (m, 7H), 3.60 (m, 2H), C-q1 3.72 (s, 6H), 4.35 (m, 2H), 4.67 (m, IH), 6.16 (m, IH), 6.29 (m, 3H), 6.62 (d, 1H), HC-0 6.83 (m, 1H), 7.05 (m, 2H), 7.13 (m, 1H), 7.22 (m, 2H), 7.33 (m, IH) ppm. MS (APCI) m/z 700 [M+H]* 41 'HNMR (CDCl1, 400MHz) 6: -0.19 (s, 3H), 0.11 (s, 3H), 0.74 (s, 9H), 1.04 (s, 3H), 1.07 N (s, 3H), 2.61-2.86 (m, 7H), 3.60 (m, 2H), ci 4.36 (m, 2H), 4.72 (m, IH), 6.30 (m, 1H), 6.55 (d, IH), 6.81 (d, IH), 7.06-7.36 (m, 9H) MS (APCI) m/z 674 [M+H]* 42 'HNMR (CDCl 3 , 400MHz) 5: -0.19 (s, 3H), ci 0.11 (s, 3H), 0.74 (s, 9H), 1.04 (s, 3H), 1.07 N (s, 3H), 2.61-2.86 (m, 7H), 3.60 (m, 2H), H 4.36 (m, 2H), 4.72 (m, 1H), 6.29 (m, IH), 6.60 (d, IH), 6.84 (d, IH), 7.02-7.36 (m, 9H) MS (APCI) m/z 674 [M+H]+ 43 1 HNMR (CDCl 3 , 400MHz) 6: -0.19 (s, 3H), 0.11 (s, 3H), 0.74 (s, 9H), 1.04 (s, 3H), 1.07 c (s, 3H), 2.61-2.86 (m, 7H), 3.60 (m, 2H), 4.36 (m, 2H), 4.72 (ni, IH), 6.45 (m, 2H), 7.76 (d, 1H), 7.08-7.33 (m, 9H) MS (APCI) m/z 674 [M+H]* WO 2005/080324 PCT/IB2005/000112 76 44 "HNMR (CDCl 3 , 400MHz) 5: -0.20 (s, 3H), 0.11 (s, 3H), 0.74 (s, 9H), 1.04 (s, 3H), 1.07 (s, 3H), 2.61-2.86 (m, 7H), 3.60 (m, 2H), N 4.36 (m, 2H), 4.72 (m, IH), 6.35 (m, 1H), 6.48 (m, 1H), 6.78 (d, IH), 6.93 (t, 2H), 7.08 (m, 2H), 7.17 (m, 3H), 7.25 (m, IH), 7.32 (m, IH) MS (APCI) m/z 658 [M+H]* 45 HNMR (CDCI 3 , 400MHz) 6: -0.18 (s, 3H), 0.10 (s, 3H), 0.73 (s, 9H), 1.04 (s, 3H), 1.07 ( N' (s, 3H), 2.59-2.86 (m, 7H), 3.59 (m, 2H), H 4.33 (m, 2H), 4.68 (m, IH), 6.48 (m, 2H), 6.78 (d, 1H), 7.05-7.38 (m, 7H) MS (electrospray) m/z 708 [M+H]+ 46 1 HNMR (CDC 3 , 400MHz) 5: -0.18 (s, 3H), 0.10 (s, 3H), 0.73 (s, 9H), 1.04 (s, 3H), 1.07 N C1 (s, 3H), 2.59-2.86 (m, 7H), 3.59 (m, 2H), Ci 4.33 (m, 2H), 4.68 (m, I H), 6.54 (m, 2H), 6.79 (m, 1H), 7.00-7.41 (m, 7H) MS (electrospray) m/z 708 [M+H]f 4HNMR (CDCIs, 400MHz) 8: -0.25 (s, 3H), 0.10 (s, 3H), 0.72 (s, 9H), 0.92 (s, 3H), 0.95 H C(s, 3H), 1.21 (s, 9H), 2.56-2.82 (m, 7H),
OH
3 3.18 (m, 2H), 4.26 (m, 2H), 4.58 (m, 1H),
OH
3 6.72 (d, 1H), 6.85-7.29 (m, 10H) MS (electrospray) m/z 696 [M+H]* WO 2005/080324 PCT/IB2005/000112 77 48 1 HNMR (CD 3 0D, 400MHz) 5: -0.17 (s, 3H), 0.00 (s, 3H), 0.82 (s, 9H), 1.04 (s, 3H), 1.06 ci (s, 3H), 2.63-2.72 (m, 3H), 2.86 (m, 4H), Nfl 3.48 (s, 2H), 4.54 (s, 2H), 4.69 (m, 1H), F 6.84 (d, IH), 7.00-7.35 (m, 8H), 7.38 (d, IH) ppm. MS (electrospray) mlz 690 [M-H]~ 49 'HNMR (CD 3 OD, 400MHz) 8: -0.18 (s, 3H), 0.00 (s, 3H), 0.78 (s, 9H), 1.04 (s, 3H), 1.07 (s, 3H), 2.16 (s, 3H), 2.24 (s, 3H), 2.60-2.78 H (m, 3H), 3.86 (m, 4H), 3.53 (s, 2H), 4.35 (s, Hc | 2H), 4.71 (m, IH), 6.83 (d, IH), 7.08 (m, CH3 5H), 7.11 (m, 1H), 7.17 (m, 2H), 7.37 (s, 1H) ppm. MS (electrospray) m/z 668 [M+H]+ 50 'HNMR (CD3OD, 400MHz) 6: -0.17 (s, 3H), 0.00 (s, 3H), 0.90 (s, 9H), 1.05 (s, 3H), 1.07 (sN (s, 3H), 2.64-2.74 (m, 3H), 2.91 (m, 4H), 3.54 (s, 2H), 4.32 (s, 2H), 4.58 (m, IH), c 6.85 (d, IH), 7.04 (m, 2H), 7.08 (s, 1H), 7.15 (s, 3H), 7.22 (m, 1H), 7.26 (m, IH), 7.36 (m, IH) 51 'HNMR (CD 3 0D, 400MHz) 6: -0.17 (s, 3H), 0.00 (s, 3H), 0.81 (s, 9H), 1.04 (s, 3H), 1.07 F F (s, 3H), 2.63-2.74 (m, 3H), 2.88 (m, 4H), N F F 3.55 (s, 2H), 4.50 (s, 2H), 4.68 (m, 1H), 6.84 (d, IH), 7.02 (m, 2H), 7.10 (m, IH), F F 7.17-7.22 (m, 2H), 7.36 (s, IH), 7.79 (m, F 3H) MS (electrospray) m/z 774 [M-H]~ WO 2005/080324 PCT/IB2005/000112 78 52 1 HNMR (CD 3 0D, 400MHz) 8: -0.13 (s, 3H), 0.04 (s, 3H), 0.85 (s, 9H), 1.07 (s, 3H), 1.09 (s, 3H), 2.18-2.30 (m, 7H), 2.65-2.75 (m,
CH
3 3H), 2.89 (s, 3H), 3.55 (s, 2H), 4.31 (s, 2H),
CH
3 4.71-4.74 (m, IH), 6.90 (d, 1H), 6.96-7.08 (m, 5H), 7.14 (s, 1H), 7.19-7.26 (m, 2H), 7.42 (s, 1H) MS (electrospray) m/z 668 [M+H]*, 666 [M H]~ 53 1 HNMR (CD 3 0D, 400MHz) 6: -0.13 (s, 3H), 0.04 (s, 3H), 0.85 (s, 9H), 1.10 (s, 3H), 1.12 (s, 3H), 2.70-2.79 (m, 4H), 2.92 (s, 3H), N C1 3.61 (s, 2H), 4.45 (s, 2H), 4.74-4.77 (m, Ha ci 1H), 6.91 (d, 1H), 7.07-7.10 (m, 2H), 7.18 (s, IH), 7.22-7.29 (m, 4H), 7.37 (d, 1H), 7.43 (s, 1H). MS (electrospray) m/z 708 [M+H]+ 54 'HNMR (400MHz, CD 3 OD) 5 : -0.13 (s, 3H), 0.04 (s, 3H), 0.85 (s, 9H), 1.12 (s, 3H), 1.14 (s, 3H), 2.70-2.82 (m, 5H), 2.92-2.95 (m, 4H), 3.44 (t, 2H), 3.48 (s, 2H), 4.74-4.77 (m, H 1H), 6.90 (d, IH), 7.06-7.10 (m, 3H), 7.14 7.21 (m, 3H), 7.22-7.23 (m, 1H), 7.25-7.29 (m, 3H), 7.42 (d, 1H) ppm. MS (electrospray) m/z 654 [M+H] + WO 2005/080324 PCT/IB2005/000112 79 55 'HNMR (CD 3 0D, 400MHz) 5: -0.14 (s, 3H), 0.03 (s, 3H), 0.84 (s, 9H), 1.09 (s, 3H), 1.11 (s, 3H), 1.78-1.86 (m, 2H), 2.60-2.64 (m, N 2H), 2.66-2.78 (m, 4H), 2.91 (s, 3H), 3.23 (t, 2H), 3.51 (s, 2H), 4.71-4.74 (m, 1h), 6.90 (d, 1H), 7.05-7.08 (m, 2H), 7.16-7.20 (m, 4H), 7.22-7.29 (m, 4H), 7.41 (d, I H) ppm. MS (electrospray) m/z 668 [M+H]+ 56 HNMR (400MHz, CD 3 0D) S : -0.12 (s, 3H), 0.05 (s, 3H), 0.86 (s, 9H), 1.09 (s, 3H), 1.12 (s, 3H), 2.68-2.78 (m, 3H), 2.88-2.93 (m, H j4H), 3.60 (s, 2H), 4.51 (s, 2H), 4.71-4.74 ',N CI (m, 1H), 6.88 (d, IH), 7.05-7.08 (m, 2H), 7.14 (dd, 1H), 7.20-7.25 (m, 4H), 7.40 (s, 1H), 7.45-7.47 (m, 1H) ppm. MS (electrospray) m/z 708/710 [M+H]+ 57 |HNMR (400MHz, CD 3 0D) S : -0.14 (s, 3H), 0.04 (s, 3H), 0.85 (s, 9H), 1.07 (s, 3H), 1.09 ci (s, 3H), 2.39 (s, 3H), 2.66-2.76 (m, 3H), H 2.88-2.95 (m, 4H), 3.52 (s, 2H), 4.54 (s, yN 2H), 4.71-4.74 (m, 1H), 6.89 (d, 1H), 7.05 cl 7.12 (m, 3H), 7.16-7.25 (m, 3H), 7.35 (dd, 1H), 7.41 (dd, 1H) ppm. MS (electrospray) m/z 720/722 [M-H][ WO 2005/080324 PCT/IB2005/000112 80 5HNMR (400MHZ, CD 3 0D) 8: -0.13 (s, 3H), 0.04 (s, 3H), 0.85 (s, 9H), 0.89-0.99 (m, 2H), 1.10 (s, 3H), 1.13 (s, 3H), 1.21-1.30 (m, 3H), 1.45-1.52 (m, IH), 1.66-1.78 (m, H 5H), 2.68-2.78 (m, 3H), 2.89-2.94 (m, 4H), 3.04-3.06 (m, 2H), 3.51 (s, 2H), 4.71-4.75 (m, 1H), 6.89 (d, 1H), 7.07 (dd, 2H), 7.14 7.27 (m, 3H), 7.41 (d, 1H) ppm. MS (electrospray) m/z 646 [M+H]* 59 --- HNMR (400MHz, CD 3 OD) 6: -0.13 (s, 3H), 0.04 (s, 3H), 0.85 (s, 9H), 1.07 (s, 3H), 1.09 (s, 3H), 2.39 (s, 3H), 2.66-2.76 (m, 3H), H 2.87-2.92 (m, 4H), 3.52 (s, 2H), 4.58 (s, N 2H), 4.71-4.74 (m, 1H), 6.89 (d, IH), 7.05 Cl 7.08 (m, 2H), 7.11-7.13 (m,, 1H), 7.16-7.31 (m, 5H), 7.40 (m, 1H) ppm. MS (electrospray) m/z 688/690 [M+H]+ 60 "HNMR (CD 3 0D, 400 MHz) 5: -0.18 (3H, s), -0.01 (3H, s), 0.80 (9H, s), 1.04 (3H, s), H 1.06 (3H, s), 2.44 (3H, s), 2.63-2.71 (3H, N im), 2.86 (4H, s, m), 3.53 (2H, s), 4.42 (2H, HC s), 4.67-4.70 (1H, m), 6.88 (1H, d), 7.01 7.32 (9H, m), 7.36 (1H, d). MS (electrospray) m/z 684 [M-H][ 61 'HNMR (CD 3 0D, 400 MHz) 8: -0.18 (3H, s), -0.01 (3H, s), 0.80 (9H, s), 1.05 (3H, s), 1.08 (3H, s), 2.43 (3H, s), 2.62-2.72 (3H, H CH), 2.86 (4H, s, m), 3.51 (2H, s), 4.30 (2H, N s), 4.67-4.70 (1H, m), 6.84 (1H, d), 7.01 7.04 (2H, m), 7.08 (IH, bs), 7.14-7.22 (6H, m), 7.36 (1H, d). MS (electrospray) m/z 684 [M-H]^ WO 2005/080324 PCT/IB2005/000112 81 62 'HNMR(400MHz, CDC13) 5: 0.00 (s, 3H), 0.13 (s, 3H), 0.95 (s, 9H), 1.27 (s, 3H), 1.29 (s, 3H), 1.61-1.70 (m, 3H), 2.29-2.33 (m, H 3H), 2.73-3.06 (m, 9H), 3.08 (s, 3H), 3.68 N 3.69 (d, 2H), 3.92-3.99 (m, 1H), 4.91-4.94 S (m, IH), 5.92 (d, 1H), 6.87 (d, 1H), 7.06 (d, IH), 7.20 (s, 1H), 7.25 (d, IH), 7.31 (d, 1H), 7.41-7.45 (m, IH), 7.52 (s, 1H) ppm. MS (APCI) m/z 650 [M+H]* 63 1 HNMR(400MHz, CD30D) 5: -0.18 (s, 3H), 0.00 (s, 3H), 0.81 (s, 9H), 1.05 (s, 3H), 1.08 H I(s, 3H), 2.62-2.75 (m, 4H), 2.84 (s, 3H), IN 3.44 (s, 2H), 4.25 (s, 2H), 4.66-4.70 (m, 1 H), 6.83 (d, 1H), 7.02-7.39 (m, 15H) ppm. MS (electrospray) m/z 716 [M+H]*, 738 [M+Na]* 64 1 HNMR(400MHz, CD30D) 6 : -0.15 (s, 3H), 0.02 (s, 3H), 0.83 (s, 9H), 1.04 (s, 3H), 1.06 (s, 3H), 2.24 (s, 3H), 2.26 (s, 6H), 2.62-2.73
H
3 C CH 3 (m, 3H), 2.85-3.03 (m, 4H), 3.48 (s, 2H), H,:H I4.36 (s, 2H), 4.69-4.71 (m, 1H), 6.85-6.87
CH
3 (m, 3H), 7.02-7.04 (m, 2H), 7.10 (m, 1H), 7.15-7.22 (m, 2H), 7.38-7.39 (m, 1H) ppm. MS (electrospray) mlz 682 [M+H], 704 [M+Na]+ WO 2005/080324 PCT/IB2005/000112 82 65 'HNMR(400MHz, CD 3 0D) 8: -0.13 (s, 3H), 0.04 (s, 3H), 0.85 (s, 9H), 1.10 (s, 3H), 1.11 (s, 3H), 2.68-2.93 (m, 7H), 3.59 (s, 2H), 4.47 (s, 2H), 4.72-7.75 (dd, I H), 6.90 (d, H ~N _"(:. F IH), 7.09-7.06 (m, 2H), 7.15-7.16 (m, 1H), ( F F 7.20-7.27 (m, 2H), 7.41-7.42 (d, IH), 7.51 7.57 (m, 4H) ppm. MS (electrospray) m/z 708 [M+H]*, 730 [M+Na]* Preparations 66 to 94 OTBDMS H Q1 HOH N HOC C HN~ '-O/ 0 //SCH 3 No Q' Data 66 { 'HNMR (CDC6, 400MHz) 5: -0.17 (s, 3H), 0.03 (s, 3H), 0.81 (s, 9H), 1.00 (t, 3H), 1.25 CH3 (s, 3H), 2.52-2.88 (m, 8H), 3.51 (m, 2H), 3.94 (q, 2H), 4.43 (m, 2H), 4.67 (m, 1H), 6.26 (m, IH), 6.60 (d, IH), 6.77-6.88 (m, 4H), 7.01 (m, 1H), 7.05 (m, 1H), 7.22 (m, 4H) ppm. MS (electrospray) m/z 670 [M+H]* WO 2005/080324 PCT/IB2005/000112 83 67 (N HNMR (CDC 3 , 400MHz) 8: -0.16 (s, 3H), H CH0.09 (s, 3H), 0.80 (s, 9H), 1.07 (m, 3H), CHa 2.19 (m, 6H), 2.62 (m, 2H), 2.84 (m, 6H), 3.57 (m, 2H), 4.36 (m, 2H), 4.67 (m, 1H), 6.16 -(m, 1H), 6.29 (d, 1H), 6.92-7.27 (m, 8H) ppm. MS (electrospray) m/z 654 [M+H]* 68HNMR (CDCl, 400MHz) 8: -0.19 (s, 3H), HCl 0.15 (s, 3H), 0.73 (s, 9H), 1.11 (m, 3H), c1 2.60-2.89 (m, 8H), 4.41 (m, 2H), 4.70 (m, IH), 6.28 (d, 1H), 6.40 (m, IH), 6.78 (m, 1H), 7.02-7.33 (m, 8H) MS (APCI) m/z 694 [M+H]* 6HNMR (CDC 3 , 400MHz) 5: -0.17 (s, 3H), 0.06 (s, 3H), 0.77 (s, 9H), 1.10 (m, 3H), H 1.81 (m, 2H), 2.62 (m, 5H), 2.87 (m, 5H), 3.29 (m, 2H), 3.54 (q, 2H), 4.68 (m, 1H), 5.93 (m, 1H), 6.42 (d, 1H), 6.73 (m, 1H), 6.97-7.26 (m, 10H) MS (electrospray) m/z 654 [M+H]+ 70 'HNMR (CD 3 0D, 400MHz) 5: -0.18 (s, 3H), H -0.02 (s, 3H), 0.83 (s, 9H), 0.88 (m, 2H), 1.05 (m, 3H), 1.17 (m, 3H), 1.42 (m, IH), 1.67 (m, 5H), 2.53 (m, IH), 2.68 (m, 2H), 2.87 (m, 5H), 2.97 (m, 2H), 3.46 (m, 2H), 4.66 (m, IH), 6.80 (d, 1H), 6.97 (m, 2H), 7.08 (m, 1H), 7.14 (m, 2H), 7.30 (s, IH) ppm. MS (electrospray) m/z 630 [M-H]~ WO 2005/080324 PCT/IB2005/000112 84 71 cI HNMR (CD 3 OD, 400MHz) 8: -0.17 (s, 3H), N H 0.01 (s, 3H), 0.84 (s, 9H), 1.01 (d, 3H), 2.51 F (iI H), 2.66 (in, 2H), 2.87 (in, 5H), 3.46 (i,2H), 4.53 (s, 2H), 4.67 (in, 1H), 6.80 (d, 1H), 6.95 (in, 2H), 7.01-7.15 (mn, 4H), 7.22 7.31 (in, 3H) MS (electros pray) m/z 676 [M-H] 72 cI HNMR (CD 3 OD, 400MHz) 8: -0.17 (s, 3H), N 0.01 (s, 3H), 0.84 (s, 9H), 1.01 (d, 3H), 2.51 H (m, IH), 2.66 (m, 2H), 2.87 (m, 5H), 3.46 (m, 2H), 4.53 (s, 2H), 4.67 (m, 1H), 6.80 (d, IH), 6.99 (m, 3H), 7.06 (m, 4H), 7.15 (i, 3H), 7.28 (m, 2H) MS (electrospray) m/z 676 [M-H]~ 7 CI 1 HNMR (CD 3 0D, 400MHz) 6: -0.16 (s, 3H), 0.01 (s, 3H), 0.84 (s, 9H), 1.00 (d, 3H), 2.51 ci (m, IH), 2.67 (m, 2H), 2.87 (m, 5H), 3.44 (m, 2H), 4.53 (s, 2H), 4.67 (m, 1H), 6.81 (d, IH), 6.93 (d, IH), 6.97 (m, IH), 7.02 (m, 3H), 7.14 (m, 4H), 7.26 (m, IH), 7.32 (m, 1H) ppm. MS (electrospray) m/z 694 [M+H] 74 7HNMR (CD 3 OD, 400MHz) 6: -0.18 (s, 3H), F 0.01 (s, 3H), 0.84 (s, 9H), 1.03 (d, 3H), 2.51 F n(m, IH), 2.67 (m, 2H), 2.85 (m, 5H), 3.44 (m, 2H), 4.53 (s, 2H), 4.67 (m, 1H), 6.80 (d, 1H), 6.94 (d, 1H), 7.00 (d, 1H), 7.08 (m, 1H), 7.17 (m, 2H), 7.31 (m, IH), 7.41 (d, 2H), 7.59 (d, 2H) MS (electrospray) m/z 692 [M-H]* WO 2005/080324 PCT/IB2005/000112 85 75 f-,N :zzci 'HNMR (CD 3 OD, 400MHz) 8: -0.16 (s, 3H), H 4 0.01 (s, 3H), 0.84 (s, 9H), 1.00 (d, 3H), 2.51 cI (in, 1IH), 2.67 (in, 2H), 2.87 (in, 5H), 3.44 (in, 2H), 4.53 (s, 2H), 4.67 (in, 1H), 6.81 (d, 1H), 6.93 (d, 1IH), 6.97 (in, I H), 7.02 (mn, 1 H), 7.14 (in, 4H), 7.31 (in, 2H) ppm. MS (electrospray) mlz 692 [M-Hr 76 F F 'HNMR (CD 3 OD, 400MHz) 8: -0.16 (s, 3H), F N 0.01 (s, 3H), 0.84 (s, 9H), 1.00 (d, 3H), 2.51 H (in, I H), 2.67 (mn, 2H), 2.87 (mn, 5H), 3.44 F (mn, 2H), 4.53 (s, 2H), 4.67 (mn, 1H), 6.79 (d, I H), 6.93 (d, 1 H), 7.00 (d, I H), 7.08 (mn, IH), 7.13 (mn, 2H), 7.26 (in, 2H), 7.44 (mn, 2H) ppm. MS (electrospray) mlz 710 [M-HI[ 77 N 'HNMR (CDOD, 400MHz) 5:-.6(s, 3H), H F 0.01 (s, 3H), 0.84 (s, 9H), 1.00 (d, 3H), 2.51 F F (m, 1H), 2.67 (m, 2H), 2.87 (m, 5H), 3.44 (m, 2H), 4.53 (s, 2H), 4.67 (m, 1H), 6.79 (d, 1H), 6.92 (d, IH), 7.00 (d, 1H), 7.04 (m, 1H), 7.13 (m, H), 7.20 (m, 2H), 7.31 (m, I H), 7.53 (mn, 2H) MS (electrospray) m/z 710 [M-H] 78 F 1 HNMR (CD 3 0D, 400MHz) 3: -0.16 (s, 3H), F F 0.01 (s, 3H), 0.84 (s, 9H), 1.00 (d, 3H), 2.51 F (m, 1H), 2.67 (m, 2H), 2.87 (m, 5H), 3.44 (m, 2H), 4.53 (s, 2H), 4.67 (m, 1H), 6.80 (d, 1H), 6.93 (d, IH), 7.00 (d, IH), 7.05 (d, 1H), 7.16-7.25 (m, 3H), 7.30 (m, IH), 7.56 (m, 2H) MS (electrospray) m/z 710 [M-H]- WO 2005/080324 PCT/IB2005/000112 86 9CH 3 HNMR (CD 3 0D, 400MHz) a: -0.18 (s, 3H), 0.00 (s, 3H), 0.79 (s, 9H), 1.00 (d, 3H), 2.27 ci ci (s, 3H), 2.54 (m, IH), 2.62 (m, 2H), 2.88 (m, 5H), 3.65 (m, 2H), 4.48 (s, 2H), 4.67 (m, 1H), 6.81 (d, 1H), 6.94 (m, 2H), 7.01 (m, 1H), 7.10 (d, 1H), 7.13 (m, 2H), 7.31 (m, 2H) ppm. MS (electrospray) m/z 706 [M-H]r 80 F 'HNMR (CD 3 OD, 400MHz) 8: -0.18 (s, 3H), F 0.00 (s, 3H), 0.84 (s, 9H), 1.04 (d, 3H), 2.57 H F ci (m, 1H), 2.66 (m, 2H), 2.88 (m, 5H), 3.01 (m, IH), 3.53 (s, 2H), 4.40 (s, 2H), 4.68 (m, 1H), 6.80 (d, 1H), 6.93 (d, IH), 7.00 (d, IH), 7.06 (s, 1H), 7.13 (d, 1H), 7.19 (t, 1H), 7.28 (s, 1H), 7.44 (d, 1H), 7.51 (d, 1H), 7.61 (s, IH) ppm. MS (electrospray) m/z 728 [M+H]+ 81 F IHNMR (CD 3 0D, 400MHz) 8: -0.18 (s, 3H), F F 0.00 (s, 3H), 0.84 (s, 9H), 1.04 (d, 3H), 2.57 (m, 1H), 2.66 (m, 2H), 2.88 (m, 5H), 3.01 (m, 1H), 3.53 (s, 2H), 4.40 (s, 2H), 4.68 (m, IH), 6.79 (d, 1H), 6.94 (d, 1H), 7.02 (d, IH), 7.10 (s, IH), 7.17 (m, 2H), 7.33 (s, IH), 7.56 (m, 3H) ppm. MS (electrospray) m/z 728 [M+H]I WO 2005/080324 PCT/IB2005/000112 87 82 F 'HNMR (CD 3 OD, 400MHz) 8: -0.18 (s, 3H), N F 0.00 (s, 3H), 0.84 (s, 9H), 1.04 (d, 3H), 2.57 HF (m, 1H), 2.66 (m, 2H), 2.88 (m, 5H), 3.01 (, 1H), 3.53 (s, 2H), 4.40 (s, 2H), 4.68 (m, F 1H), 6.79 (d, 1H), 6.93 (d, 1H), 7.01 (d, IH), 7.07 (s, 1H), 7.20 (m, 2H), 7.28 (s, IH), 7.80 (m, 3H) MS (electrospray) m/z 762 [M+H]* 83 F 1 HNMR (CD 3 0D, 400MHz) 5: -0.18 (s, 3H), F F 0.00 (s, 3H), 0.84 (s, 9H), 1.04 (d, 3H), 2.57 HF (m, 1H), 2.66 (m, 2H), 2.88 (m, 5H), 3.02 F (m, 1H), 3.53 (s, 2H), 4.40 (s, 2H), 4.68 (m, 1H), 6.79 (d, 1H), 6.95 (d, 1H), 7.00 (d, IH), 7.08 (s, IH), 7.19 (m, 3H), 7.30 (m, 2H), 7.36 (s, I H) MS (electrospray) m/z 712 [M+H]* 84 CH 3 1HNMR(400MHz, CD 3 OD) 8 : -0.15 (s, 3H), 0.03 (s, 3H), 0.86 (s, 9H), 1.04 (d, 3H), 2.26
H
3 C CH 3 (s, 3H), 2.37 (s, 6H), 2.50-2.55 (m, 1H), 2.63-2.71 (m, 2H), 2.84-2.91 (m, 5H), 3.87 (s, 2H), 4.36 (s, 2H), 4.69-4.71 (m, 1H), 6.80 (d, 1 H), 6.85-6.86 (m, 4H), 6.92-7.00 (m, 2H), 7.06 (m, IH), 7.12-7.21 (m, 2H), 7.32 (m, 1H) ppm. MS (electrospray) m/z 668 [M+H]*, 690 [M+Na]* WO 2005/080324 PCT/IB2005/000112 88 85 c 'HNMR(400MHz, CD 3 0D) 5: -0.16 (s, 3H), ci 0.02 (s, 3H), 0.85 (s, 9H), 1.05 (d, 3H), ci 2.51-2.56 (m, IH), 2.65-2.72 (m, 2H), 2.89 2.92 (m, 5H), 3.48 (s, 2H), 4.69-4.71 (m, 3H), 6.82 (d, IH), 6.95-7.00 (m, 2H), 7.05 (m, 1H), 7.11-7.20 (m, 2H), 7.33 (m, IH), 7.41 (d, 1H), 7.51 (d, 1H) ppm. MS (electrospray) m/z 728/730 [M+H], 750/752 [M+Na]* 86 cl 1HNMR(400MHz, CD 3 0D) 8: -0.16 (s, 3H), N ci -0.01 (s, 3H), 0.84 (s, 9H), 2.53-2.59 (m, I H), 2.64-2.72 (m, 2H), 2.87-2.93 (m, 5H), 3.55 (s, 2H), 4.48 (s, 2H), 4.68-4.71 (m, IH), 6.81 (d, 1H), 6.94-6.96 (m, 1H), 7.01 7.02 (m, 1H), 7.15-7.23 (m, 4H), 7.32 (m, IH), 7.43-7.45 (m, 1H) ppm. MS (electrospray) m/z 692 [M-H]~ 87HNMR(400MHz, CD30D) 5: -0.17 (s, 3H), H H 3 0.01 (s, 3H), 0.84 (s, 9H), 2.53-2.58 (m, IH), 2.62-2.71 (m, 2H), 2.86-2.91 (m, 5H), 3.52 (s, 2H), 4.32 (s, 2H), 4.69-4.71 (m, IH), 6.81 (d, IH), 7.00-7.01 (m, 1H), 7.07 7.08 (m, 2H), 7.14-7.15 (m, 1H), 7.19-7.22 (m, 3H), 7.31 (m, 1H) ppm. MS (electrospray) m/z 674 [M+H]*, 672 [M
H]~
WO 2005/080324 PCT/IB2005/000112 89 88 'HNMR (CD 3 OD, 400MHZ) 8: -0.18 (s, 3H), N 0.00 (s, 3H), 0.84 (s, 9H), 0.98 (d, 3H), 2.48 (m, IH), 2.60 (m, 2H), 2.80 (m, 2H), 2.85 (s, 3H), 3.50 (s, 2H), 4.66 (m, 1 H), 4.80 (s, 2H), 6.93 (d, 1H), 6.98 (m, 3H), 7.06 (m, 2H), 7.30 (s, 1H), 7.40 (m, 4H), 7.80 (d, 1H), 7.84 (d, IH), 7.98 (m, 1H) ppm. MS (electrospray) m/z 676 [M+H]* 89 ( N N HNMR (CD3OD, 400MHz) 8: -0.18 (s, 3H), 0.00 (s, 3H), 0.82 (s, 9H), 1.05 (d, 3H), 2.58 (m, IH), 2.64 (m, 2H), 2.80 (m, 5H), 3.59 (s, 2H), 4.48 (s, 2H), 4.66 (m, 1H), 6.93 (d, 1H), 6.98 (d, 1H), 7.03 (d, IH), 7.10 (s, IH), 7.20 (m, 2H), 7.28 (m, 2H), 7.31 (s, IH), 7.78 (t, IH), 8.45 (d, IH) ppm. MS (electrospray) m/z 627 [M+H]* 90 ( O 9F HNMR (CD 3 OD, 400MHz) 6: -0.18 (s, 3H), F 0.00 (s, 3H), 0.82 (s, 9H), 1.04 (d, 3H), 2.58 F (m, 1H), 2.64 (m, 2H), 2.84 (m, 5H), 3.51 (s, 2H), 4.38 (s, 2H), 4.66 (m, 1H), 6.78 (d, 1H), 6.90 (d, 1H), 7.01 (d, 1H), 7.03 (s, IH), 7.20 (m, 4H), 7.30 (m, 3H) ppm. MS (electrospray) m/z 710 [M+H]* 91 {N 'HNMR (CD 3 OD, 400MHz) 5: -0.18 (s, 3H), CN 0.00 (s, 3H), 0.82 (s, 9H), 1.04 (d, 3H), 2.58 (m, 1H), 2.61 (m, 2H), 2.91 (m, 5H), 3.54 (s, 2H), 4.41 (s, 2H), 4.70 (m, 1H), 6.80 (d, 1H), 6.98 (d, 1H), 7.02 (d, 1H), 7.08 (s, 1H), 7.18 (d, 1H), 7.21 (d, 1H), 7.30 (s, 1H), 7.40 (d, 2H), 7.61 (d, 2H) ppm. MS (electrospray) m/z 650 [M+H]*' WO 2005/080324 PCT/IB2005/000112 90 0 N 1 HNMR (CD 3 0D, 400MHz) 5: -0.18 (s, 3H), H 0.00 (s, 3H), 0.81 (s, 9H), 1.04 (d, 3H), 2.58 (m, IH), 2.60 (m, 2H), 2.81 (m, 11H), 3.48 (s, 2H), 4.21 (s, 2H), 4.70 (m, 1H), 6.70 (d, 2H), 6.80 (d, 1H), 6.98 (m, 2H), 7.18 (m, 5H), 7.28 (s, IH) ppm. MS (electrospray) m/z 669 [M+H]* 93 1 HNMR (CD 3 0D, 400MHz) 8: -0.20 (s, 3H), 0.00 (s, 3H), 0.81 (s, 9H), 1.02 (d, 3H), 2.60 H (m, 3H), 2.89 (m, 5H), 3.62 (s, 2H), 4.63 (m, 1H), 6.80 (d, 1H), 6.91 (d, 1H), 7.03 (m, IH), 7.10 (dd, 1H), 7.18 (s, IH), 7.20 (m, 2H), 7.23 (m, 3H), 7.58 (d, 2H) ppm. MS (electrospray) m/z 612 [M+H]* 94 N N 4 1HNMR (CD 3 0D, 400MHz) 8: -0.18 (s, 3H), 0.00 (s, 3H), 0.81 (s, 9H), 1.04 (d, 3H), 1.48 H (m, 2H), 1.80 (m, 2H), 2.14 (m, 2H), 2.58 (m, IH), 2.63 (m, 2H), 2.83 (m, 7H), 3.42 (s, 2H), 3.51 (s, 2H), 3.63 (m, 1H), 4.63 (m, IH), 6.80 (d, IH), 6.93 (m, 2H), 7.03 (s, IH), 7.08 (m, IH), 7.20 (m, 1H), 7.25 (m, 6H) ppm. MS (electrospray) m/z 709 [M+H]* WO 2005/080324 PCT/IB2005/000112 91 Preparations 95 to 102 OTBDMS H N K0
H
3 0 GH 3 I HO HC HN O0 S // CH 3 95 N cl MS (electrospray) m/z 710 [M+H]* cl 96 cl MS (electrospray) mlz 742 [M+H]* N F F F 97 F MS (electrospray) mlz 742 [M+H]+ F HI F CI 98 F MS (electrospray) m/z 776 [M+H]* F H FF F F F 99 F MS (electrospray) m/z 726 [M+H]* N F F 100 F MS (electrospray) m/z 726 [M+H]* N H F F F WO 2005/080324 PCT/IB2005/000112 92 101 F F MS (electrospray) mlz 726 [M+H] F H F 102 F MS (electrospray) m/z 726 [M+H]* N- F H F F Preparations 103 to 106 OTBDMS H N 0 HO C3Qi HN3) 7 0 0'~ CH 3 103 0 MS (electrospray) m/z 656 [M+H]* 104 0 C~H3 'HNMR (CDGI 3 , 400MHz) 8: -0.10 (s, 3H), N"6 0.03 (s, 3H), 0.85 (s, 9H), 1.20 (in, 3H), H 1.46 (t, 3H), 2.39-2.55 (in, 3H), 2.90 (s, 2H), 3.49 (s, 2H), 4.12 (mn, 2H), 4.66 (dd, I H), 6.36 (di, 1 H), 6.52 (dd, 2H), 6.78-6.86 (in, 3H), 7.27-7.32 (in, 5H) ppm. MS (electrospray) mfz 670 [M+H] + WO 2005/080324 PCT/IB2005/000112 93 105 ('HNMR (CDCl 3 , 400MHz) 5: -0.02 (s, 3H), H 0.00 (s, 3H), 0.90 (s, 9H), 1.10 (d, 3H), 2.30-2.40 (m, 2H), 2.60-2.80 (m, 2H), 2.90 (s, 3H), 3.0-3.1 (m, 1H), 3.55 (s, 2H), 3.85 (s, 1H), 4.50-4.60 (m, 3H), 6.20 (m, 1H), 6:42 -(d, IH), 6.60 (dd, 1H), 6.90 (d, 2H), 7.00 (d, 2H), 7.20-7.40 (m, 6H) ppm. MS (electrospray) m/z 626 [M+H]* 106 (N -'HNMR (CDCl 3 , 400MHz) 8: -0.015 (s, 3H), H 0.05 (s, 3H), 0.80 (s, 9H), 1.15 (d, 3H), 1.95 (m, 2H), 2.30-2.70 (m, 2H), 2.60-2.75 (m, 4H), 2.90 (s, 3H), 3.05 (m, 1H), 3.40 (m, 4H), 4.55 (m, IH), 5.85 (m, 1H), 6.40 (d, IH), 6.60 (dd, 1H), 6.85 (d, 2H), 6.95 (d, 2H), 7.20-7.30 (m, 6H) ppm. MS (APCI) m/z 654 [M+H]+ Preparation 95 - 102: not purified by column chromatography. Preparation 107 : 2-(3-((2R)-2-[((2R)-2-{4-(Benzyloxy)-3-[(methylsulfonyl) 5 amino]phenyl}-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl} phenyl)-N-(2,3-dihydro-1 H-inden-2-yl)acetamide OTBDMS H H N N 0CH 3 0 HN /,0 0 CH3 The carboxylic acid of preparation 26 (200mg, 0.32mmol) was added to a solution of 1-hydroxybenzotriazole hydrate (48mg, 0.36mmol), 1-(3 10 dimethylaminopropyl)-3-ethycarbodiimide hydrochloride (74mg, 0.42mmol), N ethyldiisopropylamine (226pL, 1.26mmol) and indan-2-ylamine (51mg, WO 2005/080324 PCT/IB2005/000112 94 0.42mmol) in N,N-dimethylformamide (3ml). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organics separated, dried (magnesium sulphate) and concentrated in vacuo. The residue was 5 purified by column chromatography on silica gel eluting with dichloromethane:methanol 99:1 to 98:2 to yield the title product, 157mg. 'HNMR (CDC[,, 400MHz) 6: -0.15 (s, 3H), 0.00 (s, 3H), 0.85 (s, 9H), 0.99 (m, 3H), 2.73 (m, 8H), 3.31 (m, 2H), 3.28 (m, 3H), 4.73 (m, 2H), 5.07 (m, 2H), 5.75 (m, 1H), 6.91-7.11 (m, 10H), 7.40 (m, 6H) ppm. 10 MS (APCI) m/z 742 [M+H]* Preparation 108: 2-(3-{(2R)-2-[((2R)-2-{4-(benzyloxy)-3-[(methylsulfonyl) amino] phenyl}-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl} phenyl) -N-(2-methoxybenzyl)acetamide OTBDMS H H N N 0
H
3 c sC HN~ /0 / CH 15 0 3 The title compound was prepared by a method similar to that described for preparation 107 using the carboxylic acid of preparation 26 and 2 methoxybenzylamine. IHNMR (CDCl 3 , 400MHz) 5: -0.15 (s, 3H), 0.00 (s, 3H), 0.85 (s, 9H), 0.99 (m, 20 3H), 2.73 (m, 8H), 3.65 (s, 3H), 4.38 (m, 2H), 5.08 (m, 2H), 6.02 (m, 1H), 6.77 7.08 (m, 7H), 7.12 (m, 4H), 7.40 (m, 5H) ppm. MS (APCI) m/z 746 [M+H]* Preparation 109: N-benzyl-2-(3-{(2R)-2-[((2R)-2-{4-(benzyloxy)-3 25 [(methylsulfonyl)amino]phenyl}-2-{[tert-butyl(dimethyl)s ilyl]oxy}ethyl) amino]propyl}phenyl)acetamide WO 2005/080324 PCT/IB2005/000112 95 OTBDMS H H N N I~YC H, OH 3 0 HN 0S-ICHa The title compound was prepared by a method similar to that described for preparation 107 using the carboxylic acid of preparation 26 and benzylamine. 1 HNMR (CDCl 3 , 400MHz) 6: -0.17 (s, 3H), 0.01 (s, 3H), 0.86 (s, 9H), 0.96 (m, 5 3H), 2.66-2.91 (m, 8H), 4.40 (m, 2H), 4.69 (m, 1H), 5.07 (m, 2H), 5.81 (m, 1H), 6.91 (d, 1H), 7.04 (m, 3H), 7.24 (m, 6H), 7.40 (m, 6H), 7.52 (m, IH) ppm. MS (APCI): m/z 716 [M+H]* Preparation 110 2-(3-{(2R)-2-[((2R)-2-{4-(benzyloxy)-3-[(methylsulfonyl) 10 amino]phenyl}-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl} phenyl)-N-(2-phenylethyl)acetamide OTBDMS H H N N HNs /0 ' CH 3 The title compound was prepared by a method similar to that described for preparation 107 using the carboxylic acid of preparation 26 and 15 phenethylamine. 'HNMR (CDCI 3 , 400MHz) 8: -0.17 (s, 3H), 0.00 (s, 3H), 0.84 (s, 9H), 0.98 (t, 3H), 2.63-2.88 (m, 8H), 3.43 (m, 5H), 4.69 (m, 1H), 5.07 (m, 2H), 5.47 (m, 1H), 6.93 (m, 2H), 7.06 (m, 5H), 7.16 (m, 4H), 7.40 (m, 5H), 7.49 (m, 1H) ppm. MS (APCI) m/z 730 [M+H]* 20 WO 2005/080324 PCT/IB2005/000112 96 Examples 1 -77 The appropriate protected alcohol (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 5 0.43mmol) in water (300ptL). The reaction mixture was then stirred at 50 0 C for 18 hours before being allowed to cool to room temperature. If a solid product precipitated the reaction mixture was filtered and washed with methanol:water (2m, 1:1 by volume) to give the title compound. If no product precipitated the reaction mixture was concentrated in vacuo and the residue purified by column 10 chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product. Alternatively, the following process can be used for the preparation of examples I to 77. A solution of the appropriate protected alcohol from preparation 30 to 15 106 (25.4mmol) in methanol (450ml) was treated with a solution of ammonium fluoride (6.6g, 178mmol) in water (200ml) and the resulting solution heated to 400C for 24 hours. The reactions mixture was cooled to room temperature an the precipitate filtered and washed with methanol : water (50:50 by volume, I 00ml). The solid was suspended in ethanol (1 50mi) and heated to 65 0 C for 30 20 minutes, cooled to room temperature and filtered, washing the solid with diethyl ether (50ml). Recrystallisation from aqueous pyridine (1:1, 150ml) gave the desired compound. Example 1: N-Benzyl-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl) 25 amino] phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide OH H H N N HO HNs /yO 0"S cH P " CH 3 Preparation 30 (0.O75mmol) was dissolved in ethanol (4m1) and the solution WO 2005/080324 PCT/IB2005/000112 97 treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300pL). The reaction mixture was then stirred at 50 0 C for 18 hours before being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on 5 silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 1 HNMR (CD 3 0D, 400MHz) 8: 1.04 (s, 3H), 1.07 (s, 3H), 2.68-2.93 (m, 7H), 3.53 (s, 3H), 4.37 (m, 2H), 4.60 (m, 1H), 6.849m, 1H), 7.02-7.28 (m, 10H), 7.37 (m, 1H) 10 MS (electrospray) m/z 526 [M+H]+ Example 2: 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfony)amino] phenyl}ethyl) amino]-2-methylpropyl}phenyl)-N-(4-methoxybenzyl)acetamide OH H O CH 3 N N
H
3 c cH 3 - 0 HO HN /O 15 Preparation 31 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300pL). The reaction mixture was then stirred at 500C for 18 hours before being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on 20 silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 'HNMR (CD 3 0D, 400MHz) 5: 1.04 (s, 3H), 1.07 (s, 3H), 2.65-2.89 (m, 7H), 3.52 (s, 2H), 3.76 (s, 3H), 4.29 (s, 3H), 4.60 (m, IH), 6.92 (m, 3H), 6.98-7.20 (m, 7H), 7.35 (m, I H) ppm. 25 MS (electrospray) m/z 556 [M+H]+ WO 2005/080324 PCT/IB2005/000112 98 Example 3: 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] phenyl} ethyl)amino]-2-methylpropyl}phenyl)-N-(2-methoxybenzyl)acetamide OH H H I -' N - IN___ HO H H H 3 CH3 HNs /0 Preparation 32 (0.075mmol) was dissolved in ethanol (4ml) and the solution 5 treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300jpL). The reaction mixture was then stirred at 50 0 C for 18 hours before being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 10 changing to 90:10:1) to yield the title product as a colourless solid. 'HNMR (CD 3 0D, 400MHz) 8: 1.04 (s, 3H), 1.07 (s, 3H), 2:65-2.91 (m, 7H), 3.56 (m, 2H), 3.71 (m, 3H), 4.35 (m, 2H), 4.42 (m, 1H), 6.81-7.23 (m, 1OH), 7.37 (m, 1 H) MS (electrospray) m/z 556 [M+H]+ 15 Example 4: N-(2-Ethoxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl) amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide OH H H N, N
H
3 I H O H 3 / o 'CHC HO O H3CH2CH3 HN 0 Preparation 33 (0.075mmol) was dissolved in ethanol (4ml) and the solution 20 treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300pL). The reaction mixture was then stirred at 501C for 18 hours before being allowed to cool to room temperature. The reaction mixture was WO 2005/080324 PCT/IB2005/000112 99 concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methano:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 'HNMR (CD 3 OD, 400MHz) 8: 1.04 (s, 3H), 1.07 (s, 3H), 1.33 (t, 3H), 1.66-1.88 5 (m, 7H), 3.53 (m, 2H), 4.01 (q, 2H), 4.36 (s, 2H), 4.61 (m, 1H), 6.79-6.91 (m, 3H), 7.01-7.22 (m, 7H), 7.35 (m, IH) ppm. MS (electrospray) m/z 570 [M+H]* Example 5: 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] 10 phenyl}ethyl)amino]-2-methylpropyl}phenyl)-N-(3-methoxybenzyl)acetamide OH HOHc O-H N N0OH H ;H 3
CXCH
3 0 SHCH HNN '-/ 0/S CH 3 Preparation 34 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300 L). The reaction mixture was then stirred at 500C for 18 hours before 15 being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 'HNMR (CD 3 0D, 400MHz) 5:1.04 (s, 3H), 1.07 (s, 3H), 2.65-2.91 (m, 7H), 3.56 20 (m, 2H), 3.71 (m, 3H), 4.35 (m, 2H), 4.42 (m, IH), 6.78 (m, 2H), 6.85 (m, 1H), 7.00-7.22 (m, 7H), 7.38 (m, 1H) ppm. MS (electrospray) m/z 556 [M'+H]* Example 6: 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] 25 phenyl}ethyl)ami no]-2-m ethylpropyl}phenyl)-N-(4-methylbenzyl)acetam ide WO 2005/080324 PCT/IB2005/000112 100 OH
CH
3 H H 'N N HO HN /0 0SCH 3 Preparation 35 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300pL). The reaction mixture was then stirred at 500C for 18 hours before 5 being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 1 HNMR (CD 3 0D, 400MHz) 8: 1.04 (s, 3H), 1.07 (s, 3H), 2.26 (s, 3H), 2.65-2.86 10 (m, 7H), 3.56 (m, 2H), 4.29 (m, 2H), 4.62 (m, 1H), 6.84 (d, IH), 6.98-7.22 (m, 9H), 7.369m, IH) ppm. MS (electrospray) m/z 540 [M+H]+ Example 7: 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] 15 phenyl}ethyl) amino]-2-methylpropyl}phenyl)-N-(2-methylbenzyl)acetamide OH H H 13 HN, ,,0 0 /IsH" 0 CH SHCH Preparation 36 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300piL). The reaction mixture was then stirred at 500C for 18 hours before 20 being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 WO 2005/080324 PCT/IB2005/000112 101 changing to 90:10:1) to yield the title product as a colourless solid. 1 HNMR (CD 3 0D, 400MHz) 8: 1.04 (s, 3H), 1.07 (s, 3H), 2.26 (s, 3H), 2.65-2.86 (m, 7H), 3.56 (m, 2H), 4.29 (m, 2H), 4.62 (m, 1H), 6.84 (d, 1H), 6.98-7.22 (m, 9H), 7.369m, 1H) ppm. 5 MS (electrospray) m/z 540 [M+H]* Example 8: 2-(3-{2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsu lfonyl)ami no] phenyl}ethyl) amino]-2-methylpropyl}phenyl)-N-(3-methylbenzyl)acetamide
CH
3 OH/ H H N N HO HN /0 Sca 0/ 'CH3 10 Preparation 37 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300ptL). The reaction mixture was then stirred at 501C for 18 hours before being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on 15 silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 'HNMR (CD30D, 400MHz) 8: 1.04 (s, 3H), 1.07 (s, 3H), 2.26 (s, 3H), 2.65-2.86 (m, 7H), 3.56 (m, 2H), 4.29 (m, 2H), 4.62 (m, IH), 6.84 (d, IH), 6.98-7.22 (m, 9H), 7.369m, 1H) ppm. 20 MS (electrospray) m/z 540 [M+H]* Example 9: N-(3,4-Dimethoxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide WO 2005/080324 PCT/IB2005/000112 102 OMe OMe OH H H ( N N HO HNs ,0 S "1CH 3 Preparation 38 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300ttL). The reaction mixture was then stirred at 50"C for 18 hours before 5 being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 'HNMR (CDOD, 400MHz) 8: 1.04 (s, 3H), 1.07 (s, 3H), 2.66-2.90 (m, 7H), 3.64 10 (m, 2H), 3.68 (s, 6H), 4.28 (s, 2H), 4.62 (m, IH), 6.76-6.88 (m, 4H), 7.00-7.21 (m, 6H), 7.38 (m, 1H) ppm. MS (electrospray) m/z 586 [M+H]* Example 10: N-(2,4-Dimethoxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 15 [(methylsulfonyl)amino)phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide OH MeO OMe H H N N H 3 COH 3 x 0 HO HNN /0 0' //,CH3 Preparation 39 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300iL). The reaction mixture was then stirred at 500C for 18 hours before 20 being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on WO 2005/080324 PCT/IB2005/000112 103 silica gel eluting with dichloromethane:methanol:0.8 8 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 'HNMR (CD 3 OD, 400MHz) 8: 1.04 (s, 3H), 1.07 (s, 3H), 2.66-2.90 (m, 7H), 3.64 (m, 2H), 3.68 (s, 6H), 4.28 (s, 2H), 4.62 (m, IH), 6.40 (d, IH), 6.47 (s, IH), 6.85 5 (d, 1H), 7.00-7.21 (m, 6H), 7.35 (m, IH) MS (electrospray) m/z 586 [M+H]* Example 11: N-(3,5-Dimethoxybenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)aceta mide OMe OH H N N OMe
H
3 c CH 0 HO HN /H 10 0 3 Preparation 40 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300ptL). The reaction mixture was then stirred at 500C for 18 hours before being allowed to cool to room temperature. The reaction mixture was 15 concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 'HNMR (CD 3 OD, 400MHz) 6: 1.04 (s, 3H), 1.07 (s, 3H), 2.66-2.90 (m, 7H), 3.64 (m, 2H), 3.68 (s, 6H), 4.28 (s, 2H), 4.62 (m, 1H), 6.32 (m, 1H), 6.37 (m, 2H), 20 6.83 (m, 1H), 7.01-7.20 (m, 5H), 7.37 (m, IH) MS (electrospray) m/z 586 [M+H]* Example 12: N-(4-Chlorobenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl) amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide WO 2005/080324 PCT/IB2005/000112 104 OH Cl H H I HH C N1 HNN 0 SHCH 0 I/S CH 3 Preparation 41 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300ptL). The reaction mixture was then stirred at 500C for 18 hours before 5 being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. IHNMR (CD 3 0D, 400MHz) 5: 1.04 (s, 3H), 1.07 (s, 3H), 2.66-2.91 (m, 7H), 3.54 10 (m, 2H), 4.37 (m, 2H), 4.62 (m, IH), 6.84 (d, 1H), 7.00-7.26 (m, 9H), 7.36 (m, I H) MS (electrospray) m/z 560 [M+H]+ Example 13: N-(2-Chlorobenzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 15 [(methylsulfonyl) amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide OH H H N N
HOH
3 C H 3 0 Cl HNs /0 S'/ CH, Preparation 42 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300[L). The reaction mixture was then stirred at 500C for 18 hours before 20 being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 WO 2005/080324 PCT/IB2005/000112 105 changing to 90:10:1) to yield the title product as a colourless solid. 'HNMR (CD 3 OD, 400MHz) 8: 1.04 (s, 3H), 1.07 (s, 3H), 2.66-2.91 (m, 7H), 3.54 (m, 2H), 4.37 (m, 2H), 4.62 (m, IH), 6.84 (m, 1H), 7.00-7.26 (m, 8H), 7.38 (m, 2H) 5 MS (electrospray) m/z 560 [M+H]* Example 14: N-(3-Chlorobenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl) amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide OH OH H H N N Cl
H
3 C CH 3 ~- 0 HO HNs 90 0 CH 10 Preparation 43 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300 L). The reaction mixture was then stirred at 50 0 C for 18 hours before being allowed to cool to room temperature. IThe reaction mixture was concentrated in vacuo and the residue purified by column chromatography on 15 silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 1 HNMR (CD 3 OD, 400MHz) 5: 1.04 (s, 3H), 1.07 (s, 3H), 2.66-2.91 (m, 7H), 3.54 (m, 2H), 4.37 (m, 2H), 4.62 (m, IH), 6.84 (m, IH), 7.01-7.29 (m, 9H), 7.36 (m, 1 H) 20 MS (electrospray) m/z 560 [M+H]* Example 15: N-(4-Fluorobenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl) amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetam ide WO 2005/080324 PCT/IB2005/000112 106 F OH OH H H F N N H H 3 C CH 3 ~ - 0 HO HN O 0 CH3 Preparation 44 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300pL). The reaction mixture was then stirred at 500C for 18 hours before 5 being allowed to cool to room temperature. as a colourless solid.reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 10 'HNMR (CD 3 0D, 400MHz) 6: 1.04 (s, 3H), 1.07 (s, 3H), 2.67-2.90 (m, 7H), 3.53 (m, 2H), 4.32 (m, 2H), 4.61 (m, 1H), 6.83 (d, 1H), 6.96-7.23 (m, 9H), 7.35 (m, 1 H) MS (electrospray) m/z 544 [M+H]+ 15 Example 16: N-(2,4-Dichlorobenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide OH Cl H H IN N HO OH H C HNs 40 0
S'TCH
3 Preparation 45 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water 20 (300pL). The reaction mixture was then stirred at 50*C for 18 hours before being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on WO 2005/080324 PCT/IB2005/000112 107 silica gel eluting with dichloromethane:methanol:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 1 HNMR (CD 3 0D, 400MHz) 5: 1.04 (s, 3H), 1.07 (s, 3H), 2.71-2.89 (m, 7H), 3.54 (s, 2H), 4.32 (m, 2H), 4.64 (m, 1H), 6.85 (d, 1H), 7.02-7.23 (m, 6H), 7.38 (m, 5 2H) MS (electrospray) m/z 594 [M+H]* Example 17: N-(3,4-Dichlorobenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide OH HCl H H I IHC OH 3 o H0O 10N Preparation 46 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300ptL). The reaction mixture was then stirred at 50'C for 18 hours before being allowed to cool to room temperature. The reaction mixture was filtered 15 and washed with methanol:water (2ml, 1:1 by volume) to give the title compound as a colourless solid. 'HNMR (CD 3 0D, 400MHz) 8: 1.04 (s, 3H), 1.07 (s, 3H), 2.71-2.89 (m, 7H), 3.54 (s, 2H), 4.32 (m, 2H), 4.64 (m, 1H), 6.85 (d, IH), 7.02-7.23 (m, 6H), 7.38 (m, 2H) 20 MS (electrospray) m/z 594 [M+H]+ Example 18: N-(4-tert-Butylbenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl) amino]phenyl}ethy)amino]-2-methylpropyl}phenyl)acetamide WO 2005/080324 PCT/IB2005/000112 108
CH
3
CH
3 OH /I C H H H 3 N N
H
3 C CH 3 ~- 0 HO HNs O 0 ,SCH 3 Preparation 47 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300tL). The reaction mixture was then stirred at 500C for 18 hours before 5 being allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane:methano:0.88 ammonia (98:2:0 changing to 90:10:1) to yield the title product as a colourless solid. 'HNMR (CD 3 0D, 400MHz) 8: 1.04 (s, 3H), 1.07 (s, 3H), 1.30 (s, 9H), 2.67-2.88 10 (m, 7H), 3.54 (s, 2H), 4.32 (m, 2H), 4.62 (m, 1H), 6.84 (m, 1H), 7.00-7.21 (m, 7H), 7.34 (d, 2H), 7.37 (m, 1H) ppm. MS (electrospray) m/z 582 [M+H]+ Example 19: N-(2-Chloro-6-fluorobenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4 15 hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]- 2 methylpropyl}phenyl)acetamide OH Cl H H N N HO H3 /,O HN" 0/ S "CH3 Preparation 48 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water 20 (300[tL). The reaction mixture was then stirred at 50'C for 18 hours before WO 2005/080324 PCT/IB2005/000112 109 being allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol:water (2ml, 1:1 by volume) to give the title compound as a colourless solid. IHNMR (DMSO-D 6 , 400MHz) 8: 0.89 (s, 3H), 0.90 (s, 3H), 2.54 (s, 2H), 2.63 (m, 5 2H), 2.89 (s 3H), 3.36 (s, 2H), 4.36-4.43 (m, 3H), 6.81 (d, 1H), 6.93-7.04 (m, 4H), 7.11-7.23 (m, 3H), 7.29-7.39 (m, 2H), 8.31 (m, 1H) ppm. MS (electrospray) m/z 576 [M-H]r Example 20: N-(2,3-Dimethylbenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 10 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide OH H H N N
CH
3
H
3 C CH 3 0 CH HO HN ,,O 0S ,CH3 Preparation 49 (0.075mmol) was dissolved in ethanol (4ml) and the solution treated with a solution of ammonium fluoride (16mg, 0.43mmol) in water (300tL). The reaction mixture was then stirred at 500C for 18 hours before 15 being allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol:water (2ml, 1:1 by volume) to give the title compound as a colourless solid. 1 HNMR (CD 3 0D, 400MHz) 8: 0.95 (s, 3H), 0.96 (s, 3H), 2.12 (s, 3H), 2.24 (s, 3H), 2.60 (s, 2H), 2.66-2.70 (m, 2H), 2.93 (s, 3H), 3.45 (s, 2H), 4.25 (m-, 2H), 20 4.46 (m, IH), 6.84 (m, IH), 6.98-7.21 (m, 8H), 8.32 (m, 1H) ppm. MS (electrospray) m/z 552 [M-Hr~ WO 2005/080324 PCT/IB2005/000112 110 Examples 21 to 36 OH H Q1 N
H
3 C CH 3 1 0 HO HN' /O S CH 3 No Q' Data 21 'HNMR (CD 3 OD, 400MHz) 5: 0.99 (m, 6H), {s ci 2.62-3.81 (m, 4H), 3.90 (s, 3H), 3.45 (s, H 2H), 4.22 (m, 2H), 4.6 (m, IH), 6.84 (d, 1H), 6.98-7.22 (m, 9H), 7.41 (s, 1H), 8.59 (m, Cl IH) ppm. MS (electrospray) m/z 592 [M-H]~ 22 'HNMR (DMSO-D,, 400MHz) 5: 0.90 (s, F F 3H), 0.91 (s, 3H), 2.56 (s, 2H), 2.62-2.69 F MS (electrospray) mlz 660 IM-Hr 23 'HNMR (CD 3 OD, 400MHz) : 1.08 (s, 3H), 1.10 (s, 3H), 2.23 (s, 3H), 2.24 (s, 3H), NOa H, 2.70-2.82 (in, 4H), 2.92 (s, 3H), 3.55 (s, 2H), 4.32 (s, 2H), 4.64-4.68 ( , IH), 6.90 3H 3 (d, 1 1H 6.95-7.00 (, 2H), 7.05-7.12 (8, 3H), 7.16-7.26 (m, 3H), 7.40 (m, 1H) ppm. MS (electrospray) m/z 554 [M+H]+ WO 2005/080324 PCT/IB2005/000112 111 24 1 HNMR (CD 3 0D, 400MHz) 8: 1.09 (s, 3H), 1.12 (s, 3H), 2.72-2.93 (m, 7H), 3.61 (s, N cl 2H), 4.46 (s, 2H), 4.65-4.68 (m, 1H), 6.90 ca (d, 1H), 7.08-7.29 (7H, m), 7.38-7.41 (m, 2H) ppm. MS (electrospray) m/z 594 [M+H]*" 25 1 HNMR (CD 3 0D, 400MHz) 5: 1.10 (s, 3H), 1.12 (s, 3H), 2.93 (s, 3H), 2.74-2.95 (m, 6H), 3.44 (t, 2H), 3.48 (s, 2H), 4.65-4.68 (m, H 1H), 6.90 (d, 1H), 7.06 (d, 1H), 7.10-7.29 (m, 9H), 7.41 (d, IH) ppm. MS (electrospray) m/z 540 [M+H]+ 26 1 HNMR (CD 3 0D, 400MHz) 5: 1.09 (s, 3H), 1.11 (s, 3H), 1.78-1.86 (m, 2H), 2.60-2.64 (dd, 2H), 2.93 (s, 3H), 2.71-2.94 (m, 4H), N 3.23 (t, 2H), 3.51 (s, 2H), 4.65-4.68 (dd, H IH), 6.90 (d, 1H), 7.06 (d, IH), 7.11 (dd, IH), 7.16-7.21 (m, 5H), 7.23-7.28 (m, 3H), 7.40 (d, IH) ppm. MS (electrospray) m/z 554 [M+H]* 27 'HNMR (DMSOd6, 400MHZ) 8: 0.90 (s, 3H), 0.91 (s, 3H), 2.56-2.65 (m, 4H), 2.89 (s, 3H), 3.46 (s, 2H), 4.34 (d, 2H), 4.40-4.43 c (m, IH), 6.81 (d, IH), 6.97-7.01 (m, 2H), CI 7.06-7.10 (m, 2H), 7.14-7.28 (m, 4H), 7.52 (dd, IH), 8.54-8.56 (m, IH) ppm. MS (electrospray) m/z 594/596 [M+H]+ WO 2005/080324 PCT/IB2005/000112 112 28 1 HNMR (DMSOd6, 400MHz) 8: 0.88 (s, 3H), 0.89 (s, 3H), 2.29 (s, 3H), 2.53-2.65 (m, 4H), 2.88 (s, 3H), 3.36 (s, 2H), 4.32 (d, 2H), H I 4.40-4.42 (m, 1H), 6.80 (d, 1H), 6.94 (d, 'N 1H), 6.98-7.04 (m, 3H), 7.11-7.18 (m, 2H), ci 7.29 (s, 1H), 7.43 (dd, IH), 8.14-8.18 (m, 1H) ppm. MS (electrospray) m/z 608/610 [M+H]* 29 'HNMR (DMSOd 6 , 400MHz) 8: 0.80-0.88 (m, 2H), 0.93 (s, 3H), 0.95 (s, 3H), 1.08-1.21 (m, 3H), 1.30-1.41 (m, IH), 1.58-1.67 (m, 5H), 2.58-2.70 (m, 4H), 2.88-2.93 (m, 5H), H 3.37 (s, 2H), 4.43-4.46 (m, IH), 6.84 (d, 1H), 6.97-7.09 (m, 4H), 7.15-7.21 (m, 2H), 7.92-7.96 (m, 1H) ppm. MS (electrospray) m/z 532 [M+H]+ 30 1 HNMR (DMSOde, 400MHz) 8: 0.91 (s, 3H), 0.93 (s, 3H), 2.32 (s, 3H), 2.56-2.70 (m, 4H), 2.89 (s, 3H), 3.41 (s, 2H), 4.40-4.45 H I (m, 3H), 6.81 (m, 3H), 6.96-7.00 (m, 2H), cl 7.05-7.08 (m, 2H), 7.14-7.25 (m, 4H), 7.31 (d, IH), 8.15-8.18 (m, 1H) ppm. MS (electrospray) m/z 574/576 [M+H]* 31 'HNMR (CD 3 0D, 400 MHz) S: 1.06 (3H, s), 1.08 (3H, s), 2.44 (3H, s), 2.67-2.88 (4H, N im), 2.88 (3H, s), 3.54 (2H, s), 4.42 (2H, s), H 34.63 (1H, s), 6.35 (1H, d), 7.02-7.31 (9H, m), 7.37 (1H, d). MS (electrospray) m/z 570 [M-H]~ WO 2005/080324 PCT/IB2005/000112 113 32 'HNMR (CD 3 0D, 400 MHz) 8: 1.05 (3H, s), 1.07 (3H, s), 2.43 (3H, s), 2.68-2.88 (4H, CH, i), 2.89 (3H, s), 3.52 (2H, s), 4.31 (2H, s), 4.64 (1H, m), 6.86 (IH, d), 7.02-7.21 (9H, m), 7.36 (1H, d) ppm. MS (electrospray) m/z 572 [M+H]* 33 'HNMR (CD 3 OD, 400 MHz) 6 1.05 (s, 3H), 1.08 (s, 3H), 1.52-1.62 (m, 2H), 2.06-2.12 (m, 2H), 2.58-2.79 (m, 7H), 2.85-2.90 (m, H IH), 2.89 (s, 3H), 3.45 (s, 2H), 3.61-3.68 <'N (m, 1H), 4.60-4.63 (m, IH), 6.85 (d, IH), 7.01 (d, 1H), 7.07 (d, 1H), 7.12 (s, IH), 7.14 (s, 1H), 7.17-7.21 (m, 1H), 7.35 (s, IH) ppm. MS (APCI) m/z 536 [M+H]* 34 'HNMR(400MHz, DMSOd 6 ) 5: 0.90 (s, 3H), 0.92 (s, 3H), 2.50-2.68 (m, 4H), 2.87 (s, H I3H), 3.40 (s, 2H), 4.13-4.16 (m, 2H), 4.38 4.43 (m, 1H), 6.80 (d, 1H), 6.94-7.40 (m, 15H), 8.37-8.40 (m, IH) ppm. MS (electrospray) m/z 602 [M+H]*, 624 [M+Na]+ 35 'HNMR(400MHz, DMSOd6) 8:1.02 (s, 3H), 1.04 (s, 3H), 2.21 (s, 3H), 2.23 (s, 6H), H 2.65-2.78 (m, 3H), 2.84-2.89 (m, 4H), 3.46 H I (s, 2H), 4.34 (s, 2H), 4.61-4.63 (m, 1H), <N 6.82-6.86 (m, 3H), 6.99-7.01 (m, 1H), 7.06
CH
3 7.20 (m, 4H), 7.35-7.36 (m, IH) ppm. MS (electrospray) m/z 568 [M+H]*, 690 [M+Na]* WO 2005/080324 PCT/IB2005/000112 114 3i "HNMR (CD 3 0D, 400 MHz) 8 1.08 (s, 3H), 1.11 (s, 3H), 2.93 (s, 3H), 2.70-2.94 (m, 4H), 3.59 (s, 2H), 4.47 (s, 2H), 4.65-4.68 NF (m, 1H), 6.90 (d, IH), 7.07-7.08 (m, 1H), F F 7.10-7.13 (m, IH), 7.17-7.27 (m, 3H), 7.41 (d, 1H), 7.49-7.56 (m, 4H) ppm. MS (electrospray) m/z 594 [M+H]* Examples 37 to 65 OH H Qi ,9
CH
3 0 HO HNs /O SCa 0// 'CH 3 No Qi Data 37 'HNMR (CD3OD, 400MHz) 8: 1.04 (t, 3H), 1.33 (t, 3H), 2.51-2.90 (m, 8H), 3.51 (m, KH3 2H), 4.00 (q, 2H), 4.34 (s, 2H), 5.48 (m,
CH
3 1 H), 6.79-7.31 (m, 11 H) ppm. MS (electrospray) m/z 556 [M+H] + 38 ( NHNMR
(CD
3 OD, 400MHz) 8: 1.08 (t, 3H), CH, 2.20 (m, 6H), 2.55-2.92 (m, 8H), 4.31 (m,
CH
3 2H), 4.589m, 2H), 5.47 (m, IH), 6.79 (m, 1 H), 6.90-7.22 (m, 8H), 7.27 (m, 1 H) ppm. MS (electrospray) m/z 540 [M+H] + 39 ( 1 HNMR (CD 3 0D, 400MHz) 5: 1.08 (t, 3H), 2.56-2.90 (m, 8H), 3.56 (m, 2H), 4.32 (m, ci 2H), 4.58 (m, IH), 6.91 (d, IH), 6.93-7.43 (m, 9H) MS APCI+ m/z 580 [M+H]* WO 2005/080324 PCT/IB2005/000112 115 40 'HNMR (CD 3 0D, 400MHz) 5: 1.05 (t, 3H), N 1.77 (m, 2H), 2, 58 (m, 4H), 2.66-2.95 (m, H 8H), 3.16 (m, 2H), 3.43 (m, 2H), 3.46 (m, 2H), 4.59 (m, 2H), 5.47 (s, IH), 6.79 (d, 1H), 6.99 (m, 3H), 7.12 (m, 4H), 7.20 (m, 3H), 7.31 (m, 1H) ppm. MS (electrospray) m/z 540 [M+H]* 41 (N 1 7HNMR (CD 3 OD, 400MHz) 5: 0.91 (m, 2H), H 1.08 (s, 3H), 1.19 (m, 3H), 1.46 (m, 1H), 1.68 (m, 5H), 2.56 (m, IH), 2.74 (m, 2H), 2.86 (m, 5H), 2.98 (d, 2H), 3.46 (s, 2H), 4.60 (m, 1H), 6.80 (d, 1H), 6.98 (m, 2H), 7.09 (m, 2H), 7.18 (m, 1H), 7.28 (m, 1H) ppm. MS (electrospray) m/z 518 [M+H]* 42 cl 'HNMR (CD 3 OD, 400MHz) 8: 1.03 (t, 3H), N 2.58 (m, IH), 2.69 (m, IH), 2.84 (m, 5H), F 3.53 (s, 2H), 4.41 (s, 2H), 4.61 (m, 1H), 6.81 (d, 1H), 6.97 (m, 2H), 7.07 (m, 3H), 7.14 (d, 1H), 7.24 (m, IH), 7.28 (m, 2H) ppm. MS (electrospray) m/z 564 [M+H]+ 43 cI 1 HNMR (CD 3 0D, 400MHz) 8: 1.06 (t, 3H), N 2.57 (m, IH), 2.70 (m, IH), 2.84 (m, 5H), F 3.53 (s, 2H), 4.40 (s, 2H), 4.61 (m, IH), 6.80 (d, 1H), 6.97 (m, 3H), 7.11 (m, 2H), 7.17 (m, 2H), 7.27 (m, 2H) ppm. MS (electrospray) m/z 564 [M+H]f WO 2005/080324 PCT/IB2005/000112 116 44 {- Cl 'HNMR (CD 3 0D, 400MHz) 8: 1.06 (t, 3H), 2.57 (m, IH), 2.70 (m, 1H), 2.84 (m, 5H), ci 3.53 (s, 2H), 4.40 (s, 2H), 4.61 (m, IH), 6.82 (d, 1H), 6.97 (d, 1H), 7.01 (d, IH), 7.07 (m, 1H), 7.13 (m, 3H), 7.20 (m, IH), 7.25 (m, 1H), 7.27 (m, 1H) ppm. MS (electrospray) m/z 580 [M+H]* 45 {,N HNMR (CD 3 0D, 400MHz) 8: 1.08 (t, 3H), F 2.55 (m, IH), 2.71 (m, 1H), 2.84 (m, 5H), F F 3.53 (s, 2H), 4.39 (s, 2H), 4.61 (m, 1H), 6.81 (d, 1H), 7.01 (m, 2H), 7.08 (m, 2H), 7.10 (m, IH), 7.14 (m, IH), 7.40 (m, 2H), 7.55 (d, 2H) ppm. MS (electrospray) m/z 580 [M+H]* 46 {>N ci 1 HNMR (CD 3 OD, 400MHz) 8: 1.06 (t, 3H)., 2.55 (ni, 1H), 2.73 (m, IH), 2.84 (m, 5H), Cl 3.53 (s, 2H), 4.39 (s, 2H), 4.61 (m, 1H), 6.81 (d, IH), 6.98 (d, 1H), 7.02 (d, 1H), 7.09 (m, IH), 7.14 (m, 1H), 7.20 (m, 3H), 7.31 (m, 2H) ppm. MS (electrospray) m/z 580 [M+H]* 47 F F 1 HNMR (CD 3 0D, 400MHz) 8: 1.06 (t, 3H), F N 2.55 (m, IH), 2.73 (m, 1H), 2.84 (m, 5H), H 3.53 (s, 2H), 4.39 (s, 2H), 4.61 (m, 1H), F 6.80 (d, 1H), 6.97 (m, 2H), 7.11 (m, 2H), 7.30 (m, 3H), 7.41 (m, 2H) ppm. MS (electrospray) mIz 596 [M-H] WO 2005/080324 PCT/IB2005/000112 117 48 (-- F HNMR (CD 3 OD, 400MHz) 8: 1.06 (t, 3H), F 2.55 (m, 1H), 2.73 (m, 1H), 2.84 (m, 5H), F F 3.53 (s, 2H), 4.39 (s, 2H), 4.61 (m, IH), 6.81 (d, IH), 6.98 (m, 3H), 7.02 (m, 3H), 7.16 (m, 2H), 7.27 (m, 1H), 7.51 (m, 2H) ppm. MS (electrospray) mlz 596 [M-H]~ 49 F 1 HNMR (CD 3 OD, 400MHz) 8: 1.04 (t, 3H), F F 2.56 (m, 1H), 2.73 (m, 1H), 2.83 (m, 5H), F 3.53 (s, 2H), 4.39 (s, 2H), 4.60 (m, 1H), 6.81 (d, IH), 7.00 (m, 3H), 7.08 (m, 2H), 7.10 (m, 2H), 7.22 (m, 3H), 7.29 (m, IH), 7.73 (m, 2H) ppm. MS (electrospray) m/z 598 [M+H]+ 50 CH, 1 HNMR (CD 3 0D, 400MHz) 5: 1.04 (t, 3H), 2.35 (s, 3H), 2.53 (m, 1H), 2.70 (m, 2H), ci c1 2.85 (m, 5H), 3.43 (s, 2H), 4.48 (s, 2H), 4.62 (m, 1H), 6.80 (d, 1H), 6.99 (m, 2H), 7.05 (m, 2H), 7.18 (m, 2H), 7.29 (m, 2H) ppm. MS (electrospray) m/z 594 [M+H]4 51 F 1 HNMR (CD 3 0D, 400MHz) 8: 1.06 (d, 3H), F F 2.60 (m, 2H), 2.71 (m, 2H), 2.89 (s, 3H), H F ci 2.91 (m, 1H), 3.74 (s, 2H), 4.37 (s, 2H), 6.80 (d, IH), 6.97 (d, 1H), 7.03 (d, 1H), 7.08 (s, IH), 7.12 (d, IH), 7.20 (t, 1H), 7.26 (s, IH), 7.44 (d, IH), 7.51 (d, IH), 7.60 (s, IH) MS (electrospray) m/z 614 [M+H]* WO 2005/080324 PCT/IB2005/000112 118 52 F 'HNMR (CD 3 OD, 400MHz) 8 1.08 (d, 3H), NF H F F 2.58 (in, 2H), 2.71 (in, 2H), 2.90 (s, 3H), H F M2.91 (in, 1), 3.57 (s, 2H), 4.49 (s, 2H), 6.80 (d, 1H), 6.96 (d, 1H), 7.04 (d, IH), 7.10 (s, 1H), 7.15 (d, 1H), 7.21 (d, 1H), 7.28 (s, 1H), 7.55 (m, 3H) ppm. MS (electrospray) m/z 614 [M+H]* 53 F 'HNMR (CD 3 0D, 400MHz) 5: 1.08 (d, 3H), F F 2.60 (m, 2H), 2.68 (m, 2H), 2.89 (s, 3H), 2.92 (m, IH), 3.55 (s, 2H), 4.48 (s, 2H), 6.79 (d, 1H), 6.97 (d, 1H), 7.03 (d, IH), 7.08 (s, 1H), 7.13 (d, 1H), 7.21 (t, IH), 7.27 (s, 1H), 7.80 (m, 3H) ppm. MS (electrospray) mlz 648 [M+H]* 54HNMR (CD 3 0D, 400MHz) 6: 1.08 (d, 3H), F F 2.57 (m, 2H), 2.68 (m, 2H), 2.90 (s, 3H), 2.92 (m, 1H), 2.56 (s, 2H), 4.42 (s, 2H), 6.80 (d, 1H), 6.93-7.24 (m, 6H), 7.28 (m, 2H), 7.36 (m, 1H) MS (electrospray) m/z 598 [M+H]+ 55 CH 3 'HNMR(400MHz, DMSOde) 6:1.06 (d, 3H), 2.23 (s, 3H), 2.26 (s, 6H), 2.53-2.58 (m,
H
3 C CH 3 1H), 2.71-2.76 (m, 2H), 2.85-2.96 (m, 5H), 3.47 (s, 2H), 4.36 (s, 2H), 4.62-4.64 (m, IH), 6.83-6.85 (m, 3H), 6.99-7.02 (m, 2H), 7.08 (m, 1H), 7.12-7.19 (m, 2H), 7.32-7.33 (m, 1H) ppm. MS (electrospray) m/z 554 [M+H]*, 576 [M+Na]+ WO 2005/080324 PCT/IB2005/000112 119 56 cl 1HNMR(400MHz, DMSOd 6 ) 3: 1.04 (d, 3H), I'ci 2.51-2.56 (m, 1H), 2.69-2.74 (m, 2H), 2.83 ci 2.95 (m, 5H), 3.47 (s, 2H), 4.58-4.62 (m, 1H), 4.87 (s, 2H), 6.81 (d, 1H), 6.97-6.99 (m, 2H), 7.05-7.10 (m, 2H), 7.15-7.19 (m, IH), 7.30 (m, 1H), 7.38 (d, IH), 7.48 (d, IH) ppm. MS (electrospray) mlz 614/616 [M+H]*, 636/638 [M+Na]+ 57 cl 1HNMR(400MHz, DMSOd6) 8:1.07 (d, 3H), N cl 2.56-2.61 (m, IH), 2.71-2.77 (m, 2H), 2.84 2.90 (m, 5H), 3.55 (s, 2H), 4.46 (s, 2H), 4.58-4.61 (m, 1H), 6.81 (d, 1H), 6.81 (d, 1H), 6.96-6.99 (m, 1H), 7.02-7.04 (m, 1H),, 7.11-7.23 (m, 5H), 7.29-7.30 (m, IH), 7.41 7.44 (m, 1H) ppm. MS (electrospray) m/z 580/582 [M+H]*, 602/604 [M+Na]* 58 N cl 'HNMR(400MHz, DMSOde) 3: 1.05 (d,.3H), H
CH
3 2.30 (s, 3H), 2.55-2.60 (m, IH), 2.69-2.75 (m, 2H), 2.83-2.96 (m, 5H), 3.51 (s, 2H), 4.29 (s, 2H), 4.58-4.60 (m, 1H), 6.80 (d, IH), 6.96-7.22 (m, 8H), 7.29 (m, 1H) ppm. MS (electrospray) m/z 560 [M+H]*, 682 [M+Na]* 59 IHNMR (CD 3 0D, 400MHz) 8: 0.98 (d, 3H), VN 2.48 (m, IH), 2.62 (m, 2H), 2.80 (m, 2H), H 2.89 (s, 3H), 3.50 (s, 2H), 4.56 (m, 1H), 4.80 (s, 2H), 6.80 (d, IH), 6.98 (m, 3H), 7.20 (m, 2H), 7.30 (s, IH), 7.40 (m, 4H), 7.80 (d, 1H), 7.84 (d, 1H), 7.98 (d, IH) ppm. MS (electrospray) m/z 562 [M+H]+ WO 2005/080324 PCT/IB2005/000112 120 60 { N HNMR (CD30D, 400MHz) : 1.05 (d, 3H), 2.60 (m, IH), 2.68 (m, 2H), 2.80 (m, 4H), 2.99 (m, IH), 3.58 (s, 2H), 4.48 (s, 2H), 4.60 (m, IH), 6.80 (d, IH), 6.98 (d, 1H), 7.02 (d, 1H), 7.18 (d, 2H), 7.20 (m, 4H), 7.78 (dd, 1H), 8.42 (d, IH) ppm. MS (electrospray) m/z 513 [M+H] 61 F 'HNMR (CD 3 0D, 400MHz) 5: 1.05 (d, 3H), H F 2.60 (m, IH), 2.71 (m, 2H), 2.93 (m, 5H), F 3.50 (s, 2H), 4.40 (s, 2H), 4.58 (m, IH), 6.80 (d, I H), 7.00 (in, 2H), 7.18 (mn, 5H), 7.33 (m, 3H) ppm. MS (electrospray) m/z 596 [M+H]* 62 ( 1 HNMR (CD30D, 400MHz) 8: 1.05 (d, 3H), cN 2.60 (m, 1H), 2.71 (m, 2H), 2.91 (m, 5H), 3.56 (s, 2H), 4.40 (s, 2H), 4.60 (m, IH), 6.80 (d, 1H), 6.98 (d, IH),. 7.04 (d, IH), 7.08 (s, IH), 7.14 (d, 1H), 7.20 (m, 1H), 7.30 (s, IH), 7.40 (d, 2H), 7.61 (d, 2H) ppm. MS (electrospray) mlz 537 [M+H]+ 63 {HNMR (CD30D, 400MHz) 8: 1.04 (d, 3H), H 2.60 (m, IH), 2.70 (m, 2H), 2.78 (m, IIH), 3.48 (s, 2H), 4.21 (s, 2H), 4.58 (m, 1H), 6.76 (d, 2H), 6.80 (d, 2H), 7.00 (m, 5H), 7.30 (s, I H) ppm. MS (electrospray) m/z 555 [M+H]+ WO 2005/080324 PCT/IB2005/000112 121 6; 'HNMR (CD 3 0D, 400MHz) 6: 1.05 (d, 3H), 2.60 (m, IH), 2.68 (m, 2H), 2.91 (m, 4H), 2.98 (m, 1H), 3.62 (s, 2H), 4.58 (m, 1H), 6.80 (d, IH), 7.00 (m, 3H), 7.20 (m,63H), 7.58 (d, 2H) ppm. MS (electrospray) m/z 498 [M+H]* 65 HNMR (CD 3 0D, 400MHz) 8: 1.05 (d, 3H), 1.50 (m, 2H), 1.78 (m, 2H), 2.11 (m, 2H), 2.60 (m, 1H), 2.78 (m, 3H), 2.80 (s, 3H), 2.98 (m, IH), 3.44 (s, 2H), 3.50 (s, 2H), 3.61 (m, 1H), 4.60 (m, IH), 6.80 (d, IH), 7.00 (m, 2H), 7.20 (m, 9H) ppm. MS (electrospray) m/z 709 [M+H]* Examples 66 to 73 OH H N
'H
3 C CH. HO Q 0 HN, // //s1- CH3 0 No Q' Data 6 (N CI HNMR (CD30D, 400MHz) 8: 1.07 (s, 3H), H C1.08 (s, 3H), 2.64-2.88 (m, 4H), 2.89 (s, 3H), 3.52 (s, 2H), 4.34 (m, 2H), 4.61-4.67 (m, IH), 6.85 (d, IH), 7.05-7.10 (m, 3H), 7.14-7.20 (m, 3H), 7.35 (d, 1H), 7.41 (d, IH) ppm. MS (electrospray) m/z 592 [M-HI~ WO 2005/080324 PCT/IB2005/000112 122 67 cI 'HNMR (CD 3 OD, 400MHz) 5: 1.10 (s, 6H), N 2.87 (s, 3H), 3.56 (s, 2H), 4.53 (s, 2H), 4.80 H (~In IH), 6.86 (d, I H), 7.08 (in, 3H), 7.22 (in, F F F 2H), 7.35 (i, IH), 7.57 (i, 3H) ppm. MS (electrospray) mlz 628 [M+H+ 68 F 'HNMR (CD 3 OD, 400MHz) 5: 1.10 (s, 6H), NF 2.87 (s, 3H), 3.56 (s, 2H), 4.53 (s, 2H), 4.80 H F (m, 1H), 6.92 (d, 1H), 7.21 (m, 3H), 7.28 (m, 2H), 7.43 (s, IH), 7.48 (q, 2H), 7.60 (s, IH) ppm. MS (electrospray) m/z 628 [M+H 69 F -HNMR (CD 3 OD, 400MHz) 8: 1.27 (s, 6H), F F 2.93 (s, 2H), 3.10 (mn, 2H), 3.36 (mn, 2H), 3.60 (s, 2H), 4.52 (s, 2H), 4.79 (, IH), mF 6.90 (d6 (H), 7.20 (m, 3H), 7.26 (d, 2H) 7.40 (s, H), 7.82 ( q2, 3H) ppm. MS (electrospray) m/z 662 [M+H+ 70 F 'HNMR (CD 3 0D, 400MHz) 8: 1.24 (s, 6H), F F 2.92 (s, 5H), 3.09 (m, 2H), 3.55 (s, 2H), 4.40 (s, 2H), 4.77 (s, IH), 6.90 (d, IH), 7.18 (d, 4H), 7.27 (m, 3H), 7.37 (s, IH), 7.41 (i, 1H) ppm. MS (electrospray) m/z 612 [M+H]* 71 F 'HNMR (CD 3 0D, 400MHz) 8: 1.24 (s, 6H), N 2.92 (m, 5H), 3.09 (m, 2H), 3.55 (s, 2H), 4.40 (s, 2H), 4.77 (m, IH), 6.90 (d, IH), F F 7.16-7.30 (m , 6H), 7.41 (s, H), 7.58 (i, 2H) ppm. MS (electrospray) m/z 612 [M+H]* WO 2005/080324 PCT/IB2005/000112 123 72 F F 'HNMR (CD 3 0D, 400MHz) 5: 1.24 (s, 6H), F N 2.92 (m, 5H), 3.09 (m, 2H), 3.55 (s, 2H), H 4.40 (s, 2H), 4.77 (m, IH), 6.88 (d, IH), 7.13-7.26 (m, 6H), 7.41 (s, IH), 7.53 (m, 2H) ppm. MS (electrospray) m/z 612 [M+H]* 73 F 1 HNMR (CD 3 OD, 400MHz) 6: 1.13 (s, 6H), F F 2.93 (s, 2H), 3.11 (m, 2H), 3.37 (m, 4H), F 3.60 (s, 2H), 4.53 (s, 2H), 4.80 (m, IH), 6.91 (d, IH), 7.12-7.32 (m, 6H), 7.44 (m, 3H) ppm. MS (electrospray) m/z 612 [M+H]* Examples 74 to 77 OH H HNN O CH3 No Q' Data 74 0C 'HNMR (CD 3 0D, 400MHz) 8: 1.09 (d, 3H), ("N 2.60 (m, 1H), 2.68 (m, 2H), 2.88-2.93 (m, H 2H), 2.91 (s, 3h), 3.52 (s, 2H), 3.80 (s, 2H), 4.36 (s, 2H), 4.57 (dd, 1h), 6.76 (d, 1H), 6.82 (d, IH), 6.93 (m, IH), 7.04 (m, 2H), 7.15 (m, 3h), 7.20 (d, 1H), 7.18 (d, 1H) ppm. MS (electrospray) m/z 542 [M+H]* WO 2005/080324 PCT/IB2005/000112 124 75 ONCH 3 HNMR (CD30D, 400MHz) 6: 1.08 (d, 3H), {N1.35 (t, 3H), 2.58 (dd, 1H), 2.88-2.95 (m, H 2H), 2.99 (s, 3H), 3.52 (s, 2H), 4.37 (s, 2H), 4.57 (dd, 1H), 6.76 (d, 1H), 6.83 (t, IH), 6.90 (d, 2H), 7.13 (m, IH), 7.17 (d, 2H), 7.19 (dd, 1H), 7.28 (d, IH) ppm. MS (electrospray) m/z 556 [M+H]+ 76 N 'HNMR (CD30D, 400MHz) 6: 1.05 (d, 3H), 2.55-2.60 (m, I H), 2.60-2.70 (m, 2H), 2.80 2.95 (m, 5H), 3.50 (s, 2H), 4.35 (s, 2H), 4.55 (m, 1H), 6.75 (d, 1H), 6.95 (dd, IH), 7.05 (d, 2H), 7.18-7.35 (m, 8H) ppm. MS APCI+ m/z 512 [M+H]* 77 {~1 N HNMR (CD 3 OD, 400MHz) 6: 1.05 (d, 3H), 1.80 (m, 2H), 2.50-2.80 (m, 5H), 2.80-2.95 (m, 5H), 3.20 (q, 2H), 3.45 (s, 2H), 4.55 (t, 1H), 6.78 (d, 1H), 6.95 (dd, 1H), 7.00-7.30 (m, IOH) ppm. MS (electrospray) m/z 540 [M+H]* Example 78 : N-(2,3-dihydro-1H-inden-2-yl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2 {4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl} phenyl)acetamide OH H H HO N N HN H 5 /SCH The product of preparation 107 (157mg, 0.21mmol), ammonium formate (66mg, 1.0mmol) and 20% Pd/C (5mg) were dissolved in ethanol (10ml) and the reaction mixture heated at reflux for 3 hours. The reaction mixture was WO 2005/080324 PCT/IB2005/000112 125 cooled to 50 0 C, treated with a solution of ammonium fluoride (40mg, 1.Ommol) in water (1ml) and then stirred at 50 0 C for 18 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and 0.880 ammonia solution. The organic layer was dried (magnesium sulphate) 5 and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.880 ammonia 98:2:0 to 95:5:0.5 to 90:10:1 to yield the title product, 90mg. 'HNMR (CD 3 OD, 400MHz) 8: 1.06 (t, 3H), 2.53-2.97 (m, 12H), 3.23 (m, 2H), 3.45 (m, 2H), 4.56 (m, 2H), 6.81 (m, I H), 6.96-7.31 (m, 11 H) ppm. 10 MS (APCI) m/z 538 [M+H]* Examples 79 - 81 The following compounds, of the general formula shown below, were prepared by a method similar to that described for example 78 using the appropriate 15 aide starting material. OH H N
H
3 0 0 HN, 'S No. Q' Data 79 --HNMR (CD 3 0D, 400MHz) 8: 1.08 (t, 3H), 2.55-2.93 o (m, 8H), 3.51 (m, 2H), 3.80 (s, 3H), 4.35 (m, 2H), 4.58 (m, 1H), 6.81 (m, 2H), 6.97 (m, 1H), 7.02 (m, 2H), 7.09 (m, 1H), 7.13 (m, 2H), 7.21 (m, 2H), 7.27 (m, IH) MS (APCI) m/z 542 [M+H]* 80 N -f 1 HNMR (CD 3 0D, 400MHz) 8: 1.06 (t, 3H), 2.54-2.91 (m, 8H), 3.52 (m, 2H), 4.36 (m, 2H), 4.60 (m, 1H), 6.80 WO 2005/080324 PCT/IB2005/000112 126 (d, 1H), 6.97-7.11 (m, 11H) ppm. MS (APCI) m/z 512 [M+H]* 81 'HNMR (CD 3 0D, 400MHz) 8: 1.26 (m, 3H), 2.76 (m, 3H), 2.91 (m, 2H), 3.16 (m, 2H), 3.32 (m, 6H), 3.43 (m, H 1H), 3.56 (m, IH), 6.90 (d, 1H), 7.12-7.30 (m, IOH), 7.41 (m, IH) ppm. Unless otherwise stated all reactions were carried out under a nitrogen atmosphere. 5 Abbreviations TBDMS = tert-butyl(dimethyl)silyl IPA: isopropyl alcohol THF: Tetrahydrofurans = singlet d = doublet 10 dd = double doublet t = triplet q = quartet m = multiplet bs = broad singlet e.g. NH, or OHIn vitro activity -of the compounds of 15 formula (1) The ability of the compounds of the formula (1) to act as potent P2 agonists therefore mediating smooth muscle relaxation may be determined by the measure of the effect of beta-2 adrenergic receptor stimulation on electrical field stimulated-contraction of guinea pig trachea strips. 20 Guinea-piq trachea Male, Dunkin-Hartley guinea pigs (475-525g) are killed by CO 2 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 25 opened by cutting the cartilage opposite the trachealis muscle, then transverse WO 2005/080324 PCT/IB2005/000112 127 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 pM Indomethacin 5 -(Sigma 17378), 10 [tM Guanethidine (Sigma G8520) and 10 pM Atenolol (Sigma A7655), heated at 37 0 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 10 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, 10 Hz and just-maximal voltage (25 Volts) continuously throughout the length of the experiment. EFS of post-ganglionic 15 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 1 minute) throughout the experiment, with the exception of when a beta-2 agonist according to the 20 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 25 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, 30 bolus addition to the bath using half log increments in concentration. The concentration range used is 1 *-9 to 1
*/
3 "-6 M. At the end of the isoprenaline curve the preparations are washed again for 40 minutes before commencing a WO 2005/080324 PCT/IB2005/000112 128 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 5 induced by isoprenaline in Curve 1. The EC 50 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 (EC 5 0 beta-2 agonist)/(EC50 Isoprenaline). 10 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 ICI 118551 (a selective P2 antagonist) which results in 15 the case of a beta-2 mediated effect in a rightward-shift of the test compound dose response curve. According to another alternative, the agonist potency for the P2 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 20 produce half maximal effect (EC 5 o) for the P2 receptor. Compound Preparation 10 mM/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 semi-log dilution curve, all in 4 % DMSO. Isoprenaline (Sigma, 1-5627) was 25 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 recombinantly expressing the human P2 adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et WO 2005/080324 PCT/IB2005/000112 129 al., Mol Pharmacol 33: 133-139 1988 CHOhp2) 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/mI puromycin (Sigma, P8833). 5 Cells were seeded to give about 90 % confluency for testing. Assay Method 25 pl / 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 pl / well PBS. Cells 10 were trypsinised (0.25% Sigma, T4049), washed with PBS (Gibco, 14040-174) and resuspended in stimulation buffer (NEN, SMP004B) to give 1x106 cells / ml CHOhB2. Compounds were incubated with 50 pl / well cells for 1 hour. Cells were then lysed by the addition of 100 pl / well detection buffer (NEN, SMP004B) containing 0.18 pCi / ml 1-cAMP (NEN, NEX-130) and plates were 15 incubated at room temperature for a further 2 hours. The amount of 1 25 1-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 20 present invention that are illustrated in examples 1 to 81 above show a P2 cAMP EC 50 between 0.02 nM and I nM. The following table illustrates the activity of the compounds of the invention: Example EC 50 (nM) 1 0.02 2 0.03 6 0.07 12 0.05 15 0.03 17 0.08 25 0.08 26 0.09 31 0.04 38 0.06 39 0.05 WO 2005/080324 PCT/IB2005/000112 130 45 0.06 60 0.02 67 0.08 76 0.02

权利要求:
Claims (29)
[1] 1. A compound of general formula (1): OH H N HO G(CH2) Q 1) HOR R2 NHSO 2 CH 3 0 wherein the (CH 2 )n-C(=O)Ql group is in the meta or para position, R 1 and R 2 5 are independently selected from H and C1C4 alkyl, n is 0, 1 or 2 and Q 1 is a group selected from: RR3 R3 R4 R 3 R (CH 2 )p R 5 -N R 5 w/R 6 R 6 and a group *-NRll-Q 2 -A, wherein p is 1 or 2, Q 2 is a C1C4 alkylene, R" is H or C1C4 alkyl and A is pyridyl, C3-C10 cycloalkyl, said cycloalkyl being optionally 10 bridged by one or more carbon atoms, tetrahydropyranyl, piperidinyl optionally substituted with benzyl, tetrahydrothiopyranyl or a group R 3 R4 R 3 _R4 R R5 or R R wherein R', R4, R', R and R are the same or different and are selected from H, Cr1C4 alkyl, OR", SR9, halo, CN, CF 3 , OCF 3 , COOR 9 , S0 2 NR 9 R 1 a 15 CONR R 1 , NR 9 R 0 , NHCOR' 0 and phenyl; WO 2005/080324 PCT/IB2005/000112 132 wherein R 8 is CrC4 alkyl and R and R 10 are the same or different and are selected from H or Cr1C4 alkyl and the * represent the attachment point to the carbonyl group; or, if appropriate, their pharmaceutically acceptable salts and/or isomers, 5 tautomers, solvates or isotopic variations thereof.
[2] 2. A compound according to claim I wherein Q 1 is NH-Q 2 -A, wherein Q2 is CH 2 and A is cyclohexyl, tetrahydrothiopyranyl, piperidinyl optionally substituted with benzyl, or naphthyl.
[3] 3. A compound according to claim 1 wherein Q 1 is R 3 R4 10 R 6 ,wherein R 3 , R 4 , R 5 and R 6 are H.
[4] 4. A compound according to claim 1 wherein Q is a group *-NHQ2 -A, wherein Q2 is a C-C4 alkylene and A is a group R3 R4 / R5 R 7 R6 15 wherein R 3 , R 4 , R 5 , R 6 and R7 are the same or different and are selected from H, C-C 4 alkyl, OR', SR', CN, halo, CF 3 , OCF 3 , S0 2 NR 9 R'", CONRR", NR 9 R 10 , NHCOR' 0 and phenyl provided at least 2 of R 3 to R 7 are equal to H; wherein R8 is C1C4 alkyl and R 9 and R1 are the same or different and are selected from H or Cr1C4 alkyl. WO 2005/080324 PCT/IB2005/000112 133
[5] 5. A compound according to claim 4 wherein Q 2 is -CH 2 -, -(CH 2 ) 2 - or -(CH 2 ) 3 .
[6] 6. A compound according to claim 5 wherein Q 2 is -CH 2 -
[7] 7. A compound according to any one of claims 4 to 6 wherein A is a group R3 R4 R5 R 7 R6 5 wherein R3, R4, R , R6 and R7 are the same or different and are selected from H, CH 3 , OCH 2 -CH 3 , SCH 3 , halo, CF 3 , OCF 3 , phenyl, dimethylamino, CN, tert butyl, provided at least 2 of R 3 to R 7 are equal to H. 3 4 5 6 7
[8] 8. A compound according to claim 7 wherein R3, R , R5, R and R are the same or different and are selected from H, CH 3 , Cl, F, CF 3 provided at least 2 10 of R 3 to R 7 are equal to H.
[9] 9. A compound according to any one of claims 1 to 8 wherein R 1 is H or C-C4 alkyl and R2 is C1C4 alkyl.
[10] 10. A compound according to claim 9 wherein R 1 is H or CH 3 and R 2 is CH 3 .
[11] 11. A compound according to claim 10 wherein n is 1. 15 12. The (R,R)-stereoisomer of a compound according to any one of claims I to 11.
[12] 13. A compound according to any one of claim I to 11 wherein the (CH 2 )n C(=O)Ql group is in the meta position.
[13] 14. A compound according to claim 1 selected from the group consisting of 20 N-Benzyl-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, WO 2005/080324 PCT/1B200510001 12 134 2-(3-{2-[((2R)-2-Hyd roxy-2-{4-hydroxy-3-[(methylsulfonyl )amino] phenyllethyl) amino]-2-methyl propyl}phenyl )-N-(4-methoxybenzyl )acetamide 2-(3-{2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsulfonyl )aminolphenyl} ethyl )aminol-2-methylpropyllphenyl)-N-(2-methoxybenzyl)acetamide, 5 N-(2-Ethoxybenzyl )-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3-[(methylsu Ifonyl) amino] phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, 2-(3-{2-[((2R)-2-Hyd roxy-27{4-hyd roxy-3-[(methylsulfonyl)a mino] phenyl} ethyl)amino]-2-methylpropyl}phenyl)-N-(3-methoxybenzyl)acetamide, 2-(3-{2-[((2R)-2-Hyd roxy-2-{4-hydroxy-3-[(methylsulfonyl )aminol phenyl} 10 ethyl )ami no]-2-methylpropyl~phenyl)-N-(4-methylbenzyl )acetamide, 2-(3-{2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsulfonyl )aminol phenyllethyl) am ino]-2-methylp ropyllp henyl)-N-(2-methyl benzyl)aceta mid e, 2-(3-{2-I((2 R)-2-Hydroxy-2-{4-hyd roxy-3-[(methylsulfonyl )aminolphenyllethyl) amino]-2-methylpropyl}phenyl )-N-(3-methylbenzyl)acetamid e, 15 N-(3,4-Dimethoxybenzyl )-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(m ethyls ulfonylam ino] phe nyl}ethyi)am ino]-2-methylp ro pyl}p henyl)aceta mid e, N-(2,4-Dimethoxybenzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methylsulfonyl)amino]phenyl}ethyl)aminol-2-methylpropyl}phenyl)acetamide, N-(3 ,5-Di methoxybenzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 20 [(methylsulIfo nyl )am ino] ph enyl}ethyl)a m ino]-2-methylp ro pyl} ph enyl)aceta mid e, N-(4-Chlorobenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hyd roxy-3-[(methylsu Ifonyl) am ino]p hen yjeth yl)a mi nol-2-methyl pro pyllph enyl )aceta mid e, N-(2-G hIo ro benzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3-[(m ethyl su Ifon yl) am ino] phenyl}ethyl)a mi nol-2--methyl pro pyl}p henyl)aceta mide, 25 N-(3-Chlorobenzy)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3-[(methylsu Ifonyl) am ino] phenyl}ethyl)a mi nol-2-methyl pro pyl}p henyl)acetam ide, N-(4- Fluo rob enzyl )-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3-[(methyl su Ifo nyl) amino]phenyllethyl)amino]-2-methylpropyllphenyl)acetamide, N-(2 ,4-D ichlo robe nzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 30 [(methylsu lfonyl)aminolphenyllethyl)ami no]-2-methylpropyllphenyl)aceta mid e, N-(3 ,4-Dichlo robenzyl )-2-(3-{2-[((2R)-2-hyd roxy-2-{4.-hyd roxy-3 [(methylsulIfonyl )a m ino] phenyl}ethyl)a mi no]-2-methyl pro pyllp he nyl)aceta mid e, WO 2005/080324 PCT/1B200510001 12 135 N-(4-tert-B utylbenzyl )-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3-[(methylsu Ifony1) amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, N-(2-Chloro-6-fluorobenzyl)-2-(3-{2.4((2R)-2-hyd roxy-2-{4-hydroxy-3 [(methylsulfonyl)aminolphenyllethyl )amino]-2-methylpropyllphenyl)acetamide, 5 N-(2, 3-Dimethylbenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hyd roxy-3 [(methylsulfonyl)amino]phenyllethyl)amino]-2-methylpropyl}phenyl)acetamide, N-(3,5-Dichlorobenzy)-2-(3-{2-I((2R)-2-hyd roxy-2-{4-hydroxy-3 [(methylsu Ifo nyl )amnino] phe nyl}ethyl)a minol-2-methylpropyl}ph enyl)aceta mid e, N-[3 ,5-bis(Trifluoromethy)benzyl]I-2-(3-{2-[((2R)-2-hydroxy-2-{4-hyd roxy-3 10 [(methyls ulfonyl)ami no] ph enyl}ethyl)a m ino]-2-methylp ropyl} ph enyl)aceta mid e, N-(3 ,4-Dimethyl benzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(m ethyls ulfonyl)am ino] phenyl}ethyl)a mi no]-2-methylp ropyl} phe nyl)aceta mid e, N-(2 ,5-Dichlorobenzyl)-2-(3-{(2R)-2-I((2R)-2-hyd roxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyllethyl)arninolpropyllphenyl)acetamide, 15 2-(3-{2-I((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyI)ami no] phenyl} ethyl )a mi no]-2-methyl propyil~phe nyl)-N-(2-phenylethyi)aceta mid e, 2-(3-{2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsulfonyl)aminolphenyllethyl) amino]-2-methylpropyl}phenyl)-N-(3-phenylpropyl)acetamide, N-(2 ,3-.Dichlo robe nzyl)-2-(3-{(2 R)-2-[((2R)-2-hyd roxy-2-(4-hyd roxy-3 20 [(methylsulfonyl)aminojphenyl}ethyl)amino]propyl}phenyl)acetamide, N-(2 ,4-Dichloro-6-methyl benzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3 [(methyls ulfo nyl)am i no] phe nyllethyl)a minoj-2-methyl pro pyl} ph enyl)aceta mid e, N-(Cyclohexyl methyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3 [(methyi suIfo nyl)a m ino] phe nyllethyl)ami no]-2-.methyl pro pyl p he nyl)aceta mid e, 25 N-(2-Chloro-6-methylbenzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methyisulfonyl)amino]phenyllethyl)amino]-2-methylpropyllphenyl)acetamide, N-(2-Ethoxybenzyl)-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methyl su Ifonyl)a mi no] phe nyllethyl)a min o]pro pyl~p henyl)aceta mid e, N-(3 ,4-D imethylbenzyl)-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4-hydroxy-3 30 [(methylisu Ifonyl)a mi no] phe nyl}ethyl)a mino p ropyl~p henyl)aceta mid e, N-(3 ,4-Dichlorobenzyl)-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methylsu Ifonyl)aminolphenyllethyl)aminojpropyllphenyl)acetamide, WO 2005/080324 PCT/IB2005/000112 136 2-(3-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino]propyl}phenyl)-N-(3-phenylpropyl)acetamide, N-(Cyclohexylmethyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, 5 N-(2-Chloro-6-fluorobenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, N-(2-Chloro-4-fluorobenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, N-(3,5-Dichlorobenzyl)-2-(3-((2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 10 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, 2-(3-{(2R)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl} ethyl)amino]propyl}phenyl)-N-[4-(trifluoromethyl)benzyllacetamide, N-(2,5-Dichlorobenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, 15 N-[4-Fluoro-2-(trifluoromethyl)benzyl]-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4 hydroxy-3-[(methylsulfonyl)amino] phenyl}ethyl)amino]propyl}phenyl)acetamide, N-[4-Fluoro-3-(trifluoromethyl)benzyl]-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4 hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, N-[2-Fluoro-4-(trifluoromethyl)benzyl]-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4 20 hydroxy-3-[(methylsulfonyl)aminolphenyl}ethyl)amino]propyl}phenyl)acetamide, N-(2,4-Dichloro-6-methylbenzyl)-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, N-[4-Chloro-3-(trifluoromethyl)benzyl]-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4 hyd roxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, 25 N-[2-Chloro-5-(trifluoromethyl)benzyl]-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4 hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, N-[3,5-bis(Trifluoromethyl)benzyl]-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, N-[3-Fluoro-5-(trifluoromethyl)benzyl]-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4 30 hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide, N-(3,4-Dichlorobenzyl)-2-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}phenyl)acetamide, WO 2005/080324 PCT/1B200510001 12 - 137 N-[2-Chloro-5-(trifluoromethyl )benzyl]-2.-(4-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3 [(methylsulfonyl)arninolphelyl}ethyl)aminoI-2-nlethylpropyllphel)acetamide, N-[4-Chloro-3-(trifl uoromethyl )benzyl]-2-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(m ethyl su Ifonyl)amni no] ph enyl}ethyl )ami no]-2-methyl propyllphenyi )acetarmid e, 5 N-[3 ,5-bis(Trifluoro methyl)benzyl]-2-(4-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3 [(methylsulIfo nyl)amni no]lphenyl}ethyl)a m inoI-2-m ethyl propyllph enyl)aceta mid e, N-[3-Fluoro-5-(trifluoromethyl)benzyll-2-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)aminolphenyl}ethyl)amino]-2-methyipropyllphenyl)acetamide, N-[2-Fluoro-5-(trifluoromethyl)benzyl]-2-(4-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3 10 [(methylsulIfo nyl)a mino] phe nyl}ethyl)a mi no]-2-methyl pro pyllphe nyl)acetam id e, N-[4-Fluoro-2-(trifluoromethyl)benzyll-2-(4-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3 [(methylsulfonyl)amino] phenyllethyl )aminol-2-methylpropyl}phenyl)acetamide, N-[4-Fluoro-3-(trifluoromethy )benzyl]-2-(4-{2-[((2R)-2-hydroxy-2-{4-hyd roxy-3 [(methyl suIfo nyl)a mino] ph enyllethyl)a mi no]-2-rnethyl pro pyl~p henyl)acetam ide, 15 2-(4-{(2R)-2-[((2R)-2-Hyd roxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] phenyl} ethyl)amino]propyllphenyl)-N-(2-methoxybenzyl)acetamide, N-(2-Ethoxybenzyl)-2-(4-{(2R)-2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(mnethylsulIfonyl)anin o] ph enyl}ethyl)a mi no] pro pyllph enyl)aceta mid e, N-13enzyl-2-(4-((2 R)-2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3-[(m ethyl sulfonyl)a mi no] 20 phenyl}ethyl)amino]propyllphenyl)acetamide, 2-(4-{(2 R)-2-[((2R)-2-Hyd roxy-2-{4-hydroxy-3-[(methylsulfonyl )ami nojphenyl} ethyl)a mi no] propyllp hen yl)-N-(3-phenyl propyl)aceta mid e, N-(2 ,3-Dihyd ro-1 H-i nden-2-yI )-2-(3-{(2R)-2-(((2R)-2-hyd roxy-2-(4-hyd roxy-3 [(methylsu to nyl )amni no] phe nyl}ethyl)a minolpro pyl}ph enyl)aceta mid e, 25 2-(3-{(2R)-2-[((2R)-2-Hyd roxy-2-{4-hydroxy-3-[(methylsu Ifonyl)amino] phenyl} ethyl)amino]propyllphenyl)-N-(2-methoxybenzyl)acetamide, N-B enzyl-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hyd roxy-3-[(methylsulfonyl) amnino] phenyllethyl)ami no]p ropyl}phenyl)aceta mide, 2-(3-{(2R)-2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsu Ifonyl )ami no] phenylI 30 ethyl)@amino]propyl}phenyl)-N-(2-phenylethyl)aceta mide, 2-(3-{(2R)-2-[((2R)-2-Hyd roxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] phenyl} ethyl)amino]propyl}phenyl)-N-(mesitylmethyl )acetamide, WO 2005/080324 PCT/1B200510001 12 138 2-(3-{(2R)-2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsulfonyl)amino] phenyl} ethyl)amino]propyilphenyl)-N-(2 ,3,6-trichlorobenzyl)acetamide, 2-(3-{2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsulfonyl)amino] phenyl}ethyl) amino]-2-methylpropyllphenyl )-N-[3-(trifluoromethyl )benzyljacetarnide, 5 N-(2 ,3-D ich loro ben zyl)-2-(3-{(2 R)-2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methyls ulfonyl)a mi no] phe nyllethyl)a m ino] propyllp henyl)aceta mid e, N-(3-Chloro-4-methylbenzyl)-2-(3-{(2R)-2-[((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methylsulfonyl)amino]phenyllethyl)amino]propyl}phenyl)acetamide, 2-(3-{2--[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsulfonyl )aminolpheny}ethyl) 10 amino]-2-methylpropyllphenyl)-N-[2-(methylthio)benzyl]acetamide, 2-(3-{2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsulfonyl)amino] pheny} ethyl)amino]-2-methylpropyllphenyl )-N-[4-(methylth io)benzyl]acetamide, 2-(3-{2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(rnethylsulfonyl)ami no]phenyl} ethyl )amino]-2-methylpropyl}pheny )-N-(tetrahyd ro-2H-th iopyran-4-yl)acetamide, 15 N-(Biphenyl-2-ylmethyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3 [(methylsulfonyl)aminolphenyl}ethyl)amino]-2-methylpropyllphenyl)acetamide, 2-(3-{(2R)-2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsulfony )amino] phenyl} ethyl)amino]propyllphenyl)-N-(l -naphthylmethyl)acetamide; 2-(3-{(2R)-2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsulfonyl )ami no] phenyll 20 ethyl)am ino] pro pyllp henyl)-N-(pyrid in-2-yl methyl )aceta mide, 2-(3-{(2R)-2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsulfonyl )amino] phenyl) ethyl)amino]propyllphenyl)-N-[4-(trifluoromethoxy)benzyllacetamide, N-(4-Cya nobenzyl )-2-(3-{(2R)-2-[I((2R)-2-hyd roxy-2-{4-hyd roxy-3 [(methylsulfonyl)arnino]phenyl}ethyl)amino]propyl}phenyl)acetamide, 25 N-[4.-(Dimethylami no)be nzyl]-2-(3-{(2R)-2-[((2R)-2-hydroxy-2-{4-hyd roxy-3 [(methylsulfonyl)amino]phenyl}ethyl)aminojpropyl~phenyl)acetamide, 2-(3-{(2R)-2-[((2R)-2-Hyd roxy-2-{4-hyd roxy-3-[(methylsu Ifo nyl )amino]phenyl} ethyl)amino]propyllphenyl)-N-phenylacetamide, N-( I -Benzyl p ipe rid in-4-yl )-2-(3-{(2R)-2-[((2R)-2-h yd roxy-2-{4-hyd roxy-3 30 [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}phenyl)acetamide and, WO 2005/080324 PCT/IB2005/000112 139 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino phenyllethyl) amino]-2-methylpropyl}phenyl)-N-(mesitylmethyl)acetamide.
[14] 15. N-Benzyl-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl) amino] phenyllethyl)amino]-2-methylpropyl}phenyl)acetamide. 5 16. 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] phenyl} ethyl) amino]-2-methylpropyl}phenyl)-N-(4-methoxybenzyl)acetamide
[15] 17. 2-(3-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] phenyl} ethyl)amino]-2-methylpropyl)phenyl)-N-(4-methylbenzyl)acetamide
[16] 18. N-(4-Chlorobenzyl)-2-(3-{2-[((2R)-2-hyd roxy-2-{4-hydroxy-3-[(methyl 10 sulfonyl)amino]phenyl)ethyl)amino]-2-methylpropyl}phenyl)acetamide
[17] 19. N-(3,4-Dichlorobenzyl)-2-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methyl sulfonyl)amino]phenyllethyl)amino]-2-methylpropyllphenyl)acetamide
[18] 20. A pharmaceutical composition including a compound of the formula (1) as described in any one of claims 1 to 19 or a pharmaceutically acceptable salt or 15 derived form thereof, together with customary pharmaceutically innocuous excipients and/or additives.
[19] 21. A compound of the formula (1) as described in any one of claims 1 to 19 or a pharmaceutically acceptable salt, derived form or composition thereof, for use as a medicament. 20 22. A compound of the formula (1) as described in any one of claims I to 19 or a pharmaceutically acceptable salt, derived form or composition thereof, for use in the treatment of diseases, disorders, and conditions in which the P2 receptor is involved.
[20] 23. A compound of the formula (1) as described in any one of claims 1 to 19 or 25 a pharmaceutically acceptable salt, derived form or composition 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, SUBSTITUTE SHEET (RULE 26) WO 2005/080324 PCT/IB2005/000112 140 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 5 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, 10 0 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 15 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 (ARDS), exacerbation of airways hyper 20 reactivity 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, 25 catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis, * acute lung injury, WO 2005/080324 PCT/IB2005/000112 141 * bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry 5 bronchiectasis and follicular bronchiectasis.
[21] 24. The use of a compound of the formula (1) as described in any one of claims 1 to 19 or of a pharmaceutically acceptable salt, derived form or composition thereof, for the manufacture of a drug having a P2 agonist activity.
[22] 25. The use of a compound of the formula (1) as described in claim I or of a 10 pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a drug for the treatment of diseases, disorders, and conditions selected from the group as described in claim 23.
[23] 26. A method of treatment of a mammal, including a human being, with a P2 agonist including treating said mammal with an effective amount of a compound 15 of the formula (1) as described in any one of claims 1 to 19 or with a pharmaceutically acceptable salt, derived form or composition thereof.
[24] 27. A method according to claim 26 where the disease, disorder or condition is selected from the group as described in claim 19.
[25] 28. A process for the preparation of a compound of formula (1) according to 20 any one of claims I to 19, said process comprising the following steps: (a) coupling an acid of formula (2): OH H O R(CH 2 ), OH HOO 0 NHSO2Me wherein R 1 , R 2 and n are as defined in claim 1, with an amine of formula NH 2 -Q 2 -A (3), WO 2005/080324 PCT/IB2005/000112 142 R1 R2 R 1 R 2 /R 3 H 2 N | HN R 3 R 4 (3'), or R 4 (3"), wherein R3 to R6, Q2 and A are as defined in claim 1, (b) isolating said compound of formula (1).
[26] 29. A process for the preparation of a compound of formula (1) according to 5 claim 1 wherein R1 and R2 are methyl and n is 1, said process comprising the following steps (a) reacting a compound of formula (21) OH H HO j NHSO 2 Me (21) where X is H, Li, K or Na and potentially an organic amine base or other metal 10 salt, with a suitable amine of formula NHR -Q2 -A (3) RR3 R3 R4 R 3 R N (CH 2 )P R 5 H 'R5 HN R 6 (3'), or R 6 (3") in the presence of a conventional coupling agent such as 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent such as pyridine 15 dimethylformamide and dimethylacetamide, optionally in the presence of an organic base and an additive, in order to obtain said compound of formula (1). (b) islolating said compound of formula (1). WO 2005/080324 PCT/IB2005/000112 143
[27] 30. A process according to claim 29 where said compound of formula (21) is obtained by hydrogenation of a compound of formula (22) -OH H O~ N ~r NHSO 2 Me 2 (22) wherein X is H, Na, Li or K and an potentially an organic amine or other metal 5 salts, in the presence of a suitable solvent such as methanol, IPA, THF and water and in the presence of a suitable catalyst such as palladium hydroxide on carbon or palladium on carbon.
[28] 31. A process according to claim 30 where said compound of formula (22) is obtained by by reacting a compound of formula (23) OH H N CC0 2 -C-c 4 alkyl S 0 NHSO 2 Me 10 (23) with M-OH wherein M is selected from Na, K or Li, optionally in the presence of a suitable solvent such as propionitrile, tetrahydrofunan or dioxane.
[29] 32. . A process according to claim 31 wherein said compound of formula (23) is 15 obtained by deprotecting a compound of formula (24) OTBDMS H N _ c 0 2 -C-c 4 alkyl NHSO2Me (24) WO 2005/080324 PCT/IB2005/000112 144 using a deprotecting agent such as tetrabutylammonium fluoride, HF, or triethylamine trihydrofluoride in the presence of a suitable solvent such as propionitrile. 5 33. A process according to claim 32 wherein said compound of formula (24) is by reacting a compound of formula H2N O-C-C 4 alkyl H 3 c CH 3 I with a compound of formula OTBDMS Br O HN CH 3 o 0 10 in the presence of a suitable solvent such as propionitrile, THF, toluene, ethyl acetate, acetonitrile, propionitrile, dioxane, DMF, DMSO, and optionally in the presence of a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, Hunig's base or triethylamine, at a temperature between 500C and 1500C for 12 to 36 hours. 15 34. Combination of a compound according to any one of claims I to 19 with other therapeutic agent(s) selected from: (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (b) Leukotriene antagonists (LTRAs) including antagonists of LTB 4 , LTC 4 , 20 LTD 4 , and LTE 4 , (c) Histamine receptor antagonists including H1 and H3 antagonists, WO 2005/080324 PCT/IB2005/000112 145 (d) a1- and a 2 -adrenoceptor 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, 5 (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, such as DAGR (dissociated 10 agonists of the corticoid receptor) (k) Monoclonal antibodies active against endogenous inflammatory entities, (1) Anti-tumor necrosis factor (anti-TNF-a) agents, (m)Adhesion molecule inhibitors including VLA-4 antagonists, (n) Kinin-B 1 - and B2 -receptor antagonists, 15 (o) Immunosuppressive agents, (p) Inhibitors of matrix metalloproteases (MMPs), (q) Tachykinin NK 1 , NK 2 and NK 3 receptor antagonists, (r) Elastase inhibitors, (s) Adenosine A2a receptor agonists, 20 (t) Inhibitors of urokinase, (u) Compounds that act on dopamine receptors, e.g. D2 agonists, (v) Modulators of the NFKp pathway, e.g. IKK inhibitors, (w)modulators of cytokine signalling pathways such as p38 MAP kinase, syk kinase or JAK kinase inhibitor 25 (x) Agents that can be classed as mucolytics or anti-tussive, and (y) Antibiotics.

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NO20063761L|2006-10-23|

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IL176629D0|2006-10-31|

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PL1708992T3|2007-12-31|

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法律状态:
2008-05-22| FGA| Letters patent sealed or granted (standard patent)|

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2013-08-08| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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EP04290168||2004-01-22||

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EP04290168.6||2004-01-22||

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GB0406388A|GB0406388D0|2004-03-22|2004-03-22|Sulfonamide derivatives for the treatment of diseases|

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GB0406388.9||2004-03-22||

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US60025904P| true| 2004-08-09|2004-08-09||

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US60/600,259||2004-08-09||

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PCT/IB2005/000112|WO2005080324A1|2004-01-22|2005-01-12|Sulfonamide derivatives for the treatment of diseases|

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