ZA200602358B - Derivatives of hydroxamic acid as metalloproteinase inhibitors - Google Patents
Derivatives of hydroxamic acid as metalloproteinase inhibitors Download PDFInfo
- Publication number
- ZA200602358B ZA200602358B ZA200602358A ZA200602358A ZA200602358B ZA 200602358 B ZA200602358 B ZA 200602358B ZA 200602358 A ZA200602358 A ZA 200602358A ZA 200602358 A ZA200602358 A ZA 200602358A ZA 200602358 B ZA200602358 B ZA 200602358B
- Authority
- ZA
- South Africa
- Prior art keywords
- phenyl
- hydroxy
- carbonyl
- hexanoic acid
- acid hydroxyamide
- Prior art date
Links
- 239000003475 metalloproteinase inhibitor Substances 0.000 title claims description 3
- 239000002253 acid Substances 0.000 title description 6
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title description 4
- ZXKINMCYCKHYFR-UHFFFAOYSA-N aminooxidanide Chemical compound [O-]N ZXKINMCYCKHYFR-UHFFFAOYSA-N 0.000 claims description 62
- 150000001875 compounds Chemical class 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- -1 methoxy, ethoxy, trifluoromethoxy, methyl Chemical group 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
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- 238000002360 preparation method Methods 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
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- 125000006413 ring segment Chemical group 0.000 claims description 9
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
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- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 4
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
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- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
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- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
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Description
DERIVATIVES OF HYDROXAMIC ACID AS METALLOPROTEINASE INHIBITORS
The present invention relates to therapeutically active hydroxamic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in medicine. In particular, the compounds are inhibitors of matrix metalloproteinases.
The matrix metalloproteinases (MMP's) are a family of zinc containing endopeptidases which are capable of cleaving large biomolecules such as the collagens, proteoglycans and gelatins. Imbalance between active MMPs and endogenous inhibitors, leads to excessive tissue disruption. The three main groups of MMPs are the collagenases, the gelatinases, and the stromelysins.
Collagenases include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), and collagenase 3 (MMP-13). Gelatinases include 72 kDa gelatinase (gelatinase A; MMP-2) and 92 kDa gelatinase (gelatinase B; MMP- 9). Stromelysins include stromelysin 1 (MMP-3), stromelysin 2 (MMP-10) and matrilysin (MMP-7). However there are MMPs which do not fit neatly into the above groups, for example metalloelastase (MMP-12), membrane-type MMP (MT-MMP or MMP-14) and stromelysin 3 (MMP-11).
Over-expression and activation of MMPs have been linked with a wide range of diseases such as cancer; rheumatoid arthritis; osteoarthritis; chronic inflammatory disorders, such as asthma, bronchitis and emphysema; cardiovascular disorders, such as atherosclerosis; comeal uiceration; dental diseases such as gingivitis and periodontal disease; neurological disorders, such as multiple sclerosis and restenosis. For example, MMP-12 is required for the development of cigarette smoke-induced emphysema in mice,
Science, 277, 2002 (1997). Inhibition of MMPs is therefore a strategy for treatment of such disease states. However, there is evidence that non- selective inhibition of matrix metalloproteinase activity may affect normal physiological process leading to dose limiting side effects. Selective inhibition of MMP-12 and/or MMP-9 is thought to be a particularly relevant strategy for intervention in inflammatory conditions.
Some MMPs can hydrolyse the membrane-bound precursor of the pro- inflammatory cytokine tumour necrosis factor a (TNF-a). This cleavage yields mature soluble TNF-a. and some inhibitors of MMPs can block production of
TNF-a both in vitro and in vivo. This pharmacological action is a probable contributor to the anti-inflammatory action of this class of compounds.
For a recent review of MMP inhibition as reflected in the patent literature, see
Doherty et. al. Therapeutic Developments in Matrix Metalloproteinase
Inhibition; Expert Opinions on Therapeutic Patents, 2002, 12, 665-707.
Very many of the MMP inhibitors of the prior art have a hydroxamic acid metal binding group (-CONHOH).
The present invention provides a class of compounds which in general are selective inhibitors of MMP-12 relative to the collagenases and stromelysins.
In addition, compounds of the invention can exhibit selective activity towards
MMP-9. Compounds of the invention are therefore indicated for treatment of diseases primarily mediated by MMP-12 and/or MMP-9, especially inflammatory conditions such as multiple sclerosis and fibrosis.
According to the invention, there is provided a compound of formula (l),or an enantiomer or diastereocisomer thereof, or a salt, hydrate or solvate thereof: 0
Ar-(Alk)
NR,R,
RO CONHOH
0) wherein
Ar represents an optionally substituted aryl, heteroaryl, Cz-Cs cycloalkyl or heterocycloakyl group;
R represents hydrogen or C+-Cs alkyl, or C3-C¢ cycloalkyl;
Alk represents a divalent C4-Cs alkylene or C»-Cs alkenylene radical; and
Ry and R; taken together with the nitrogen atom to which they are attached form a first heterocycloalkyl ring which is optionally fused to a second C3-Csg cycloalkyl or heterocycloalkyl! ring, the said first and second rings being optionally substituted by a at least one group of formula (ll):
SHAK), (X)-Ak—Z (I) wherein m, p and n are independently O or 1;
Z represents, hydrogen, or an optionally substituted carbocyclic or heterocyclic ring of from 5 to 7 ring atoms which is optionally fused to another optionally substituted carbocyclic or heterocyclic ring of from 5 to 7 ring atoms;
Alk' and Ali? independently represent optionally substituted divalent C4-C3 alkylene radicals;
X represents -O-, -S-, -S(0)-, -S(0z)-, -C(=0)-, -NH-, -NRa-, -S(O2)NH-, -S(O2)NR3-, -NHS(Oz)-, or -NR3S(02)-, where Rj is C4-C; alkyl.
As used herein the term “(C,-Cp)alkyl“ where a and b are integers refers to a straight or branched chain alkyl moiety having from a to b carbon atoms, including for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl , n-pentyl and n-hexyl, depending on the values of a and b.
As used herein the term "divalent (C,-Cp)alkylene radical" where a and b are integers refers to a saturated hydrocarbon chain having from a to b carbon atoms and two unsatisfied valences.
As used herein the term “(Ca-Cp)alkenyl“ where a and b are integers refers to a straight or branched chain alkenyl moiety having from a to b carbon atoms having at least one double bond of either E or Z stereochemistry where applicable. The term includes, for example, vinyl, allyl, 1- and 2-butenyl and 2- methyl-2-propenyl, depending on the values of a and b.
As used herein the term "divalent (C4-Cp)alkenylene radical refers to a hydrocarbon chain having from a to b carbon atoms, at least one double bond, and two unsatisfied valences.
As used herein the unqualified term "carbocyclyl” or “carbocyclic” refers to a ring or ring system of from 3 to 14 ring atoms which are all carbon, and includes “aryl”, “cycloalkyl”, and “cycloalkenyl” as defined below.
As used herein the unqualified term "cycloalkyl refers to a saturated alicyclic moiety having from 3-8 carbon atoms consisting of a single ring (e.g. cyclohexyl) or multiple condensed rings (e.g.norbornyl). Preferred cycloalkyl include cyclopentyl, cyclohexyl, norbomyl and the like.
As used herein the unqualified term "cycloalkenyl® refers to an unsaturated alicyclic moiety having from 3-8 carbon atoms and includes, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. In the case of cycloalkenyl rings of from 5-8 carbon atoms, the ring may contain more than one double bond.
As used herein the unqualified term "aryl® refers to an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings and to two covalently linked monocyclic carbocyclic aromatic groups.
Examples of aryl include phenyl, biphenyl and the like.
As used herein the unqualified term "heterocyclyl or “heterocyclic” refers to a ring or ring system whose ring members include one or more hetero atoms selected from O, S, and N, and the term includes “heteroaryl” and “heterocycloalkyl” as defined below.
As used herein, the unqualified term “heterocycloalkyl” refers to a cycloaklyl group as defined above, in which up to 3 ring carbon atoms are replaced by heteroatoms selected from O, S and N. Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1-methyl piperazine, morpholine, and the like.
As used herein the unqualified term "heteroaryl" refers to a monocyclic, or fused bicyclic or tricyclic aromatic ring or ring system containing one or more heteroatoms selected from O, S and N, and to groups consisting of two covalently linked monocyclic aromatic rings containing one or more such heteroatoms; and to groups consisting of a monocyclic carbocyclic aromatic group covalently linked to monocyclic aromatic ring containing one or more heteroatoms. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro}benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2,-c]pyridyl, benzothiazolyl, benzoxazolyl, quinazolyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnolyl, naphthyridinyl, pyrido[3,4-c]pyridyl, pyrido[3,2-c]pyridyl, pyrido{3,4,3-C]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.
Unless otherwise specified in the context in which it occurs, the term "substituted as applied to any moiety herein means substituted, for example, with at least one substituent selected from (C1-Cg)alkyl, (C1-Cg)alkoxy, hydroxy, hydroxy(C4-Cg)alkyl, mercapto, mercapto(C1-Ce)alkyl, (C+-
Ce)alkylthio, halo (including fluoro and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, phenyl, -COOH, -COOR*, -COR*, -SO,R*, -CONH;, -SO,NH,, -CONHR", -SO,NHR*, -CONR*R®, -SO.NR*R®, -NHz, -NHR*, -NR"RE, -OCONH,, -OCONHR* ,-OCONR*R®, -NHCOR?, -NHCOOR?", -NRBCOORA, -NHSO.0R?, -NR®SO,0R", -NHCONH,,
-NRACONH,, -NHCONHR® -NR*CONHRE, -NHCONR*R® or -NRACONR*R®? wherein R* and R® are independently a (C;-Cg)alkyl or phenyl group.
As used herein the term “salt” includes base addition, acid addition and quaternary salts. Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane,
L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like. Those compounds (1) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like.
For a review on suitable salts, see Handbook of Pharmaceutical Salts:
Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, Weinheim,
Germany, 2002).
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.
Compounds with which the invention is concemed which may exist in one or more stereocisomeric form, because of the presence of asymmetric atoms or rotational restrictions, can exist as a number of stereoisomers with R or S stereochemistry at each chiral centre or as atropisomeres with R or S stereochemistry at each chiral axis. The invention includes all such enantiomers and diastereoisomers and mixtures thereof. In particular the invention includes compounds having the stereochemical configuration (IA):
O
Ar-(Alk)
RO CONHOH
(1A)
The compounds of the invention include compounds of formula (I) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (0).
The group Ar
Ar may be, for example, a 5- or 6- membered monocyclic ary! or heteroaryl ring, which is optionally substituted, for example in the 4- position in the case of a 6-membered ring, or in the 2- and/or 3- position in the case of a 5- membered ring, by at least one substituent selected from (C;-Cs)alkyl, (C-
Ca)alkoxy, hydroxy, hydroxy(C+-Cs)alkyl, mercapto, mercapto(C4-Cs)alkyl, (C4-
Cs)alkyithio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), -COOH, -COOR*, -COR? -SO;R", -CONHz, -SO-NH,, -CONHR*, -SO.NHR", -CONR*R®, -SO;NR"R®, -NH,, -NHR", -NR"RE, -OCONH,, -OCONHR" -OCONR*R®, -NHCOR", -NHCOOR*, -NRECOOR", -NHSO,OR", -NRBSO.0R", -NHCONH,, -NRACONH,, -NHCONHR® -NRACONHR®, -NHCONRAR®, or -NR*CONR"RE wherein R* and R® are independently C,-C; alkyl, phenyl or a 5- or 6-membered monocyclic aryl or heteroaryl ring.
Ar may be, for example phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-thienyl, or 2-, or 3- furanyl, optionally substituted as specified above in relation to formula (I).
Preferably the substituent can be, for example, methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl, hydroxyl, mercapto, fiuoro, chloro, or bromo. Presently it is preferred that Ar be 4-(C4-Csalkoxy)phenyl, and the most preferred being the ethoxyphenyl.
The group R
In one embodiment of the invention R is hydrogen.
In another embodiment of the invention R is (C4-Cg)alkyl, for example ethyl, n- propyl, isopropyl, n-, sec or tert-butyl. In a preferred embodiment, R is methyl.
In yet another embodiment R is C3-Ce cycloalkyl, for example cyclopropyl, or cyclopentyl.
The Alk radical
Alk may be, for example, -CHa-, -CH2CH.-, -CH,CH(CH3)-, -CH2CH,CH-, -CH,CH>CH,CH,-, -CH=CH-, -CH,CH=CH-, -CH,CH=CHCH,-, or -CH=CHCH=CH-. Presently it is preferred that Alk be -CH,CH,CHo-.
The group -NR;R.
This group is a saturated heterocyclic first ring of 5 to 7 atoms which is optionally fused to a saturated or unsaturated carbocyclic or heterocyclic second ring of 5 to 7 atoms. (The said first and/or second ring may optionally be substituted by a group of formula (ll), discussed below). One of the heteroatoms of the group -NR+R: is of course the nitrogen shown, and it may be the sole heteroatom in the ring system of there may be other nitrogen, oxygen or sulphur ring atoms.
The group -NR1R2 may be unsubstituted or substituted by at least one group (mn: —HAK),-X-AKTZ ()
It will be noted that since an optional substituent in either Alk' or Alk® may be oxo, a carbonyl group may be located adjacent the X element, forming for example combinations such as amide, reverse amide and carboxy linkages.
In one embodiment of the invention, R; and R; taken together with the nitrogen atom to which they are attached form a morpholyl group, optionally substituted by at least one group of formula (li).
In another embodiment of the invention, Ry and R; taken together with the nitrogen atom to which they are attached form a thiomorpholyl group, optionally substituted by at least one group of formula (Il).
In another embodiment of the invention, Ry and R; taken together with the nitrogen atom to which they are attached form a piperidinyl group, optionally substituted by at least one group of formula (l1).
In another embodiment of the invention, Ry and R; taken together with the nitrogen atom to which they are attached form a pyrrolidinyl group, optionally substituted by at least one group of formula (lI).
In another embodiment of the invention, Ry and R: taken together with the nitrogen atom to which they are attached form a piperazinyl group, optionally substituted by at least one group of formula (Hi).
In one particular embodiment of the invention, group (ll) is such thatp is 0, Z is hydrogen and at least one of n and m is 1. In this subclass the group (Il) is optionally substituted C,-Cs alkyl, which may be linked to a ring carbon or to a ring nitrogen of the -NR;R. group. For example when -NR;R; is piperidinyl or piperazinyl, the 4-C (in the former) and the 4-N (in the latter) may be substituted by methyl, ethyl, or n- or iso-propyl.
In a second particular embodiment of the invention, group (ll) is such that m, n and p are all 0 and Z is a carbocyclic or heterocyclic ring directly linked to a ring carbon or ring nitrogen of the -NR1R2 group. Examples of such directly linked rings Z include cyclopentyl and cyclohexyl, and (preferably) aryl or heteroaryl! rings such as phenyl, pyridyl, thienyl, furanyl, and pyrimidinyl.
These directly linked rings may themselves be substituted by optional substituents, for example methoxy, ethoxy, n- or iso-propoxy, trifluoromethoxy, methylenedioxy, ethylenedioxy, methyl, ethyl, n- or isopropyi, trifluoromethyl, fluoro, chloro, bromo, methylsutfonyl, phenylsulfonyl, or mono- or di-(C4-Cs)alkylamino.
In a third particular embodiment of the invention, group (Il) is such that p is 0, at least one of mand nis 1, and Z is a carbocyclic or heterocyclic ring linked to a ring carbon or ring nitrogen of the -NR¢R group via a C4-Cg alkylene linker between Z and the -NR+Rz ring. In this case, the ring Z may be any of those optionally substituted Z rings discussed and preferred above in the case of the second subclass of groups (11), but here Z is linked to the -NR;R; ring via an optionally substituted C-Cg alkylene linker radical, such as a ~CHa- or ~CH,CHy- radical.
In a fourth particular embodiment of the invention, group (il) is such that p is 1, so that the group (ll) contains the X heteroatom. Clearly when mis 0, X is directly linked to the -NR:R. ring; when m and n are both 1 X interrupts a Cs-
Ce alkylene linker between Z and the -NR:Rz ring; and when one of m and n is 1 and the other 0, the group (ll) represents a variety of O, S- or N containing substituents either directly linked to the -NR;R: ring, or linked via a C,-
Csalkylene linker.
A particular embodiment of the invention comprises compounds of formula (IB) or (IC) and salts, hydrates and solvates thereof, especially compounds having the stereoconfiguration shown in formula (IA above):
R, r 0 0
N N
R, RO CONHOH R; RO CONHOH (IB) (IC) wherein R is hydrogen or methyl, Rs is trifluoromethyl, trifluoromethoxy C-
Caalkoxy, hydroxy, or halo; Ry is (i) -SO2Rs or -CORs wherein Rs is C1-Cgalky!
or phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, optionally substituted by (C4-Ca)alkyl, (C1-Cs)alkoxy, hydroxy, hydroxy(C1-Cz)alkyl, mercapto, mercapto(C+-Ca)alkyl, (C4-Cs)alkylthio, halo, trifluoromethyl, trifluoromethoxy or (ii) phenyl or monocyclic heteroaryl having 5 or 6 ring atoms; optionally substituted by (C-Cs)alkyl, (C4-Ca)alkoxy, hydroxy, hydroxy(C,-Cs)alkyl, mercapto, mercapto(C+-Cs)alkyl, (C1-Cs)alkylthio, halo, trifluoromethyl, trifluoromethoxy). Examples of heteroaryl rings forming part of
Ra4 in this embodiment include pyridyl, pyrimidinyl, triazinyl, thienyl, and furanyl.
Specific embodiments of the invention are compounds selected from the group consisting of the following: 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(pyrrolidine-1-carbonyl)-hexanoic acid hydroxyamide. 3R-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-6-(4-ethoxy- phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(3-methoxy-phenyl)-piperazine-1- carbonyl]-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(4-methoxy-phenyl)-piperazine-1- carbonyl]-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-pyridin-2-yl-piperazine-1-carbonyl)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-pyridin-4-yi-piperazine-1-carbonyl)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(morpholine-4-carbonyl)-hexanoic acid hydroxyamide.
6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(2RS-methyl-morpholine-4-carbonyi)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(2,6-RS-dimethyl-morpholine-4-carbonyl)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(thiomorpholine-4-carbonyl)-hexanoic acid hydroxyamide. 3R-(4-benzy!-piperidine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. 3R-(4-benzo[1,3]dioxol-5-yimethyl-piperazine-1-carbonyl)-6-(4-ethoxy-phenyl)- 2S-hydroxy-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-pyridin-4-ylmethyl-piperazine-1- carbonyl)-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-benzylpiperazine-1-carbonyl)-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-pyrimidin-2-yl-piperazine-1-carbonyl)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(4-trifluoromethyi-pyrimidin-2-yl)- piperazine-1-carbonyl]-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(4-chloro-pyrimidin-2-yl)-piperazine-1- carbonyl]-hexanoic acid hydroxyamide.
3R-[4-(4,6-dimethoxy-[1,3,5triazin-2-yl)-piperazine-1-carbonyl}-6-(4-ethoxy- phenyl)-2S-hydroxy-hexanoic acid hydroxyamide.
6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(3-trifluoromethyl-phenyl)-piperazine-1- carbonyl]-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(2-fluoro-phenyl)-piperazine-1- carbonyl]-hexanoic acid hydroxyamide. 3R-[4-(acetyl-methyl-amino)-piperidine-1-carbonyl]-6-(4-ethoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-{4-(methyl-propyl-amino)-piperidine-1- carbonyl]-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyi)-2S-hydroxy-3R-(3S-benzyl-morpholine-4-carbonyl)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(3S-isobutyl-morpholine-4-carbonyi)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(3S-phenyl-morpholine-4-carbonyl)- hexanoic acid hydroxyamide. 3R-(4-benzyl-3RS-methyl-piperazine-1-carbonyi)-6-(4-ethoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 3R-(3S,4-dibenzyl-piperazine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S-hydroxy- hexanoic acid hydroxyamide. 3R-(4-benzyl-3RS-phenyl-piperazine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 4-(4-benzo[1,3]dioxol-5-yimethyl-piperazin-1-yi)-2S,N-dihydroxy-4-oxo-3R-(4- trifluoromethoxy-benzyl)-butyramide. 3R-benzyl-28,N-dihydroxy-4-morpholin-4-yl-4-oxo-butyramide.
3R-(4-Benzyloxy-benzy!)-2S,N-dihydroxy-4-oxo-4-piperidin-1-yl-butyramide. 2S,N-dihydroxy-3R-(4-hydroxy-benzyl)-4-oxo-4-piperidin-1-yl-butyramide. 4-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-3R-(4-benzyloxy-benzyl)- 2S,N-dihydroxy-4-oxo-butyramide. 6-(3,5-bis-trifluoromethyl-phenyl)-2S-hydroxy-3R-(morpholine-4-carbonyl)- hexanoic acid hydroxyamide. 3R-(4-benzyl-piperidine-1-carbonyl)-6-(3,5-bis-trifluoromethyl-phenyi)-2S- hydroxy-hexanoic acid hydroxyamide. 6-(3,5-bis-trifluoromethyl-phenyl)-2S-hydroxy-3R-(4-pyridin-2-yl-piperazine-1- carbonyl)-hexanoic acid hydroxyamide. 6-(3,5-bis-trifluoromethyl-phenyl)-3R-(6,7-dimethoxy-3,4-dihydro-1H- isoquinoline-2-carbonyl)-2S-hydroxy-hexanoic acid hydroxyamide. 6-(3,5-bis-trifluoromethyl-phenyl)-2S-hydroxy-3R-(pyrrolidine-1-carbonyl)- hexanoic acid hydroxyamide 3R-(2S-benzyl-4-methyl-piperazine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S-
hydroxy-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(4-trifluoromethoxy-benzenesulfonyl)- piperazine-1-carbonyi]-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(toluene-4-sulfonyl)-piperazine-1- carbonyl}-hexanoic acid hydroxyamide. 3R-{4-(5-bromo-thiophene-2-sulfonyl)-piperazine-1-carbonyl]-6-(4-ethoxy- phenyl)-2S-hydroxy-hexanoic acid hydroxyamide.
3R-[4-(5-benzenesulfonyl-thiophene-2-sulfonyl)-piperazine-1-carbonyl]-6-(4- ethoxy-phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. 3R-[4-(4-butoxy-benzenesulfonyl)-piperazine-1-carbonyl]-6-(4-ethoxy-phenyl)- 2S-hydroxy-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(4-methoxy-2,3,6-trimethyl- benzenesulfonyl)-piperazine-1-carbonyl}-hexanoic acid hydroxyamide. 3R-[4-(3,4-dimethoxy-benzenesulfonyl)-piperazine- 1-carbonyl}-6-(4-ethoxy- phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. 6-(4-methoxy-phenyl)-2S-hydroxy-3R-[{4-(2-fluoro-phenyl)-piperazine-1- carbonyl}-hexanoic acid hydroxyamide. 6-(4-methoxy-phenyl)-2S-hydroxy-3R-(4-pyridin-2-yl-piperazine-1-carbonyl)- hexanoic acid hydroxyamide. 6-(4-fluoro-phenyl)-3R-[4-(2-fluoro-phenyl)-piperazine-1-carbonyli]-2S-hydroxy- hexanoic acid hydroxyamide. 6-(4-fluoro-phenyl)-2S-hydroxy-3R-(4-pyridin-2-yl-piperazine-1-carbonyl)- hexanoic acid hydroxyamide. 3R-(4-benzyl-2S-methyl-piperazine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 3R-(4-benzyl-2S-methyl-piperazine-1-carbonyl)-6-(4-methoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 3R-(4-benzyl-2S-i-butyl-piperazine-1-carbonyl)-6-(4-methoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide.
3R-~(4-benzyl-2S-methyl-piperazine-1-carbonyl)-6-(4-fluoro-phenyi)-2S- hydroxy-hexanoic acid hydroxyamide. 3R-(4-benzyl-2S-i-butyl-piperazine-1-carbonyl)-6-(4-fluoro-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 4-[5-(4-ethoxy-phenyl)-2R-(1S-hydroxy-hydroxycarbamoyl-methyi)-pentanoyl)- 2S-methyl-piperazine-1-carboxylic acid tert-butyl ester. 4-[5-(4-ethoxy-pheny!)-2R-(1S-hydroxy-hydroxycarbamoyl-methyl)-pentanoyi)- 28-i-butyl-piperazine-1-carboxylic acid tert-butyl ester. 4-[5-(4-methoxy-phenyl)-2R-(1S-hydroxy-hydroxycarbamoyl-methyl)- pentanoyl]-2S-methyl-piperazine-1-carboxylic acid tert-butyl ester. 4-[5-(4-methoxy-phenyl)-2R-(1S-hydroxy-hydroxycarbamoyl-methyl)- pentanoyi]-2S-i-butyl-piperazine-1-carboxylic acid tert-butyl ester. 4-[5-(4-fluoro-phenyl)-2R-(1S-hydroxy-hydroxycarbamoyl-methyl)-pentanoyl]- 2S-methyl-piperazine-1-carboxylic acid tert-butyl ester. 4-[5-(4-fluoro-phenyl)-2R-(1S-hydroxy-hydroxycarbamoyl-methyi)-pentanoyi}- 2S-i-butyl-piperazine-1-carboxylic acid tert-butyl ester. 6-(4-ethoxy-phenyl)-2S-methoxy-3R-[4-(2-fluoro-phenyl)-piperazine-1- carbonyl]-hexanoic acid hydroxyamide.
As mentioned above, the present compounds are useful in human or veterinary medicine since they are active as inhibitors of MMPs, in particular as selective inhibitors of MMP-12 (and/or MMP-9) relative to MMP-1 and other collagenases and stromelysins. Accordingly in another aspect, this invention concems:
(i) a method of management (by which is meant treatment or prophylaxis) of diseases or conditions responsive to inhibition of MMP-12 and/or MMP-9 in mammals, in particular in humans, which method comprises administering to the mammal an effective amount of a compound of formula (1) defined above, or a pharmaceutically acceptable salt thereof; and (ii) a compound of formula (1) defined above, for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions responsive to inhibition of MMP-12 and/or MMP-9. (Diseases or conditions responsive to inhibition of MMP-12 and/or MMP-9 include bone resorption, tumour growth or invasion by secondary metastases; rheumatoid arthritis, septic arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, cardiac hypertrophy, acute respiratory distress syndrome, neuroinflammatory disorders, e.g. multiple sclerosis; restenosis; emphysemia; fibrotic didease e.g. fibrosis post radiotherapy, kerotid scarring, liver fibrosis and cystic fibrosis; chronic obstructive pulmonary disease; bronchitis; asthma; autoimmune disease; transplant rejection (e.g. graft versus host disease); cystic fibrosis; psoriasis; psoriatic arthritis; degenerative cartilage loss; inflammatory gastric conditions, e.g.
Crohn's disease, inflammatory bowel disease, and ulcerative colitis; atopic dermatitis, epidermolysis bullosa; epidermic ulceration; a neuropathy or nephropathy e.g.interstitial nephritis, glomerulonephriris or renal failure; ocular inflammation; liver cirrhosis, Sjoegren’s syndrome; or an inflammatory condition of the nervous system.); and
(iii) a compound of formula (1) for use as a medicament; and
(iv) the use of a compound of formula (I) defined above in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions responsive to inhibition of MMP-12 and/or MMP-9; and (v) the use of a compound of formula (I) for the preparation of a medicament for the prevention or treatment of a disease selected from inflammatory diseases including multiple sclerosis, emphysemia, bronchitis, asthma, and a disease related to MMP-12 and/or MMP-9.
In a further aspect of the invention there is provided a pharmaceutical or veterinary composition comprising a compound of formula (1) defined above together with a pharmaceutically or veterinarily acceptable excipient or carrier.
It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Optimum dose levels and frequency of dosing will be determined by clinical trial.
The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleats, or acacia;
non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British
Pharmacopoeia.
For topical application to the eye, the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle. Additives, for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
The active ingredient may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
Compounds of formula (I) may be prepared by standard literature methods, as illustrated in the Examples herein. In general, the compounds wherein R is hydrogen may be prepared by coupling a dioxolane-protected di-carboxylic acid of formula (Ill) with the desired cyclic amine HNRRz:
Ar-(Alk) COOH 1 (11)
wherein Ry, Ra: Ar and Alk are as defined in relation to formula (1), to form the intermediate (IIIA) oO
Ar-(Alk)
NR,R, 0) (INA) i then reacting intermediate (lllA) with hydroxylamine.
Methods of coupling amines with carboxylic acids to form amides are very well known, for example from the art of peptide synthesis.
Thus, the invention also includes (vj a compound of formula (IIIB) wherein Ry, Rz, Ar and Alk are as defined in relation to formula (1) (vii) a process for the preparation of a compound of formuia (I) defined above, comprising the deprotection and/or transformation of a compound of formula (il1A) as defined above, ) wherein Rs, Ra, Ar and Alk are as defined in relation to formula (1) (viii) a process for the preparation of a compound of formula (IlIA) comprising the step of reacting a compound of formula (ll) with a cyclic amine
HNR;R.., wherein Ry, Ra: Ar and Alk are as defined in relation to formula (1),
The following preparative Examples describe the preparation of compounds useful in accordance with the invention
The following abbreviations have been used in the examples:
AcOEt - Ethyl acetate
CH3CN - Acetonitrile
DMF - N,N-Dimethylformamide
HOBT - 1-Hydroxybenzotriazole
HOAT - 1-Hydroxyazobenzotriazole
MgSO, — Magnesium sulfate
Pfp — Pentafluorophenol
WSCDI - N-(3-Dimethylaminopropy!)-N'-ethylcarbodiimide hydrochloride
HCI - Hydrochloric acid
P(O-Tol)s — Tri-O-tolylphosphine
THF — Tetrahydrofuran
TFA — Trifluoroacetic acid
Z - Benzyloxycarbonyl
Example 1: 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(pyrrolidine-1-carbonyl)- hexanoic acid hydroxyamide. 0 0
EtO HO o
HN
OH jal Step A he Gl Step B ox" Step C
HO” ~CO,iPr HO” ~CO,iPr EtO HO” ~Cco,iPr
EtO HO” ~CO,iPr Eto HO” ~COH ‘ F oF F
CoH
Step F 0 F step G
EtO Q 0 ~ 80 o F ’
Fe Fe 0 .
EtO o~ ——" EO HO lo) 4 HN
OH
Reagents and conditions. A: LIHMDS, AllBr, THF, -78C to RT; B: ArBr, P(o-Tol);, Pd(OAc),, NEt,;, CH,CN;
C: 10%Pd/C, H,, MeOH; D: LiOH, MeOH, H,0; E: CuCl,, dimethoxypropane, acetone; F: pentafiuorophenol,
WSCDI, HOAt, CH,CL,; G: pyrrolidine, NEty, CH,Cl,, H: , ,NH,OH, iPrOH
Scheme 1
Example 1 was prepared as outlined in Scheme 1 using procedures described below.
Step A: 2R-allyl-3S-hydroxy-succinic acid diisopropylester.
To a cold (-78C) solution of 2S-hydroxy-succinic acid diisopropyl ester (19.70 ml, 95 mmol) in THF (35 ml) was added LiHMDS (200 ml, 0.2 mol, 2.1 eq.)
dropwise. The reaction mixture was stirred at -78C for two hours and then at - 30C for 30 min. The reaction mixture was then cooled to -78C and ally! bromide (12.36 ml, 0.14 mol, 1.5 eq.) added dropwise. The reaction mixture was then allowed to warm to RT ovemight. It was poured into a saturated solution of NH4Cl/ice (200 ml). Extraction with AcOEt (3 X 200 ml) followed by a wash with water (50 ml) and with brine (50 ml) afforded a yellow oil after removal of the solvents under vacuo. Purification by flash chromatography gave 2R-allyl-3S-hydroxy-succinic acid diisopropylester as a colourless oil (7.76 g, de = 80%, 40% yield). "H-NMR; delta (CDCls): 5.77-5.88 (1H, m), 4.98-5.21 (4H, m), 4.22 (1H, brs), 3.18 (1H, brs), 2.87-2.94 (1H, m), 2.56-2.65 (1H, m), 2.40-2.48 (1H, m), 1.29 (6H, d, J=6.3 Hz), 1.22 (6H, d, J=6.3 Hz).
LRMS: +ve ion 281 (M+Na).
Step B: 2R-[3-(4-ethoxy-phenyl)-allyl}-3S-hydroxy-succinic acid diisopropyl ester.
To a solution of 2R-allyl-3S-hydroxy-succinic acid diisopropylester (4.79 g, 18.5 mmol), 4-bromo phenetole (3.19 mi, 22.2 mmol, 1.2 eq.) and NEt; (6.22 ml, 44.6 mmol, 2.4 eq.) in CHsCN (40 ml), was added a sonicated (for 2 min) suspension of P(O-Tol)s (0.57 g, 2.22 mmol, 0.1 eq.) and Pd(OAc). (209 mg, 5%) in CH3CN (5 ml). The reaction mixture was heated to reflux for 2 hrs.
CH3CN was removed under vacuo. The crude was extracted with AcOEt (3 X 200 ml), washed with water (50 ml) and with brine (50 ml). A purification by flash chromatography afforded the desired 2R-[3-(4-ethoxy-phenyl)-allyl]-3S- hydroxy-succinic acid diisopropyl ester (5.92 g, 84% yield). "H-NMR; delta (CDCls): 7.28 (2H, d, J=8.8 Hz), 6.83 (2H, d, J=8.8), 6.46 (1H, d, J=15.7 Hz), 6.02-6.12 (1H, m), 4.98-5.13 (2H, m), 4.26 (1H, dd, J=7.1, 3.0
Hz), 4.02 (2H, q, J=7.0 Hz): 3.23 (1H, d, J=7.1 Hz), 2.92-2.97 (1H, m), 2.68- 2.79 (1H, m), 2.49-2.62 (1H, m), 1.41 (3H, t, J=7.0 Hz), 1.19-1.30 (12H, m).
LRMS: +ve ion 401 (M+Na).
Step C: 2R-[3-(4-ethoxy-phenyl)-propyl}-3S-hydroxy-succinic acid diisopropyl ester.
To a solution of 2R-[3-(4-ethoxy-phenyl)-allyl]-3S-hydroxy-succinic acid diisopropyl ester (129 mg, 0.34 mmol) in MeOH (10 ml) under an inert. atmosphere, was added 10%Pd/C (13 mg). H, was bubbled through the resulting suspension for 30 min. The reaction mixture was then stirred under 1 atmosphere of H, for 16 hrs. Pd/C was filtered off and the solvent removed under reduced pressure to give 2R-[3-(4-ethoxy-phenyl)-propyl]-3S-hydroxy- succinic acid diisopropyl ester (115 mg, 88% yield).
H-NMR; delta (CDCls): 7.08 (2H, d, J=8.6 Hz), 6.81 (2H, d, J=8.6), 4.97-5.14 (2H, m), 4.20 (1H, dd, J=7.3, 3.5 Hz), 4.01 (2H, q, J=7.0 Hz), 3.18 (1H, d,
J=7.3 Hz), 2.77-2.83 (1H, m), 2.55-2.62 (2H, m), 1.45-1.94 (4H, m), 1.40 (3H, t, J=7.0 Hz), 1.12-1.30 (12H, m).
LRMS: +ve ion xx (M+Na).
Step D: 2R-[3-(4-ethoxy-phenyl)-propyl]-3S-hydroxy-succinic acid.
To a solution of 2R-[3-(4-ethoxy-phenyl)-propyl]-3S-hydroxy-succinic acid diisopropyl ester (4.78 g, 12.6 mmol) in THF/water (3:1, 120 ml) was added
NaOH (1.66 g, 41.5 mmol, 5.5 eq.). The reaction mixture was then stirred for 16 hrs at RT. The mixture was concentrated under reduced pressure and acidify to pH = 3 by addition of HCI 1N. The hydroxy diacid was extracted with
AcOEt. The organic layer was dried over MgSO, and the solvent removed under reduced pressure to give the desired 2R-[3-(4-ethoxy-phenyl)-propyl}- 3S-hydroxy-succinic acid (3.66 g, 85% yield). 'H-NMR; delta (MeQD): 7.07 (2H, d, J=8.6 Hz), 6.79 (2H, d, J=8.6), 4.23 (1H, d, J=5.8 Hz), 3.98 (2H, q, J=7.0 Hz), 2.76-2.81 (1H, m), 2.53-2.59 (2H, m), 1.55-1.72 (4H, m), 1.35 (3H, t, J=7.0 Hz).
LRMS: +ve ion 319 (M+Na); -ve ion 295 (M-H).
Step E: 2R-(2,2-dimethyl-5-oxo-{1,3]dioxolan-4S-yl)-5-(4-ethoxy-phenyl)- pentanoic acid.
To a solution of 2R-[3-(4-ethoxy-phenyl)-propyl]-3S-hydroxy-succinic acid (3.66 g, 12.3 mmol) in acetone (50 mi) under an inert atmosphere were added dimethoxy propane (2.58 mi, 21 mmol, 1.7 eq.) and copper chloride (165 mg, 1.2 mmol, 0.1 eq.). The reaction mixture was stirred at RT for 16 hrs. The solvent was then removed under vacuo to give 2R-(2,2-dimethyl-5-oxo- [1,3]dioxolan-4S-yl)-5-(4-ethoxy-phenyl)-pentanoic acid (4.03 g, 97% yield). "H-NMR; delta (CDCl): 7.08 (2H, d, J=8.5 Hz), 6.82 (2H, d, J=8.5), 4.48 (1H, d, J=4.8 Hz), 4.01 (2H, q, J=7.0 Hz), 2.91-2.98 (1H, m), 2.54-2.64 (3H, m), 1.23-2.20 (4H, m), 1.58 (3H, s), 1.53 (3H, 5), 1.40 (3H, t, J=7.0 Hz).
LRMS: +ve ion 359 (M+Na); -ve ion 335 (M-H).
Step F. 2R-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4S-yl)-5-(4-ethoxy-phenyl)- pentanoic acid pentafluorophenyl ester.
To a cold (OC) solution of 2R-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4S-yl)-5-(4- ethoxy-phenyl)-pentanoic acid (4.03g, 12 mmol) and pentafluoro phenol (2.43 g, 13.2 mmol, 1.1 eq.) in CHCl: (50 ml) was added WSC (2.54 g, 13.2 mmol, 1.1 eq.). The reaction mixture was allowed to warm to RT ovemight. CH.Cl. was removed under vacuo and the resulting crude reaction mixture was dissolved in AcOEt (200 ml). The organic layer was washed with water (50 ml), NaHCO; sat (20 ml) and finally with brine (20 ml). Solvent was removed under reduced pressure to give an oil which was purified by flash chromatography to fumish the expected 2R-(2,2-dimethyl-5-oxo-[1,3]dioxolan- 4S-yl)-5-(4-ethoxy-phenyl)-pentanoic acid pentafluorophenyl ester (3.94 g, 65% yield). 'H-NMR; delta (CDCls): 7.09 (2H, d, J=8.4 Hz), 6.83 (2H, d, J=8.4 Hz), 4.56 (1H, d, J=6.0 Hz), 4.01 (2H, q, J=7.0 Hz), 3.20-3.28 (1H, m), 2.64 (2H, t, J= 7.6 Hz), 1.98-2.08 (2H, m), 1.70-1.86 (2H, m), 1.62 (3H, s), 1.57 (3H, s), 1.40 (8H, t, J=7.0 Hz).
Step G. 5-(4-Ethoxy-phenyl)-2R-[(2,2-dimethyl-5-oxo-[1,3]dioxolan-4S-yl)]-1- pyrrolidin-1-yl-pentan-1-one.
To a solution of 2R-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4S-yl)-5-(4-ethoxy- phenyl)-pentanoic acid pentafluorophenyl ester (150 mg, 0.30 mmol) in
CHCl, (10 ml) was added pyrrolidine (30 pl, 0.36 mmol, 1.2 eq.). The reaction mixture was stirred for 16 hrs and the solvent was removed under vacuo. The crude was taken-up in AcOEt (70 ml) and washed with water (10 ml), then with NaHCO3 eat (10 ml) and finally with brine (10 mi). The solvent was dried over MgSO, and removed under reduced pressure to give the desired 5-(4-
Ethoxy-phenyl)-2R-[(2,2-dimethyl-5-oxo-[1,3]dioxolan-4S-yl)}-1-pyrrolidin-1-yl- pentan-1-one (116 mg, quant.). "H-NMR; delta (CDCls): 7.05 (2H, d, J= 8.6Hz), 6.8 (2H, d, J= 8.6Hz), 4.55 (1H, d, J= 8.4Hz), 3.99 (2H, m), 3.8-3.3 (10H, m), 3.05 (1H, m), 2.55 (2H, t, J= 7.6Hz), 2.1-1.7 (2H, m), 1.6 (3H, 8), 1.5 (3H, s), 1.4 (3H, t, J= 7.0Hz).
LRMS: +ve ion 405 (M+H), 428 (M+Na).
Step H. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(pyrrolidine-1-carbonyl)-hexanoic acid hydroxyamide
To a solution of 5-(4-Ethoxy-phenyl)-2R-[(2,2-dimethyl-5-oxo-[1,3]dioxolan-4S- yi)}-1-pyrrolidin-1-yl-pentan-1-one (116 mg, 0.30 mmol) in <PrOH (5 ml), was added an aqueous solution of hydroxylamine (50%, 99 wl, 1.5 mmol, 5 eq.).
The reaction mixture was allowed to stir at RT for 16 hrs. The solvent was removed under reduced pressure to yield an oil which was purified by preparative reverse phase chromatography to give the required product.
H-NMR; delta (CD30D): 7.05 (2H, d, J=8.6Hz), 6.8 (2H, d, J=8.6Hz), 4.0 (4H, my), 3.85 (1H, m), 3.7 (1H, m), 3.4 (2H, m), 3.1 (1H, m), 2.55 (2H, m), 1.9-1.5 (7H, m), 1.35 (3H, t, J= 7.0Hz).
LRMS: +ve ion 387 (M+Na); -ve ion 363 (M-H)
The compounds of Examples 2-20 were prepared by the method of Example 1 by parallel synthesis, using the appropriate amine in Step G. The products were purified by preparative HPLC.
Example 2: 3R-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-6-(4- ethoxy-phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. oo 0 >
OMe
EtO HO 0
HN OMe
OH
LRMS: +ve ion 487 (M+H), 509 (M+Na); -ve ion 485 (M-H).
Example 3: 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(3-methoxy-phenyl)- piperazine-1-carbonyl]-hexanoic acid hydroxyamide.
OMe
SOO)
N N
\—/
SOT
HN
OH
LRMS: +ve ion 486 (M+H), 508 (M+Na); -ve ion 484 (M-H).
Example 4: 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(4-methoxy-phenyl)- piperazine-1-carbonyl]-hexanoic acid hydroxyamide.
EO Oom \__/ ®
Beane:
HN,
OH
LRMS: +ve ion 486 (M+H), 508 (M+Na); -ve ion 484 (M-H).
Example 5: 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-pyridin-2-yl-piperazine-1- carbonyl)-hexanoic acid hydroxyamide.
L/\ N=
NH)
EtO HO 0)
HN_
OH
'H-NMR; delta (CD30D): 8.1 (1H, d, J= 1.4Hz), 7.55 (1H, m), 7.05 (2H, d, J= 8.7Hz), 6.9-6.6 (4H, m), 3.95 (1H, d, J= 7.0Hz), 3.55 (4H, m), 2.55 (1H, m), 1.8-1.5 (6H, m), 1.35 (3H, m).
LRMS: +ve ion 457 (M+H); -ve ion 455 (M-H).
Example 6: 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-pyridin-4-yl-piperazine-1- carbonyl)-hexanoic acid hydroxyamide. /~\ =
Nr
EtO HO 0
HN_
OH
Example 7: 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(morpholine-4-carbonyl)- hexanoic acid hydroxyamide. /\
N 0 —/
HN
OH
"H-NMR; delta (CDsOD): 7.05 (2H, d, J= 8.6Hz), 6.8 (2H, d, J= 8.6Hz), 4.05- 3.90 (3H, m), 3.8-3.4 (8H, m), 2.55 (2H, t, J= 6.7Hz), 1.75-1.4 (4H, m), 1.35 (3H, t, J=7.0Hz).
LRMS: +ve ion 403 (M+Na); -ve ion 379 (M-H).
Example 8: 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(2RS-methyl-morpholine-4- carbonyl)-hexanoic acid hydroxyamide.
0 {
N 0 n/
LOC
HN,
OH
LRMS: +ve ion 417 (M+Na), 395 (M+H); -ve ion 393 (M-H).
Example 9: 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(2,6-RS-dimethyl-morpholine- 4-carbonyl)-hexanoic acid hydroxyamide. 0 {
N 0 \—_—
LOC
HN_
OH
LRMS: +ve ion 431 (M+Na), 409 (M+H); -ve ion 407 (M-H).
Example 10: 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(thiomorpholine-4-carbonyl)- hexanoic acid hydroxyamide. 1 /\
N S n_/
Hoang:
HN_
OH
"H-NMR; delta (CDsOD): 7.05 (2H, d), 6.8 (2H, d), 4.0 (5H, m), 3.8-3.5 (2H, m), 2.9-2.4 (7H, m), 1.55 (4H, m) and 1.3 (3H, t).
LRMS: +ve ion 419 (M+Na). 397 (M+H); -ve ion 395 (M-H).
Example 11: 3R-(4-benzyl-piperidine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide.
DQ Ph
Oa
LOC
HN
OH
"H-NMR; delta (CD;OD): 7.3-7.0 (8H, m), 6.8 (2H, m), 4.55 (1H, d, J=12.4Hz), 4.05 (2H, dd, J=2.0Hz), 3.9 (2H, m), 2.9 (1H, m), 2.6-2.4 (5H, m), 1.84 (1H, d,
J=2.9Hz), 1.7-1.5 (6H, m), 1.35 (3H, 1, J= 7.0Hz).
LRMS: +ve ion 491 (M+Na); -ve ion 467 (M-H).
Example 12: 3R-(4-benzo[1,3]dioxol-5-yimethyl-piperazine-1-carbonyl)-6-(4- ethoxy-phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. 0) 0
N N
/
Hoare
HN
OH
LRMS: +ve ion 514 (M+H); -ve ion 512 (M-H).
Example 13: 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-pyridin-4-ylmethyl- piperazine-1-carbonyl)-hexanoic acid hydroxyamide. /N\
N N
_/
Beane. ba
HN =N
OH
LRMS: +ve ion 471 (M+H); -ve ion 469 (M-H).
Claims (30)
1. A compound of formula (1), or an enantiomer or diastereoisomer thereof, or a salt, hydrate or solvate thereof: Ar-(Alk) NR,R, RO CONHOH (0) wherein Ar represents an optionally substituted aryl, heteroaryl, C3-Cs cycloalkyl or heterocycloakyl group; R represents hydrogen or C1-Cg alkyl, or C3-Cg cycloalkyt; Alk represents a divalent C4-Cs alkylene or C-C5 alkenylene radical; and Ri: and Rx taken together with the nitrogen atom to which they are attached form a first heterocycloalkyl ring which is optionally fused to a second C3-Cs cycloalkyl or heterocycloalkyl ring, the said first and second rings being optionally substituted by at least one group of formula (li): AK O-AkR—Z (I) wherein m, p and n are independently 0 or 1; Z represents, hydrogen, or an optionally substituted carbocyclic or heterocyclic ring of from 5 to 7 ring atoms which is optionally fused to another optionally substituted carbocyclic or heterocyclic ring of from 5 to 7 ring atoms; Alk' and Alk? independently represent optionally substituted divalent C;-C3 alkylene radicals;
X represents -O-, -S-, -S(0)-, -S(02)-, -C(=0)-, -NH-, -NR3-, -S(O2)NH-, -S(O2)NRs-, -NHS(Oz)-, or -NR3S(0Q,)-, where Ra is C4-C3 alkyl.
2. A compound as claimed in claim 1 wherein R is hydrogen.
3. A compound as claimed in claim 1 wherein R is methyl.
4, A compound as claimed in claim 1 wherein R is ethyl, n-propyl, isopropyl, n-, sec- or tert-butyl, cyclopropyl, or cyclopentyl.
5. A compound as claimed in any of the preceding claims wherein Ar is a 5- or 6- membered monocyclic aryl or heteroaryl ring, which is optionally substituted by at least one substituent selected from (C1-Cj)alkyl, (C;- Cs)alkoxy, hydroxy, hydroxy(C1-Cs)alkyl, mercapto, mercapto(C+-Cs)alkyl, (C;- Ca)alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), -COOH, -COOR?*, -COR?,-SO,R*, -CONH, -SO2NH,, -CONHR*, -SO,NHR, -CONR"R®, -SO.NR*R®, -NHz, -NHR*, -NR*RB, -OCONH,, -OCONHR*, -OCONR"R®, -NHCOR?*, -NHCOOR*, -NRECOOR?*, -NHSO.0R*, -NR®SO,0R", -NHCONH;, -NR*CONH,, -NHCONHRE -NRACONHRE, - NHCONR*R®, or -NRACONR*R® wherein R* and RP are independently C1-Ca alkyl, phenyl or a 5- or 6-membered monocyclic aryl or heteroaryl ring.
6. A compound as claimed in claim 5 wherein an optional substituent is in the 4- position in the case of a 6-membered ring, or in the 2- and/or 3- position in the case of a 5-membered ring.
7. A compound as claimed in any of the preceding claims wherein Ar is optionally substituted phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-thienyl, or 2-, or 3- furanyl.
8. A compound as claimed in any of the preceding claims wherein optional substituents in Ar are selected from methoxy, ethoxy,
trifluoromethoxy, methyl, ethyl, trifluoromethyl, hydroxyl, mercapto, fluoro, chloro, and bromo.
9. A compound as claimed in claim 5 wherein Ar is 4-(C,Csalkoxy)phenyi.
10. A compound as claimed in claim § wherein Ar is 4-ethoxyphenyl
11. A compound as claimed in any of the preceding claims wherein Alk is —CHg-, -CH2CH_-, -CH2CH(CHj3)-, -CHCH2CHa-, -CH,CH.CH,>CH,-, —CH=CH-, -CH,CH=CH-, -CH,CH=CHCH,-, or -CH=CHCH=CH-.
12. A compound as claimed in any of the preceding claims wherein -NR;R> forms a pyrrolidinyl, morpholyi, or thiomorpholyl ring
13. A compound as claimed in any of claims 1 to 11 wherein -NR;R; forms a piperidinyl, or piperazinyl ring
14. A compound as claimed in any of the preceding claims wherein in the group (Il), when present, p is 0, Z is hydrogen and at least one of n and m is
1.
15. A compound as claimed in any of claims 1 to 13 wherein in the group (I), when present, m, n and p are all 0 and Z is a carbocyclic or heterocyclic ring directly linked to a ring carbon or ring nitrogen of the -NR4R; group.
16. A compound as claimed in any of claims 1 to 13 wherein in the group (I), when present, p is 0, at least one of mand nis 1, and Z is a carbocyclic or heterocyclic ring linked to a ring carbon or ring nitrogen of the -NR:R: group via a C4-Cg alkylene linker between Z and the -NR;R; ring.
17. A compound as claimed in any of claims 1 to 13 wherein in the group (it), when present, pis 1.
18. A compound as claimed in claim 1 of formula (IB) or (IC) or an enantiomer or diasterecisomer thereof, or a salt, hydrate or solvate thereof: R, x ( 0) 0) N N OC, JOT R; RO CONHOH R, RO CONHOH (1B) (IC) wherein R is hydrogen or methoxy, Rj is trifluoromethyl, triflucromethoxy C;- Caalkoxy, hydroxy, or halo; Ry is (i) -SO2Rs or -CORs wherein Rs is C1-Cealkyl or phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, optionally substituted by (C+-Cs)alkyl, (C-Cs)alkoxy, hydroxy, hydroxy(C-Cs)alkyl, mercapto, mercapto(C-Cs)alkyl, (C1-Cs)alkyithio, halo, trifluoromethyl, trifluoromethoxy or (ii) phenyl or monocyclic heteroaryl having 5 or 6 ring atoms; optionally substituted by (C1-Cs)alkyl, (C1-Cs)alkoxy, hydroxy, hydroxy(C1-Cs)alkyl, mercapto, mercapto(C4-Cs)alkyl, (C,-Ca)alkytthio, halo, trifluoromethyl, trifluoromethoxy.
19. A compound as claimed in claim 18 wherein a heteroaryl ring forming part of Rs is pyridyl, pyrimidinyl, triazinyl, thienyl, or furanyl.
20. A compound as claimed in any of the preceding claims having the stereochemical configuration shown in formula (1A): Ar-(Alk) NR,R, RO CONHOH (1A)
21. A compound as claimed in claim 1, which is selected from the group consisting of: 6-(4-ethoxy-pheny!)-2S-hydroxy-3R-(pyrrolidine-1-carbonyl)-hexanoic acid hydroxyamide. 3R-(8,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-6-(4-ethoxy- phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(3-methoxy-phenyl)-piperazine-1- carbonyl]-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(4-methoxy-phenyl)-piperazine-1- carbonyl]-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-pyridin-2-yl-piperazine-1-carbonyl)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-pyridin-4-yl-piperazine-1-carbonyl)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(morpholine-4-carbonyl)-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(2RS-methyl-morpholine-4-carbonyl)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(2,6-RS-dimethyl-morpholine-4-carbonyi)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(thiomorpholine-4-carbonyl)-hexanoic acid hydroxyamide. 3R-(4-benzyl-piperidine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S-hydroxy-hexanoic acid hydroxyamide.
3R-(4-benzo[1,3]dioxol-5-ylmethyl-piperazine-1-carbonyl)-6-(4-ethoxy- phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-pyridin-4-yimethyl-piperazine-1- carbonyl)-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-benzylpiperazine-1-carbonyl)-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(4-pyrimidin-2-yl-piperazine-1-carbonyl)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(4-trifluoromethyi-pyrimidin-2-yi)- piperazine-1-carbonyl]-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(4-chioro-pyrimidin-2-yl)-pipe razine-1- carbonyl}-hexanoic acid hydroxyamide. 3R-[4-(4,6-dimethoxy-[1,3,5}triazin-2-yl)-piperazine-1 -carbonyl]-6-(4-ethoxy- phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyi)-2S-hydroxy-3 R-{4-(3-trifluoromethyl-phenyl)-piperazine-1- carbonyl]-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(2-fluoro-phenyi)-piperazine-1- carbonyl}-hexanoic acid hydroxyamide. 3R-[4-(acetyl-methyl-amino)-piperidine-1 -carbonyl]-6-(4-ethoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(methyi-propyl-amino)-piperidine-1 - carbonyl]-hexanoic acid hydroxyamide.
6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(3S-benzyl-morpholine-4-carbonyl)- hexanoic acid hydroxyamide. 6-(4-sethoxy-phenyl)-2S-hydroxy-3R-(3S-isobutyl-morpholine-4-carbonyl)- hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(3S-phenyl-morpholine-4-carbonyl)- hexanoic acid hydroxyamide. 3R-(4-benzyl-3RS-methyl-piperazine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 3R-(3S,4-dibenzyl-piperazine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S-hydroxy- hexanoic acid hydroxyamide. 3R-(4-benzyl-3RS-phenyl-piperazine-1-carbonyl)-6-(4-ethoxy-phenyt)-2S- hydroxy-hexanoic acid hydroxyamide. 4-(4-benzo[1,3]dioxol-5-yimethyl-piperazin-1-yl)-2S,N-dihydroxy-4-oxo-3R-(4- trifluoromethoxy-benzyl)-butyramide. 3R-benzyl-2S,N-dihydroxy-4-morpholin-4-yi-4-oxo-butyramide.
3R-(4-Benzyloxy-benzyl)-2S,N-dihydroxy-4-oxo-4-piperidin-1-yl-butyramide. 2S,N-dihydroxy-3R-(4-hydroxy-benzyl)-4-oxo-4-piperidin-1-yl-butyramide. 4-(4-benzo[1,3]dioxol-5-yimethyl-piperazin-1-yl)-3R-(4-benzyloxy-benzyl)-
25,N-dihydroxy-4-oxo-butyramide. 6-(3,5-bis-trifluoromethyl-phenyl)-2S-hydroxy-3R-(morpholine-4-carbonyl)- hexanoic acid hydroxyamide.
3R-(4-benzyl-piperidine-1-carbonyl)-6-(3,5-bis-trifluoromethyl-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 6-(3,5-bis-trifluoromethyl-phenyl)-2S-hydroxy-3R-(4-pyridin-2-yl-piperazine-1- carbonyl)-hexanoic acid hydroxyamide. 6-(3,5-bis-trifluoromethyl-phenyl)-3R-(6,7-dimethoxy-3,4-dihydro-1H- isoquinoline-2-carbonyl)-2S-hydroxy-hexanoic acid hydroxyamide. 6-(3,5-bis-trifluoromethyl-phenyl)-2S-hydroxy-3R-(pyrrolidine-1-carbonyl)- hexanoic acid hydroxyamide 3R-(2S-benzyi-4-methyl-piperazine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(4-trifluoromethoxy-benzenesulfonyl)- piperazine-1-carbonyl}-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-{4-(toluene-4-sulfonyl)-piperazine-1- carbonyl}-hexanoic acid hydroxyamide. 3R-[4-(5-bromo-thiophene-2-sulfonyl)-piperazine-1-carbonyl]-6-(4-ethoxy- phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. 3R-[4-(5-benzenesulfonyl-thiophene-2-sulfonyl)-piperazine-1-carbonyi}-6-(4- ethoxy-phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. 3R-[4-(4-butoxy-benzenesulfonyl)-piperazine-1-carbonyl]-6-(4-ethoxy-phenyl)- 2S-hydroxy-hexanoic acid hydroxyamide. 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-[4-(4-methoxy-2,3,6-trimethyl- benzenesulfonyl)-piperazine-1-carbonyl]-hexanoic acid hydroxyamide.
3R-{4-(3,4-dimethoxy-benzenesulfonyl)-piperazine-1-carbonyi]-6-(4-ethoxy- phenyl)-2S-hydroxy-hexanoic acid hydroxyamide. 6-(4-methoxy-phenyl)-2S-hydroxy-3R-[4-(2-fluoro-phenyl)-piperazine-1- carbonyl]-hexanoic acid hydroxyamide. 6-(4-methoxy-phenyl)-2S-hydroxy-3R-(4-pyridin-2-yl-piperazine-1-carbonyl)- hexanoic acid hydroxyamide. - 6-(4-fluoro-phenyl)-3R-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-2S- hydroxy-hexanoic acid hydroxyamide. 6-(4-fluoro-phenyl)-2S-hydroxy-3R-(4-pyridin-2-yl-piperazine-1-carbonyl)- hexanoic acid hydroxyamide. 3R-(4-benzyl-2S-methyl-piperazine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 3R-(4-benzyl-2S5-methyl-piperazine-1-carbonyl)-6-(4-methoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 3R-(4-benzyl-2S-i-butyl-piperazine-1-carbonyl)-6-(4-methoxy-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 3R-(4-benzyl-2S-methyl-piperazine-1-carbonyl)-6-(4-fluoro-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 3R-(4-benzyl-28-i-butyl-piperazine-1-carbonyl)-6-(4-fluoro-phenyl)-2S- hydroxy-hexanoic acid hydroxyamide. 4-[5-(4-ethoxy-phenyl)-2R-(1S-hyd roxy-hydroxycarbamoyl-methyl)-pentanoyl]- 2S-methyi-piperazine-1-carboxylic acid tert-butyl ester.
26. A method as claimed in claim 24 or a use as claimed in claim 25 wherein the disease or condition is bone resorption, tumour growth or invasion by secondary metastases; rheumatoid arthritis, septic arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, cardiac hypertrophy, acute respiratory distress syndrome, neuroinflammatory disorders, e.g. multiple sclerosis; restenosis; emphysemia; fibrotic didease e.g. fibrosis post radiotherapy, kerotid scarring, liver fibrosis and cystic fibrosis; chronic obstructive pulmonary disease; bronchitis; asthma; autoimmune disease; transplant rejection (e.g. graft versus host disease); cystic fibrosis; psoriasis; psoriatic arthritis; degenerative cartilage loss; inflammatory gastric conditions,
e.g. Crohn's disease, inflammatory bowel disease, and ulcerative colitis; atopic dermatitis, epidermolysis bullosa; epidermic ulceration; a neuropathy or nephropathy e.g.interstitial nephritis, glomerulonephriris or renal failure; ocular inflammation; liver cirrhosis, Sjoegren’s syndrome; or an inflammatory condition of the nervous system.
27. A method as claimed in claim 24 or a use as claimed in claim 25 wherein the disease or condition is fibrotic disease, multiple sclerosis, emphysemia, bronchitis or asthma.
28. A method of preparing metalloproteinase inhibitors of formula (IA) according to any of claims 1 to 21 wherein R is hydrogen, comprising the de- protection and/or transformation step of: Oo Ar-(Alk) vou J NR,R, NR,R, x HO CONHOH Je (1A)
(m.) wherein Ar, Alk, Ry and R; are as defined in any of claims 1 to 16.
29. A compound of formula (IIB)
0] Ar-(Alk) NR,R, Q Oo Ad (1B) wherein Ar, Alk, Ry and R; are as defined in any of claims 1 to 19.
30. A process for the preparation of a compound as claimed in claim 29 comprising comprising the step of reacting a compound of formula (ill) Ar-(Alk) COOH x (mn i with a cyclic amine HNR;R.., wherein Ar, Alk, Ry and R; are as defined in any of claims 1 to 19.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0319917A GB0319917D0 (en) | 2003-08-23 | 2003-08-23 | Metalloproteinase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200602358B true ZA200602358B (en) | 2007-09-26 |
Family
ID=28460251
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200602358A ZA200602358B (en) | 2003-08-23 | 2006-03-22 | Derivatives of hydroxamic acid as metalloproteinase inhibitors |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1930139B (en) |
| ES (1) | ES2365731T3 (en) |
| GB (1) | GB0319917D0 (en) |
| ZA (1) | ZA200602358B (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9501737D0 (en) * | 1994-04-25 | 1995-03-22 | Hoffmann La Roche | Hydroxamic acid derivatives |
| US5703092A (en) * | 1995-04-18 | 1997-12-30 | The Dupont Merck Pharmaceutical Company | Hydroxamic acid compounds as metalloprotease and TNF inhibitors |
| US5917090A (en) * | 1995-06-30 | 1999-06-29 | British Biotech Pharmaceuticals Ltd. | Matrix metalloproteinase inhibitors |
| GB9804504D0 (en) * | 1998-03-03 | 1998-04-29 | Leo Pharm Prod Ltd | Matrix metalloproteinase inhibitors |
| AU2268401A (en) * | 1999-12-17 | 2001-06-25 | Versicor Inc | Novel succinate compounds, compositions and methods of use and preparation |
| ATE360014T1 (en) * | 2001-06-15 | 2007-05-15 | Vicuron Pharm Inc | BICYCLIC PYRROLIDINE COMPOUNDS |
-
2003
- 2003-08-23 GB GB0319917A patent/GB0319917D0/en not_active Ceased
-
2004
- 2004-08-18 CN CN2004800237488A patent/CN1930139B/en not_active Expired - Fee Related
- 2004-08-18 ES ES04768117T patent/ES2365731T3/en active Active
-
2006
- 2006-03-22 ZA ZA200602358A patent/ZA200602358B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB0319917D0 (en) | 2003-09-24 |
| ES2365731T3 (en) | 2011-10-10 |
| CN1930139A (en) | 2007-03-14 |
| CN1930139B (en) | 2011-07-27 |
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