Sulfonylamino Derivatives Which Inhibit Matrix-Degrading Metalloproteinases

专利摘要:
The present invention relates to compounds of formula (I) Compound I is an inhibitor of matrix degradation metalloproteinases and is used to treat diseases associated with it. <Formula I> Where W is -OH or -NHOH; X is an optionally substituted heterocycle, -NR 1 SO 2 R 2 , heterocyclyltylthio, -CONR 2 R 3 or -NR 1 COR 2 ; Y, Z, R 1 to R 3 and n are as defined in the specification.
公开号:KR20010040698A
申请号:KR1020007008576
申请日:1999-02-02
公开日:2001-05-15
发明作者:파이비 자아나 쿡콜라；레슬리 앤 로빈슨；준이찌 사가끼；모또오 나까지마
申请人:한스 루돌프 하우스, 헨리테 브룬너, 베아트리체 귄터；노파르티스 아게；
IPC主号:

专利说明:

Sulfonylamino Derivatives Which Inhibit Matrix-Degrading Metalloproteinases
<Summary of invention>
Sulfonylamino acid and sulfonylamino hydroxamic acid derivatives of the present invention, methods for preparing the same, pharmaceutical compositions containing the compounds, methods for inhibiting matrix degradation metalloproteinases in mammals using the compounds and their derivatives It relates to the use as a medicine.
The present invention relates to sulfonylamino acid and sulfonylamino hydroxamic acid derivatives of the formula (I) and pharmaceutically acceptable salts thereof.
Where
W is -OH or -NHOH;
X is
a) pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thia Diazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, oxadizolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- Oxopyrrolodinyl, 2-oxoazinyl, azepinyl, 4-piperidinyl, pyridyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl Sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-l, l-dioxothienyl, benzothiazolyl, benzoxazolyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl , Isoquinolinyl, benzimidazolyl, benzopyranyl, indolinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, synol Linyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydrobenzoisothiazolyl, dihydroquinazolinyl, tetrahydroquinazolinyl and a 10-15 membered tricyclic ring system (bicyclic system) May have one or more heteroatoms in the ring comprising one or more carbon atoms and each ring of the heterocyclic radical comprising the hetero atoms may have one, two or three heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms Substituted or unsubstituted heterocyclic radicals selected from the group consisting of: wherein X is a heterocyclic radical comprising nitrogen, the heterocyclic radical is attached to the (CH ₂ ) m moiety by a ring nitrogen, Nitrogen and sulfur hetero atoms of the heterocyclic radical may be oxidized);
b) —NR ₁ SO ₂ R ₂ , wherein R ₁ is hydrogen, alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl, and R ₂ is hydrogen, alkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl , Aryl or heteroaryl;
c) heterocyclylalkylthio;
d) -CONR ₂ R ₃ , wherein R ₂ and R ₃ together with the nitrogen atom to which they are attached form a 5-7 membered ring which may optionally contain another hetero atom selected from oxygen, nitrogen and sulfur ; or
e) -NR ₁ COR ₂ , wherein R ₁ is hydrogen, alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl, and R ₂ is hydrogen, heterocyclylalkyl, aralkyl, heteroarylalkyl or aryl ego;
Y is carbon, nitrogen, oxygen or sulfur, where n is 2 when Y is carbon;
Z is alkyl, aryl, alkoxy, aryloxy, aralkoxyaryl, alkoxyheteroaryl, heteroaryl, heterocyclyl, heteroaryloxy, -CONR ₂ R ₃ , -NR ₁ COR ₂ , -NR ₁ CONR ₂ R ₃ , -OCONR ₂ R ₃ , -NR ₁ COOR ₄ or -SO ₂ R ₂ , wherein R ₁ is hydrogen, alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl, and R ₂ and R ₃ are independently hydrogen , Alkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, aryl or heteroaryl or R ₂ and R ₃ may optionally contain another hetero atom selected from oxygen, nitrogen and sulfur together with the nitrogen atom to which they are attached Forms a 5-7 membered ring, R ₄ is alkyl, heterocyclylalkyl, aralkyl, aryl or heteroaryl;
m is an integer from 1 to 6;
n is an integer of 1 or 2.
Compounds of formula (I) are inhibitors of matrix degrading metalloproteinases and are useful for the treatment of related diseases.
The present invention relates to compounds of formula (I), pharmaceutical compositions using said compounds and methods of using said compounds. Definitions of various terms used to disclose the compounds of the invention are listed below. These definitions apply to the terms used throughout the specification (unless they are limited to particular cases individually or as part of a larger group).
The term "heterocyclic radical is a 4-7 membered monocy having optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic cyclic groups, for example having one or more heteroatoms in a ring comprising one or more carbon atoms. Cyclic, 7 to 11 membered bicyclic or 10 to 15 membered tricyclic ring system, each ring of a heterocyclic radical comprising a hetero atom is selected from a nitrogen atom, an oxygen atom and a sulfur atom; It may comprise three hetero atoms, and the nitrogen and sulfur hetero atoms may be optionally oxidized.
Monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, thiazolyl, Isoxazolyl, isoxazolinyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, thienyl, tetrahydrofuryl, oxadiazolyl, piperidinyl, piperazinyl, 2-jade Sofiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazinyl, azepinyl, 4-piperidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetra Hydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-l, l-dioxothienyl and the like.
Bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinucridinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl , Indolinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, furopyridinyl (eg, furo [2,3-c] pyridinyl, furo [3, 2-b] pyridinyl] or furo [2,3-b] pyridinyl), pyrrolopyridyl, dihydrobenzoisothiazolyl, dihydroisoindolyl, dihydroquinazolinyl (e.g. 3,4-di Hydro-4-oxo-quinazolinyl), tetrahydroquinazolinyl, and the like.
Examples of the tricyclic heterocyclic group include tetrahydroimidazo [1,5-b] isoquinolinyl, carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenantridinyl, xanthenyl and the like.
The term "heterocyclic radical" also includes substituted heterocyclic groups. Substituted heterocyclic groups
(a) alkyl;
(b) hydroxy (or protected hydroxy);
(c) halo;
(d) oxo (ie = O);
(e) amino, alkylamino or dialkylamino;
(f) alkoxy;
(g) cycloalkyl;
(h) carboxy;
(i) heterocyclyloxy;
(j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl;
(k) carbamyl, alkylcarbamyl or dialkylcarbamyl;
(l) mercapto;
(m) nitro;
(n) cyano;
(o) sulfonamido, aminosulfonyl, alkyl or dialkylsulfonyl;
(p) aryl or heteroaryl;
(q) alkylcarbonyloxy;
(r) arylcarbonyloxy;
(s) arylthio;
(t) aryloxy;
(u) alkylthio;
(v) formyl;
(w) arylalkyl; or
(x) refers to heterocyclic groups substituted with 1, 2, 3, 4 or 5 of allyl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino or halo.
The term "alkyl" denotes an optionally substituted straight or branched chain hydrocarbon group having 1 to 8 carbon atoms, preferably 1 to 5 carbons. Unsubstituted alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, various abrasive isomers thereof, for example isopropyl, t-butyl, isobutyl, isohexyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl etc. are mentioned. Substituted alkyl groups include those alkyl groups substituted with one or more substituents selected from halogen, alkoxy, cycloalkyl, hydroxy, amino, nitro, cyano or thiol.
The term "alkoxy" refers to the above alkyl group connected to an oxygen atom.
The term "cycloalkyl" denotes a saturated cyclic hydrocarbon group comprising 3 to 7 ring carbons, with cyclopropyl, cyclopentyl and cyclohexyl being preferred.
The term "halogen" or "halo" refers to chlorine, bromine, iodine and fluorine.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups containing 6 to 12 carbon atoms in the ring portion, for example phenyl, naphthyl, tetrahydronaphthyl or biphenyl groups, each of which is 1 to 4 substituents Optionally substituted with alkyl, halo, hydroxy, alkoxy, amino, thiol, nitro, cyano, carboxy, heterocycle, and the like.
The term "aralkyl" denotes an aryl group, for example benzyl, bonded directly to an alkyl group.
The term "aryloxy" denotes an aryl group linked to an oxygen atom.
The term "aralkoxy" denotes an aryl group which is directly bonded through an alkoxy group.
The term "aroyl" refers to aryl-C (O)-.
The term "heterocyclyl" refers to a heterocyclic radical.
The term "heterocyclylalkyl" refers to a heterocyclic radical bonded directly via an alkyl group.
The term "heterocyclyloxy" refers to a heterocyclic group bonded through an oxygen bridge.
The term "heteroaryl" refers to an aromatic heterocyclic radical.
The term "heteroarylalkyl" refers to an aromatic heterocyclic radical bonded directly via an alkyl group.
The term “heteroarylsulfonyl” refers to heteroaryl-S— (O) ₂ —.
The term "heteroaroyl" refers to heteroaryl-C (O)-.
In the entire specification, the groups and their substituents are selected to provide stable moieties and compounds.
Depending on the nature of the substituents, the compounds of the present invention have one or more asymmetric carbon atoms. The present invention therefore encompasses the resulting stereoisomers, enantiomers and geometric isomers.
It is preferred that the compounds of the present invention have an (R) -configuration of the asymmetric carbon atoms of the compounds of formula (I).
Preferred compounds of formula I are W is -OH or -NHOH, X is pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiadia Zolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, oxadizolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-jade Sopyrrolodinyl, 2-oxoazinyl, azepinyl, 4-piperidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolane, thiamorpholinyl, thia Morpholinyl sulfoxide, thiamorpholinyl sulfone, tetrahydroisoquinolinyl, tetrahydro-1, l-dioxothienyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzopyranyl, indoli Genyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cynolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopy Neyl, dihydrobenzoisothiazolyl, dihydroquinazolinyl, tetrahydroquinazolinyl and a 10 to 15 membered tricyclic ring system, which has at least one hetero atom in a ring containing at least one carbon atom Each ring of a heterocyclic radical comprising a hetero atom may have one, two or three hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom); a substituted or unsubstituted heterocyclic radical selected from the group consisting of And the remaining symbols and radicals are the same compounds as defined above.
Another preferred embodiment of the invention is that W is -OH or -NHOH, X is pyrazolyl, oxetanyl, pyrazolinyl, imidazolinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl , Thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, oxadiazolyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2 Oxoazinyl, pyridyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, Tetrahydro-l, l-dioxothienyl, benzothiazolyl, benzoxazolyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzopyranyl, benzofuryl, chromonyl, Coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, di Drawbenzoisothiazolyl, dihydroquinazolinyl, tetrahydroquinazolinyl and a 10 to 15 membered tricyclic ring system, which has at least one hetero atom in a ring containing at least one carbon atom and Each ring of the containing heterocyclic radical is a substituted or unsubstituted heterocyclic radical selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, which may have one, two or three hetero atoms selected from the group consisting of Symbols and radicals are compounds of formula I which have the same meanings as above.
Other preferred embodiments of the present invention are those wherein W is -OH or -NHOH, X is a nitrogen-containing heterocyclic radical, Y is carbon, n is 2, and Z is aryl, aryloxy, heteroaryl or heteroaryloxy And m is a compound of formula (I) which is an integer from 2 to 4.
Particularly preferred compounds of formula I are those wherein W is -OH or -NHOH, X is 1,2,3,4-tetrahydro-1-methyl-2,3-dioxo-quinazolinyl, 3,4,4- Trimethyl-2,5-dioxoimidazolinyl, 4-methylbenzenesulfonylamino or 1,1,3-trioxo-2,3-dihydrobenzoisothiazolyl, Z is aryl, aryloxy , Heteroaryl or heteroaryloxy, Y is carbon, nitrogen oxygen or sulfur, where Y is carbon, n is 2, n is an integer of 1 or 2 and m is an integer of 2-4.
Particularly preferred compounds of formula I are those wherein W is —OH and the remaining symbols and radicals have the same meanings as above.
Another preferred embodiment of the invention is that in formula I, W is -OH or -NHOH and X is -CONR ₂ R ₃ , wherein R ₂ and R ₃ together with the nitrogen atom to which they are attached comprise oxygen as another hetero atom To form a 5 to 7 membered ring), Y is carbon, n is 2, Z is aryl or aryloxy, and m is an integer of 1 to 3.
In addition, W is -OH, X is 1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-quinazolinyl or 1,1,3-trioxo-2,3-di A compound of Formula I wherein hydrobenzo-isothiazolyl, Y is carbon, n is 2, Z is aryl or aryloxy, in each case aryl is substituted or unsubstituted with halogen, and m is an integer from 2 to 4 Also preferred.
Another preferred embodiment of the invention is that W in formula I is -OH or -NHOH, X is -NR ₁ COR ₂ (wherein R ₁ is hydrogen and R ₂ is aralkyl or aryl) and Y is carbon , N is 2, Z is alkoxy or aryl and m is an integer of 3 to 4.
In addition, W is -OH or -NHOH, X is -NR ₁ SO ₂ R ₂ (wherein R ₁ is hydrogen, R ₂ is alkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, aryl or heteroaryl Is a compound of formula I wherein Y is carbon, n is 2, Z is alkoxy or aryl, and m is an integer of 3-4.
Pharmaceutically acceptable salts of the acidic compounds of the invention are salts formed with bases, ie cationic salts, for example alkali and alkaline earth metal salts, for example sodium, lithium, potassium, calcium, magnesium, and ammonium salts, for example Ammonium, trimethylammonium, diethylammonium and tris- (hydroxymethyl) -methylammonium salts.
Similarly, when basic groups such as pyridyl constitute part of the structure, acid addition salts such as inorganic acids, organic carboxylic acids and organic sulfonic acids, ie hydrochloric acid, methane sulfonic acid, maleic acid are possible.
Compounds of formula (I) wherein X is a heterocyclic radical or heterocyclylalkylthio are formulated with an N- (diphenylmethylene) glycine t-butyl ester (commercially available) and a compound of formula (II) in an organic solvent such as tetra It can be prepared by treating with a base in hydrofuran and N, N-dimethylformamide, for example sodium hydride or potassium hydride to form a compound of formula III.
Y- (CH ₂ ) _m -X
Wherein Y is a halide such as chloride, bromide or iodide, or leaving group such as sulfonate (prepared according to the literature) such as methanesulfonate, trifluoromethanesulfonate or methylbenzenesulfonate to be.
Compounds of formula III can be converted to compounds of formula IV by treatment with a weak acid, such as 4-methylbenzenesulfonic acid, in an organic solvent such as acetonitrile and tetrahydrofuran in the presence of a small amount of water.
Sulfonylation of a compound of formula IV with a sulfonyl chloride such as 4'-chlorobiphenyl-4-sulfonyl chloride or a compound of formula V yields a compound of formula VI.
Sulfonylation can be carried out in an organic solvent such as dichloromethane, tetrahydrofuran, acetonitrile or N, N-dimethylformamide in the presence of a base such as triethylamine or N-methylmorpholine. Sulfonyl chlorides of formula V can be obtained by methods disclosed in the art.
Compounds of formula VI can be converted to compounds of formula I wherein W is a hydroxy group by treatment with anhydrous acids such as trifluoroacetic acid or hydrochloric acid in an organic solvent such as dichloromethane, diethyl ether or ethyl acetate. If trifluoroacetic acid is used the reaction can take place without solvent.
Compounds of formula (I) wherein W is -NHOH can be obtained from compounds of formula (I) wherein W is a hydroxy group by reaction with a protected hydroxylamine such as trityl-, allyl- or t-butylhydroxylamine. The reaction was carried out in 1-hydroxy-7-azabenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbane in an organic solvent such as dichloromethane, tetrahydrofuran, acetonitrile or N, N-dimethylformamide. It may be carried out in the presence of a coupling agent such as a bodyimide and a base such as triethylamine or N-methylmorpholine. The protecting group can be removed according to methods known in the art.
Alternatively, compounds of formula (I) wherein X is a heterocyclic radical or heterocyclylalkylthio and m is 2 or 3 can be obtained from formula (VII).
Wherein m 'is an integer of 2 or 3, and Ra, Rb and Rc are independently suitable protecting groups. For example, when Ra is methyl or ethyl and Rb and Rc are t-butyl, the compound of formula VII is dissolved in lithium hydroxide, sodium hydroxide or hydroxide in an aqueous solution of an organic solvent such as tetrahydrofuran, dioxane, methanol or ethanol. Treatment with a base such as potassium can form a compound of formula VIII.
The compound of formula VIII is then subjected to alkylchloroformate, for example ethylchloroform, in an organic solvent such as tetrahydrofuran, dioxane or ethylene glycol dimethyl ether in the presence of a base such as N-methylmorpholine or triethylamine. After treating with mate or isobutylchloroformate and reducing with sodium borohydride, a compound of formula IX may be obtained.
Using standard methods in the literature, compounds of formula (IX) are converted to compounds of formula (X)
Wherein Ya is a halide such as iodide, bromide or chloride, or a sulfonate such as methanesulfonate, trifluoromethanesulfonate or 4-methylbenzenesulfonate.
The compound of formula X is then a compound (X ′) which is a heterocyclic radical in an organic solvent such as N, N-dimethylformamide in the presence of a base such as sodium hydride, potassium hydride, potassium carbonate or cesium carbonate, for example Saccharin, 1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin, 3,4,4-trimethyl-2,5-dioxoimidazolidine or heterocyclylalkylthiol Treatment with to form a compound of formula
Subsequently, compounds of formula (XI) are selectively removed from the nitrogen atoms using methods known in the art to form compounds of formula (XII).
For example, when Rb and Rc are t-butyl, the protecting group removal reaction may be performed by treating with anhydrous acid such as trifluoroacetic acid in an organic solvent such as dichloromethane.
The compound of formula XII is then sulfonylated with a sulfonyl chloride of formula V, such as 4'-chlorobiphenyl-4-sulfonyl chloride. Sulfonylation to form Formula XIII is carried out using a base such as triethylamine or N-methylmorpholine in an organic solvent such as dichloromethane, tetrahydrofuran, acetonitrile or N, N-dimethyformamide. Can be.
Compounds of formula (XIII) are converted to compounds of formula (IA)
In the above formula, when the carboxyl protecting group is removed using a known method, W becomes OH. For example, when Rc is a t-butyl group, the protecting group can be removed by treatment with anhydrous acid such as trifluoroacetic acid or hydrochloric acid in an organic solvent such as dichloromethane, diethyl ether or ethyl acetate. When trifluoroacetic acid is used, it can be reacted without a solvent.
Compounds of formula (IA) in which W is -NHOH can be obtained from compounds of IA in which W is a hydroxyl group through reaction with a protected hydroxylamine such as trityl-, allyl- or t-butylhydroxylamine. The reaction is carried out in 1-hydroxy-7-azabenzotriazole and 1- (3-dimethylaminopropyl) -3- in an organic solvent such as dichloromethane, tetrahydrofuran, acetonitrile or N, N-dimethyformamide. It may be carried out in the presence of a coupling agent such as ethylcarbodiimide and a base such as triethylamine or N-methylmorpholine. Protecting groups can be removed by methods disclosed in the art.
Compounds of formula (VII) are described in Schönfelder, A .: Mann, A., Synth. Commun., 20, 2585-8 (1990).
Compounds of formula (I) wherein m is 1 or 2 and X is -CONR ₂ R ₃ or NHCOR ₂ can be prepared from compounds of formula VIII by methods known in the art or by modifications disclosed herein.
Compounds of formula (I) wherein m is 3 or 4 and X is -NH-SO ₂ -R ₂ are either commercially available or known in the literature using methods known in the art or using the modification methods disclosed herein. It can be prepared from).
Wherein m "is an integer of 3 or 4.
Compounds of formula (I) wherein m is 1 and X is heterocyclylalkylthio are obtained from compounds of formula (XVI) (commercially available or known in the art) using methods known in the art or modified methods disclosed herein. Can be prepared.
In the above formula, Yb may be a protecting group such as acyl or form a disulfide dimer.
Other compounds of formula I can be prepared by variations of known methods or by the examples disclosed herein.
Starting compounds and intermediates in which functional groups such as amino, thiol, carboxyl and hydroxy groups are present, which are converted to the compounds of the present invention by the methods disclosed herein, are optionally protected by conventional protecting groups commonly used in manufacturing organic chemistry. . Protected amino, thiol, carboxyl and hydroxy groups are groups that can be converted under free conditions to free amino, thiol, carboxyl and hydroxy groups without disruption of the molecular structure or unwanted side reactions.
The purpose of introducing protecting groups is to protect the functional groups from unwanted reactions with the reaction components under the conditions used to effect the desired chemical conversion. The need and selection of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxy group, amino group, etc.), the structure and stability of the molecule of which the substituent is part, and the reaction conditions.
Well known protecting groups suitable for these conditions and their introduction and removal are described, for example, in J.F.W. McOmie, "Protective Group in Organic Chemistry", Plenum Press, London, New York, 1973, T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York, 1991.
In the methods mentioned herein, reactive functional derivatives of carboxylic acids represent, for example, anhydrides (particularly mixed anhydrides), acid halides, acid azides, lower alkyl esters and activated esters thereof. The mixed anhydrides are preferably derived from lower alkyl (ethyl, isobutyl) hemiesters of pivalic acid or carboxylic acid, the acid halides are for example chlorides or bromide, the activated esters are succinimides, Phthalimido or 4-nitrophenyl esters are exemplified, and lower alkyl esters are, for example, methyl or ethyl esters.
The above-mentioned reactions are preferably inert to reagents and are preferably low temperature, room temperature or elevated temperature (preferably in the presence or absence of diluents such as reaction solvents, catalysts which shorten the reaction or other reagents and / or inert atmospheres thereof). At or near the boiling point of the solvent used) and under atmospheric or overpressure according to standard methods. Preferred solvents, catalysts and reaction conditions are disclosed in the accompanying examples.
In addition, the present invention provides that the intermediate product obtainable at all stages of the manufacturing process is used as the starting material, and the remaining steps are carried out, or the starting material is formed in the reaction system under the reaction conditions, or the reaction component is a salt thereof or optically. As used in the form of pure coliforms.
The compounds and intermediates of the present invention may also be converted to each other according to generally known methods.
The invention also relates to novel starting materials and methods for their preparation.
Depending on the choice of starting materials and methods, the new compounds are possible forms of isomers or mixtures thereof, such as substantially pure geometric (cis or trans) isomers, optical isomers (colon), racemates or mixtures thereof. Can be Possible isomers or mixtures thereof mentioned above fall within the scope of the invention.
The resulting mixture of isomers can be separated into pure geometric or optical isomers, diastereomers, racemates, depending on the physicochemical differences of the components, for example using chromatography and / or fractional crystallization.
The racemates of the final products or intermediates produced are optically determined by known methods, for example by the separation of their diastereomeric salts obtained with optically active acids or bases and the release of optically active acidic or basic compounds. Can be divided into colons. Carboxylic acid intermediates are, for example, of d- or l- (alpha-methylbenzylamine, synconidine, synconin, quinine, quinidine, ephedrine, dehydroabiethylamine, brucin or stychinin) -salts. It can be divided into optical cognates by differential determination. The racemate product may be partitioned by asymmetric chromatography, for example high pressure liquid chromatography with an asymmetric adsorbent.
Finally, the compounds of the present invention are obtained in free form or in the form of their salts when salt forming groups are present.
The acidic compounds of the present invention can advantageously be converted to salts using pharmaceutically acceptable bases, for example aqueous alkali metal hydroxides, in the presence of ethereal or alcoholic solvents such as lower alkanols. Salts in this solution can be precipitated with ethers, for example diethyl ether. The resulting salt can be converted to the free compound by acid treatment. These or other salts can also be used for the purification of the compounds obtained.
Compounds of the invention comprising a basic group can be converted to acid addition salts, in particular pharmaceutically acceptable salts. These are (C ₁ -C ₄ ) -alkanecarboxylic acids (eg acetic acid) unsubstituted or substituted with inorganic acids such as mineral acids (eg sulfuric acid, phosphoric acid, hydrohalic acid) or organic carboxylic acids such as halogen. ), Saturated or unsaturated dicarboxylic acids (e.g. oxalic acid, succinic acid, maleic or fumaric acid), hydroxycarboxylic acids (e.g. glycolic acid, lactic acid, malic acid, tartaric acid or citric acid), amino acids (e.g. aspartic acid or glutamic acid) ), Or organic sulfonic acids such as (C ₁ -C ₄ ) -alkylsulfonic acids (eg methanesulfonic acid) or substituted or unsubstituted arylsulfonic acids (eg by halogen). Preferred are salts formed using hydrochloric acid, methane sulfonic acid and maleic acid.
Given the intimate relationship between the free compounds and the compounds in their salt form, when referring to a compound herein, the corresponding salts are also intended, if possible or suitable under those conditions.
In addition, the compounds and their salts may be obtained in the form of hydrates or may include the solvent used for their crystallization.
The present invention provides for the treatment of diseases responsive to matrix-degraded methylloproteinases suitable for oral or rectal, transdermal and parenteral administration to mammals, including humans, which inhibit matrix-degraded metalloproteinases. A pharmaceutical composition comprising an effective amount of a pharmaceutically active compound of the invention, alone or in combination with one or more pharmaceutically acceptable carriers, is suitable.
Pharmaceutically active compounds of the invention are useful for preparing pharmaceutical compositions comprising an effective amount of such compounds, in combination with or in combination with excipients or carriers suitable for small intestine or parenteral administration. The active ingredient may be a) diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, b) lubricants such as silica, talc, stearic acid, magnesium or calcium thereof Salts and / or polyethylene glycols, for tablets c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, Preference is given to d) disintegrants, for example, starches, agar, alginic acid or sodium salts or foamed mixtures thereof, if necessary, and / or e) tablets and gelatin capsules comprising together with absorbents, colorants, fragrances or sweeteners. Injectable compositions are preferably isotonic solutions or suspensions, and suppositories are preferably prepared in fatty emulsions or suspensions. The composition may be sterilized and / or include adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for adjusting osmotic pressure and / or buffers. It may also contain substances useful for other treatments. The composition is prepared according to conventional mixing, granulation or coating methods and comprises about 0.1 to 75%, preferably about 1 to 50% of the active ingredient.
Formulations suitable for transdermal administration include an effective amount of a compound of the invention in combination with a carrier. Advantageous carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin of the subject to be administered. Characteristically, the transdermal device is a decahedron, a reservoir containing the compound with any carrier, an optional rate controlling membrane for delivering the compound to the subject's skin continuously at a controlled, predetermined rate and means for securing the device of the skin. It is a bandage form comprising a.
Formulations suitable for topical application, such as skin and eyes, are preferably aqueous solutions, ointments, creams or gels known in the art.
Pharmaceutical formulations may be used in the art alone or in anti-rheumatic agents, such as anti-inflammatory agents or methotrexate, having a cyclooxygenase inhibitory activity, alone or in combination with the substrate-degrading metalloproteinase inhibitory effective amount of the invention as defined above. Included with the reported therapeutically effective amount. Such therapeutic agents are known in the art.
Examples of the anti-inflammatory agent having a cyclooxygenase inhibitory activity include diclofenac, naproxen, ibuprofen and the like.
The compounds of the present invention may be administered simultaneously with other active ingredients, before or after the administration of the other active ingredients or separately or together in the same pharmaceutical formulation by the same or different routes of administration.
Dosage of the active compound depends on the species, weight, age and individual disease and dosage form of the warm-blooded animal (mammal). For oral administration of about 50 to 70 kg of mammals, the unit dosage may comprise about 10 to 1000 mg, advantageously about 25 to 500 mg of the active ingredient.
Compounds of the invention include matrix degrading metalloproteinases such as gelatinase, stromelysine, collagenase (including collagenase 1 and 3) and macrophage metalloelastatase and MT-MMP1 and 2 Inhibits the membrane-like substrate methylloproteinases such as. The compounds are particularly useful as collagenase-3 inhibitors.
Accordingly, the compounds of the present invention are useful for inhibiting substrate degradation and for the treatment of gelatinase-, stromelysin-, collagenase- and macrophage metalloelastatase dependent pathological diseases in mammals. The disease includes malignant and nonmalignant tumors (tumor growth, tumor metastasis, tumor progression or invasion, and / or inhibiting tumor angiogenesis), which include breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer and skin cancer do. Other diseases that can be treated with the compounds of the present invention include rheumatoid arthritis, osteoarthritis bronchial diseases (e.g., asthma treatment by inhibiting the degradation of elastin), atherosclerosis (e.g., inhibit the destruction of atherosclerosis), acute coronary syndrome , Heart attack (heart ischemia), stroke (cerebral ischemia), restenosis after angioplasty, and vascular ulcers, dilators and aneurysms.
In addition, diseases treated with the compounds of the present invention include inflammatory myelin elimination diseases of the nervous system (eg, multiple sclerosis), optic neuritis, optic neuromyelitis (Devic disease), epidemic and metastatic sclerosis (Shider's disease), acute Epidemic encephalomyelitis or demyelination peripheral neuropathy, such as Rendrid-Charlem-Barré-Strol syndrome in movement disorders, or tissue ulcers (eg epithelial and gastric ulcers), abnormal wound healing, periodontal disease, bone diseases (eg par Jet disease and osteoporosis). There are also endometriosis, septic shock, inflammatory bowel disease, Crohn's disease, and the like.
The compounds of the present invention can be applied to the eye including the treatment of ophthalmitis, corneal ulcers, pterygium, keratitis, keratoconus, open right glaucoma, retinopathy, and also used with refractive surgery (laser or incision) to minimize side effects. do.
The compounds are particularly useful for the treatment of diseases of, for example, inflammatory diseases, osteoarthritis, rheumatoid arthritis and tumors.
Useful effects are assessed according to pharmacological tests generally known in the art and as exemplified herein.
The properties recited above may advantageously be demonstrated in vitro and in vivo using enzyme preparations of mammals such as rats, guinea pigs, dogs, rabbits or isolated organs and tissues, mammals. The above compounds may be applied in vivo in the form of a solution, for example in an aqueous solution, in vitro, enterally or parenterally, preferably orally, for example in suspension or aqueous solution. In vitro dosages may range from about 10 ⁻⁵ moles to 10 ⁻¹⁰ moles, and in vivo dosages range from about 0.1 to 100 mg / kg depending on the route of administration.
Anti-inflammatory activity can be measured in standard inflammation and arthritis animal standard models known in the art, such as adjuvant arthritis models in rats and collagen II induced arthritis models in mice. Mediators of Inflam. 1, 273-279 (1992).
One assay for determining the inhibition of stromelysin activity is described in Harrison, RA, Teahan J. and Stein R., A semicontinuous, high performance chromatography based assay for stromelysin, Anal. Biochem. 180, 110-113 (1989)] is based on the hydrolysis of substance P using a modified method. In this assay, substance P is hydrolyzed by recombinant human stromelysin to produce the fragment P7-11, which is quantified by HPLC. In a typical assay, a 10 mM stock of the compound being tested is diluted to 50 mM in assay buffer and 8 mg recombinant human stromelysin (molecular weight. 45-47 kDa, 2 units; 1 unit contains substance P 7-11 for 30 minutes). 20 mmol), and incubate with 0.5 mM material P for 30 minutes at 37 ° C. in a final volume of 0.125 ml. The reaction is stopped by addition of 10 mM EDTA and the substance P7-11 is quantified by RP-8 HPLC. IC ₅₀ and Ki for inhibition of stromelysin activity are calculated from control response without inhibitor.
Tromelilysin activity can be measured using human aggrecan as a substrate. This assay confirms in vitro whether the compound can inhibit the activity of stromelysin against aggrecan (agglomerated large proteoglycans), a highly negative natural substrate. Proteoglycans exist as aggregates bound to hyaluronic acid salts in cartilage. Human proteoglycans aggregated with hyaluronic acid salts are used as enzyme substrates. This assay is run on 96-well microtiter plates to allow for rapid evaluation of compounds. The method consists of three main steps.
step:
1) Plates were coated with hyaluronic acid salt (human umbilical cord, 400 μg / ml) and blocked with BSA (5 mg / ml), proteoglycans (human articular cartilage D1-chondroitinase ABC digested, 2 mg / ml ) Is bound to the hyaluronic acid salt. The plate is washed between each step.
2) Buffer + Inhibitor (1 to 5,000 nM) + Recombinant Human Stromellisin (1 to 3 units / well) is added to the wells. The plate is sealed with tape and incubated overnight at 37 ° C. The plate is then washed.
3) Primary (3B3) antibody (mouse IgM, 1: 10,000) is used to detect residual fragments. The secondary antibody, peroxidase-bound anti-IgM, is bound to the primary antibody. OPD is added as a substrate of peroxidase and the reaction is stopped with sulfuric acid. IC ₅₀ for the inhibition of stromelysin is derived from the graph and Ki is calculated.
Collagenase-1 inhibitory activity is measured as follows. First, a 96 well bottom flat microtiter plate is coated with bovine Type 1 collagen (35 μg / well) at 30 ° C. for 2 days in wet atmosphere followed by dry atmospheric conditions. The plates are washed, air dried for 3-4 hours, wrapped in saran wrap and stored in the refrigerator. Human recombinant fibroblast collagenase and test compound (or buffer) are added to the wells (total volume = 0.1 ml) and the plates are incubated at 35 ° C. for 2 hours in humid conditions. The amount of collagenase used per well is the amount that induces about 80% of the maximum degradation of collagen. The incubation medium is removed from the wells and washed with buffer and then with water. Coomassie Blue stain is added to the wells for 25 minutes and the wells are washed again with water. Sodium dodecyl sulfate (20% in 50% aqueous dimethylformamide solution) is added to dissolve the stained residual collagen and measure the optical density at 570 nm wavelength. The decrease in optical density by collagenase (from the kinematic density of collagen without enzyme addition) is compared with the decrease in optical density by enzymes in the presence of the test compound and the inhibition rate of enzyme activity is calculated. IC ₅₀ in the inhibitor concentration range (4-5 concentrations, three for each sample) is determined and the Ki value is calculated.
Collagenase-3 inhibitory activity was determined as follows.
1 nM stock and 10 nM of inhibitor stock of substrate (MCA-Pro-Leu-Gly-Dpa-Ala-Arg-NH ₂ , J. Biol. Chem. 271, 1544-1550, 1996) were prepared in DMSO and assay buffer ( Dilute as needed with 10 mM CaCl ₂ , 20 nM Tris with 0.002% sodium azide, pH 7.5). Recombinant pro-collagenase-3 is activated with 1 mM APMA, dialyzed in assay buffer and stored in assay buffer. Recombinant enzyme solution (0.05 mL, 1.3 nM) is mixed with 0.05 mL of different concentrations of inhibitor solution for 10 minutes at room temperature. Add 0.025 mL of 8 μM substrate solution and measure fluorescence (λex = 325; λem = 405) continuously at room temperature. The rate of inhibition of collagenase-3 activity is determined from the effect of inhibitors of various concentrations on the change in fluorescence. IC ₅₀ is calculated from the graph.
In vivo effects of the compounds of the invention were measured in rabbits. Four rabbits are dosed orally with the compound for up to 4 hours, followed by intraarterial injection of both knees with 40 Units of recombinant human stromelysin dissolved in 20 mM Tris, 10 mM CaCl ₂ and 0.15 M NaCl, pH 7.5. After 2 hours the rabbits are sacrificed to recover the synovial lavage fluid and quantify the keratin sulfate (KS) and sulfated glycosaminoglycan (S-GAG) fragments secreted into the joints. Keratan sulfate is described by Thoner, EJ-MA, Lens, ME, Klinsworth, GK, caterson, B., Pachman, LM, Glickman, P., Katz, R., Huff, J., Keuttner, KE Quantitation of keratan sulfate in blood as a marker of cartilage catabolism, Arthr. Rheum. 28, 1367-1376 (1985)] by the inhibition ELISA using the method. Sulfated glycosaminoglycans were first digested with synovial lavage fluid with Strepmyces hyaluronidase, followed by Goldberg, RL and Kolibas, L. An improved method for determining proteoglycan synthesized by chondrocytes in culture. Connect. Tiss. Res. 24., 265-275 (1990)], to measure DMB dye binding. Compounds are dissolved in 1 ml PEG-400 for intravenous studies and the compound is administered within 5 ml of fortified corn starch per kilogram of body weight for oral dosing studies.
Protective effects against cartilage degradation in arthritis diseases are described, for example, in Arthritis and Rheumatism, Vol. 26, 875-886 (1983) can be determined in the surgical model of osteoarthritis.
The effect on ulcers, for example ocular ulcers, can be determined by measuring the reduction of corneal ulcers following an alkali burn of the rabbit cornea.
Macrophage metalloelastatase (MME) inhibitory activity can be determined by measuring inhibition of [ ³ H] -elastin degradation by truncated recombinant mouse macrophage metalloelastatase as follows.
Recombinant terminally truncated mouse macrophage metalloelasterase purified by Q-Sepharose column chromatography (FASEB Journal Vol. 8, A151, 1994) about 2 ng was replaced with 5 nM CaCl ₂ , 400 nM NaCl, [ ³ H] Incubate overnight at 37 ° C. with the desired concentration of test compound in the presence of elastin (60,000 cpm / tube) and 20 mM tris, pH 8.0. Samples are microcentrifuged at 12,000 rpm for 15 minutes. An aliquot of the supernatant was measured with a scintillation counter to quantify the degraded [ ³ H] -elastin. IC ₅₀ is determined from the range of test compound concentrations and the inhibition rate of the enzyme activity obtained.
The effectiveness of the compounds of the present invention for the treatment of emphysema can be measured in the animal models described in American Review of Respiratory disease 117, 1109 (1978).
The antitumor effect of the compounds of the present invention can be measured by comparing the growth of human tumors subcutaneously implanted in Balb / c nude treated mice according to methods known in the art as compared to placebo treated mice. Examples of tumors include estrogen dependent human breast cancer BT20 and MCF7, human bladder cancer T24, human colon cancer Colo 205, human lung adenocarcinoma A549 and human ovarian cancer NIH-OVCAR3.
See Garaldy et al., Cancer Res. 54, 4715 (1994), the effect on tumor angiogenesis in rats implanted with Walker 256 carcinoma pelleted to stimulate angiogenesis in peripheral blood vessels can be measured.
Gelatinase A and MT1-MMP inhibitory activity can be measured as follows; Matrix [MCA-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH ₂ , Knight, CG, Willenbrock, F., Murphy, G., A novel coumarin-labelled peptide for sensitive continous assays of the matrix metalloproteinases, FEBS lett., 296, 263-266 (1992)] The stock solutions are prepared in 100% DMSO to a concentration of 1.0 mM. Inhibitor stocks are prepared in 100% DMSO. The inhibitor is diluted from the solution in 100% DMSO to the assay sample and the control is replaced with the same amount of DMSO to bring the final DMSO concentration of the inhibitor and substrate diluent of all assays to 6%. Substrates and inhibitors are diluted with assay buffer containing 6.0% DMSO (150 mM NaCl, 10 mM CaCl ₂ , 50 mM Tris-Cl pH 7.5, 0.05% Brij-35) and then assayed in assay buffer. The substrate concentration used for the analysis is 10 μΜ. The test is carried out at 37 ° C. Fluorescence changes are monitored using excitation wavelength 320 nm and emission wavelength 340 nm. The reaction mixture is added in duplicate to the wells of a 96 well microfluer plate. The reaction mixture is preincubated with the inhibitor for 30 minutes and the reaction is initiated by the addition of MMP enzyme and the fluorescence intensity is measured for 10 minutes. The time point on the straight line in the curve is selected for the active measurement. Inhibition results are expressed as inhibitor concentrations that 50% inhibit (IC ₅₀ ) activity in a control (non-suppressive) response.
Inhibition of tumor metastasis can be measured in two lung metastasis models. In the B16-F10 melanoma model, metastasis is measured by counting the number of lung metastatic melanoma nodules produced by intravenous injection of B16-F10 melanoma cells into BDF1 treated mice according to methods known in the art. In the HT1080 model, metastasis is determined by measuring the fluorescence intensity of elevated green fluorescent protein (EGFP) in the lungs of Balb / c nude mice generated by tumors metastasized from fibrosarcoma HT1080 cells of humans expressing intravenously injected GFP. Is quantified. In both methods, inhibition is confirmed by comparing compound treated mice with placebo treated mice. After transfection with an EGFP expression vector (pEGFP-Cl) (CLONTECH Laboratories Inc., Palo Alto, Calif.) In the HT1080 model, EGFP expressing HT1080 cells are prepared by limiting dilution in the presence of geneticin. Cell suspensions (10 ⁶ cells / 0.1 mL PBS) are injected intravenously in Balb / c nude mice. Three weeks after oral administration of the test compound and vehicle, mice are sacrificed and homogenized by removal of the tumor metastasized lung of the mouse. After centrifugation, cells are washed three times with lysis reagent (150 mM NH ₄ Cl, 0.1 mM EDTA-4Na, 10 mM KHCO ₃ , pH 7.4) to lyse red blood cells and twice with PBS. After centrifugation, EGFP is extracted from cells with 10% Triton in PBS and placed in 96-well plates. Fluorescence intensity is measured using a fluorescent plate reader at excitation and emission wavelengths of 486 and 530 nm, respectively.
The effects of the compounds of the present invention on atherosclerosis diseases are described in atherosclerosis of cholesterol fed rabbits comprising activated matrix metalloproteinases as disclosed in Sukhova et al, Circulation 90, 1404 (1994). It can be measured using plaques. Inhibitory effects on matrix metalloproteinase enzyme activity in atherosclerotic plaques in rabbits are described by Galis et al, J. Clin. Invest. 94, 2493 (1994), which can be determined by zymography in situ and indicates plaque failure.
Effects on inhibition of vascular aneurysms, such as aneurysm formation, can be measured in experimental models, such as Apo-E transduced mice and / or LDL receptor knockout mice.
The effect on recurrent stenosis and vascular remodeling can be measured in an expanded carotid artery model.
The effects on myelin deficiency diseases of the nervous system, such as multiple sclerosis, are described in Gibbells et al, J. Clin. Invest. 94, 2177 (1994)] can be evaluated by measuring the reversal of experimental autoimmune encephalomyelitis in mice.
The compounds of the present invention are particularly useful in mammals, for example, of anti-inflammatory agents for the treatment of osteoarthritis, rheumatoid arthritis and of anti-tumor agents and atherosclerotic plaque destruction for the treatment and prevention of tumor growth, tumor metastasis, tumor infiltration or progression. It is useful as an anti- atherosclerotic agent for treatment and prevention.
The invention also provides for the inhibition of matrix degrading metalloproteinases, such as stromelysin, gelatinase, collagenase and macrophage metalloelastatase, inhibition of tissue matrix degradation and substrates disclosed herein in mammals. Of the compounds of the present invention and pharmaceutically acceptable salts thereof for the treatment of degrading metalloproteinase dependent diseases such as inflammation, rheumatoid arthritis, osteoarthritis, tumors (tumor growth, metastasis, progression or infiltration), lung diseases, etc. It relates to methods of use and pharmaceutical compositions thereof. Tumors (cancers) include breast cancer, lung cancer, bladder cancer, colon cancer, prostate cancer and ovarian cancer of mammals and skin cancers including melanoma and Kaposi's sarcoma.
The following examples are not intended to illustrate the invention and are not to be construed as limited to the invention. Temperature means degrees Celsius. Unless stated otherwise, all evaporations are carried out under reduced pressure, preferably at about 15 to 100 mmHg (= 20 to 133 mbar). The structures of the final products, intermediates and starting materials are identified by standard analytical methods such as microanalysis and spectral properties (eg MS, IR, NMR). Abbreviations used are those conventional in the art. Concentrations for [α] _D measurements are given in mg / ml.
Example 1 (Reference Example)
(2)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-dihydroisoindol-2-yl) pentanoic acid
A. D-glutamic acid g-methyl ester hydrochloride
34.0 μl (468 mmol) of thionyl chloride was added dropwise to 230 mL of methanol over 50 minutes at −10 ° C., and 50.0 g (340 mmol) of D-glutamic acid was added in several portions over 20 minutes to form a white slurry. Warmed over 30 min. The clear solution was slowly poured into 330 ml of diethyl ether to precipitate a white solid which was recovered by vacuum filtration, washed three times with 60 ml of diethyl ether and dried to give 47.4 g (71%) of D-glutamic acid g-methyl ester hydrochloride as a white solid. Obtained: NMR (DMSO-d ₆ ) 1.95-2.13 (m, 2H), 2.41-2.63 (m, 2H), 3.60 (s, 3H), 3.90 (m, 1H), 8.48 (br s, 3H ); IR 1736, 1720; ESI-MS 160 (M ^- 1).
B. D-N- (t-butyloxycarbonyl) glutamic acid g-methyl ester
A slurry of 47.4 g (240 mmol) of the title A compound in 800 mL of tetrahydrofuran (THF) was treated with 99.0 mL (710 mmol) of triethylamine over 20 minutes at 0 ° C. and di-t-butyl dicarbonate 54.5 g (250 mmol) was added dropwise to the cold mixture over 40 minutes. The reaction was slowly warmed to room temperature, after 16 h the mixture was concentrated and the residue was partitioned between 800 ml of ethyl acetate and 240 ml of cold 2N hydrochloric acid (HCl) aqueous solution. The organic solution was washed twice with 200 ml of cold water, dried over anhydrous magnesium sulfate (MgSO ₄ ) and concentrated to give 59.1 g (94%) of colorless oil DN- (t-butyloxycarbonyl) glutamic acid g-methyl ester. NMR (CDCl ₃ ) 1.43 (s, 9H), 1.95-2.05 (m, 1H), 2.16-2.28 (m, 1H), 2.42-2.53 (m, 2H), 3.670 (s, 3H), 4.30-4.38 (m, 1 H), 5.19 (br d, 1 H, J = 7.0).
C. D-N- (t-butyloxycarbonyl) glutamic acid a-t-butyl, g-methyl ester
25.0 g (93.1 mmol) of the title B compound, DN- (t-butyloxycarbonyl) glutamic acid g-methyl ester, in 200 ml of toluene at 80 ° C. was added with 25.0 g of N, N-dimethylformamide di-t-butyl acetal. 122.9 mmol) was added dropwise over 3 hours. After an additional 2 hours at 80 ° C., the solution was cooled and concentrated and the residue was partitioned between 400 ml of ethyl acetate and 200 ml of water. The organic solution was washed twice with 100 mL of 1 M aqueous sodium bicarbonate (NaHCO ₃ ) solution, followed by 100 mL of water, dried over anhydrous MgSO ₄ , and concentrated. Chromatography (eluent; 3 / 7-ethyl acetate / hexanes) on silica gel gave 10.1 g (34%) of DN- (t-butyloxycarbonyl) glutamic acid at-butyl, g-methyl ester as a colorless oil: NMR ( CDCl ₃ ) 1.42 (s, 9H), 1.45 (s, 9H), 1.86-1.97 (m, 1H), 2.10-2.21 (m, 1H), 2.30-2.50 (m, 2H), 3.66 (s, 3H) , 4.17-4.25 (m, 1H), 5.06 (br d, 1H, J = 7.6).
D. D-N- (t-butyloxycarbonyl) glutamic acid a-t-butyl ester
A 10.3 g (32.8 mmol) solution of the title C compound, DN- (t-butyloxycarbonyl) glutamic acid at-butyl, g-methyl ester, in 100 mL of methanol at room temperature was added at once with 35.0 mL (35.0 mmol) of a 1 M aqueous lithium hydroxide solution. Treated. After stirring for 1 hour, a white waxy solid was precipitated by adding 1 M HCl aqueous solution, and extracted with 200 ml of ethyl acetate. The organic solution was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to yield 9.72 g (99%) of DN- (t-butyloxycarbonyl) glutamic acid at-butyl ester as a white solid: NMR (CDCl ₃ ) 1.42 (s, 9H ), 1.45 (s, 9H), 1.85-1.95 (m, 1H), 2.10-2.24 (m, 1H), 2.36-2.52 (m, 2H), 4.19-4.27 (m, 1H), 5.17 (br d , 1H, J = 7.7); ESI-MS 302 (M ^- l).
E. (2R)-(t-butyloxycarbonylamino) -5-hydroxypentanoic acid t-butyl ester
A solution of 9.72 g (32.0 mmol) of DN- (t-butyloxycarbonyl) glutamic acid at-butyl ester and 3.70 mL (33.6 mmol) of N-methylmorpholine (NMM) in 50 mL of THF at −15 ° C. 3.37 ml (35.2 mmol) of ethyl chloroformate was added dropwise over 15 minutes. After 10 minutes N-methylmorpholine hydrochloride was filtered off and the filtrate was cooled to -40 ° C and a solution of 1.99 g (52.5 mmol) sodium borohydride in 20 ml of water was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature over 1 hour and partitioned between 200 ml of ethyl acetate and 200 ml of 1M NaHCO ₃ aqueous solution. The organic solution was washed with 200 ml of 1 M aqueous sodium hydroxide (NaOH) solution and 50 ml of saturated NaHCO ₃ aqueous solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated. Chromatography (eluent 3 / 7-ethyl acetate / hexanes) on silica gel gave 9.12 g (98%) of (2R)-(t-butyloxycarbonylamino) -5-hydroxypentanoic acid t-butyl ester as a colorless oil. ) Were obtained: NMR (CDCl ₃ ) 1.42 (s, 9H), 1.44 (s, 9H), 1.55-1.92 (m, 4H), 3.66 (t, 2H, J = 5.7), 4.19-4.27 (m, 1H), 5.15 (br d, 1H, J = 7.4); ESI-MS 290 (M ⁺ + l).
F. (2R)-(t-butyloxycarbonylamino) -5-iodopentanoic acid t-butyl ester
Title E compound in 300 mL of THF, 9.12 g (31.5 mmol) of (2R)-(t-butyloxycarbonylamino) -5-hydroxy-pentanoic acid t-butyl ester, 3.22 g (47.3 mmol) of imidazole and tri To a solution of 12.40 g (47.3 mmol) of phenylphosphine was added dropwise 9.60 g (37.8 mmol) of iodine over 5 minutes at room temperature. After 2 hours the mixture was concentrated by filtration. First, the residue was filtered through silica gel (eluent; ethyl acetate), and then chromatographed on silica gel (eluent; 10% ethyl acetate in hexane) to give (2R)-(t-butyloxycarbonylamino) -5 as a colorless oil. 9.05 g (72%) of iodopentanoic acid t-butyl ester was obtained: NMR (CDCl ₃ ) 1.42 (s, 9H), 1.46 (s, 9H), 1.65-1.95 (m, 4H), 3.14-3.28 ( m, 2H), 4.19-4.26 (m, 1H), 5.06 (br d, 1H, J = 7.4); IR 1712, 1500, 1155; ESI-MS 400 (M ⁺ + l).
G. (2R)-(t-butyloxycarbonylamino) -5- (1,3-dioxo-1,3-dihydroisoindol-2-yl) pentanoic acid t-butyl ester
0.522 g (13.05 mmol) of sodium hydride were added to a solution of 2.33 g (15.84 mmol) and 18-crown-6 and 18-crown-6 in 20 mL of N, N-dimethylformamide (DMF). After stirring for 20 minutes at room temperature, 4.61 g (11.55 mmol) of the title F compound, (2R)-(t-butyloxycarbonylamino) -5-iodopentanoic acid t-butyl ester, in 5 ml of DMF was added and the solution Was stirred at room temperature for 30 minutes and then at 60 ° C. for 8 hours. Under reduced pressure, the solvent was removed and the residue was partitioned between 300 ml of ethyl acetate and 225 ml of 0.05 M HCl aqueous solution. The organic phase was washed with 100 ml of water and 50 ml of brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give (2R)-(t-butyloxycarbonylamino) -5- (1,3-dioxo-1) as a brown solid. 4.83 g (100%) of, 3-dihydroisoindol-2-yl) pentanoic acid t-butyl ester were obtained: NMR (CDCl ₃ ) 1.43 (s, 9H), 1.45 (s, 9H), 1.60-1.88 ( m, 4H), 3.71 (t, 2H, J = 6.6), 4.18-4.26 (m, 1H), 5.06 (br d, 1H, J = 7.9), 7.70-7.73 (m, 2H), 7.83-7.86 ( m, 2H); IR 1712, 1500, 1155; ESI-MS 290 (M ⁺ + l).
H. (2R) -Amino-5- (1,3-dioxo-1,3-dihydroisoindol-2-yl) pentanoic acid t-butyl ester
A solution of 4.83 g (11.55 mmol) of the title G compound in 18 mL of dichloromethane was treated with 6.00 mL (78 mmol) of trifluoroacetic acid (TFA) at 0 ° C. After stirring for 1 h at this temperature, the solution was concentrated under reduced pressure without heating and the residue was partitioned between 100 ml of ethyl acetate and 50 ml of a 1M NaHCO ₃ aqueous solution. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. Chromatography (eluent; 1 / 1-ethyl acetate / hexanes) on silica gel to give (2R) -amino-5- (1,3-dioxo-1,3-dihydroisoindol-2-yl) phene as a colorless foam. 2.58 g (70%) of carbonic acid t-butyl ester were obtained: NMR (CDCl ₃ ) 1.46 (s, 9H), 1.80-2.06 (m, 4H), 3.73 (t, 2H, J = 6.2), 3.97 (t, 1 H, J = 6.3), 7.68-7.71 (m, 2H), 7.82-7.85 (m, 2H).
I. (2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-dihydroisoindol-2yl) pentanoic acid t-butyl ester
1. 4'-chlorobiphenyl-4-sulfonyl chloride
A solution of 7.02 g (37.2 mmol) of 4-chlorophenylbenzene in 70 mL of dichloromethane was treated with 4.55 g (39.1 mmol) of chlorosulfonic acid at room temperature. The reaction was stirred for an additional 2 hours, and the formed precipitate was collected by vacuum filtration, washed with dichloromethane and dried to give 9.6 g (96%) of 4'-chlorobiphenyl-4-sulfonic acid as a white solid.
A suspension of 4'-chlorobiphenyl-4-sulfonic acid in 100 ml of thionyl chloride was warmed to countercurrent for 6 hours and the resulting homogeneous solution was cooled to room temperature. The mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether and dried to give 9.8 g (95%) of a 4'-chlorobiphenyl-4-sulfonyl chloride as a gray solid.
2. (2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-dihydroisoindol-2-yl) pentanoic acid t-butyl ester
1.02 g (3.19 mmol) of the title H compound, (2R) -amino-5- (1,3-dioxo-1,3-dihydroisoindol-2-yl) pentanoic acid t-butyl ester, in 20 mL of dichloromethane And a solution of 1.34 mL (9.61 mmol) of triethylamine were treated at 0.9C with 0.92 g (3.19 mmol) of the title 1 compound, 4'-chlorobiphenyl-4-sulfonyl chloride. After stirring 30 hours at the same temperature and then 16 hours at room temperature, the solution was washed with 35 ml of 2M HCl aqueous solution, the organic solution was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Chromatography on silica gel (eluent; ethyl acetate) gave (2R)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-) as a waxy white solid. 0.96 g (53%) of dihydroisoindol-2-yl) pentanoic acid t-butyl ester was obtained: NMR (CDCl ₃ ) 1.21 (s, 9H), 1.60-1.68 (br m, 1H), 1.75-1.84 ( br m, 3H), 3.68-3.74 (m, 2H), 3.82-3.92 (m, 1H), 5.24 (d, 1H, J = 9.2), 7.44 (d, 2H, J = 8.6), 7.49 (d, 2H, J = 8.6), 7.65 (d, 2H, J = 8.5), 7.70-7.74 (m, 2H), 7.83-7.86 (m, 2H), 7.92 (d, 2H, J = 8.5); IR 1774, 1712, 1348, 1162; ESI-MS 569 (M ⁺ + l).
J. (2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-dihydroisoindol-2-yl) pentanoic acid
Title I compound in 10 mL (130 mmol) of TFA, (2R)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-dihydroisoindole- A solution of 0.96 g (1.69 mmol) of 2-yl) pentanoic acid t-butyl ester was stirred at room temperature for 2.5 hours. The solution was concentrated under reduced pressure to give a white solid, which was triturated with 20 ml of diethyl ether, collected by filtration and dried to give (2R)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (1, 837 mg (97%) of 3-dioxo-1,3-dihydroisoindol-2-yl) pentanoic acid were obtained: mp 179-181 ° C .; NMR (1: 100 CD ₃ 0D / CDCl ₃ ) 1.65-1.86 (m, 4H), 3.63 (t, 3H, J = 6.4), 3.93 (t, 3H, J = 6.4), 7.39 (d, 2H, J = 8.6), 7.47 (d, 2H, J = 8.6), 7.60 (d, 2H, J = 8.4), 7.65-7.68 (m, 2H), 7.76-7.79 (m, 2H), 7.86 (d, 2H, J = 8.4); IR 1772, 1708, 1340, 1153; ESI-MS 511 (M ⁻ -l), 513 (M ⁺ + l).
Example 2 (Reference Example)
(2R)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-dihydroisoyne
Dol-2-yl) pentanoic acid hydroxyamide
A. (2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-dihydroisoindol-2-yl) pentanoic acid 0-trityl Hydroxyamide
The compound of Example 1 in 10 ml of dichloromethane, (2R)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-dihydroisoindole-2 -Yl) pentanoic acid 304 mg (0.593 mmol) and 0.330 mL (3.00 mmol) of NMM were added 89 mg (0.654 mmol) and 1- (3-dimethylaminopropyl) -3-l-hydroxy-7-azabenzotriazole-3- 170 mg (0.886 mmol) of ethylcarbodiimide hydrochloride were treated at room temperature. After stirring for 30 minutes, 489 mg (1.776 mmol) of 0-tritylhydroxylamine were added and the reaction was stirred for 16 hours. The mixture was partitioned between 60 ml of dichloromethane and 40 ml of water. The organic solution was washed with 30 ml of 1 M NaHCO ₃ aqueous solution, dried over anhydrous Na ₂ SO ₄ and concentrated. Chromatography on silica gel (eluent: 4 / 6-ethyl acetate / hexanes) gave the waxy solid (2R)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo- 293 mg (64%) of 1,3-dihydroisoindol-2-yl) pentanoic acid O-tritylhydroxyamide were obtained: NMR (CDCl ₃ ) 0.62-0.76 (br m, 1H), 1.08-1.24 ( br m, 1H), 1.46-1.65 (br m, 1H), 1.72-1.87 (br m, 1H), 3.65-3.73 (m, 2H), 3.94 (t, 1H, J = 8.7), 5.31 (d, 1H, J = 9.2), 7.20-7.27 (m, 15H), 7.48 (d, 4H, J = 8.4), 7.59 (d, 2H, J = 8.5), 7.70 (d, 4H, J = 8.3), 7.91 (d, 2H, J = 8.3), 8.27 (s, 1 H); IR 1770, 1710, 1349, 1166; ESI-MS 770 (M ⁺ +1).
B. (2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-dihydroisoindol-2-yl) pentanoic acid hydroxyamide
Title A compound in 3 ml of dichloromethane, (2R)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-dihydroisoindol-2-yl A solution of 288 mg (0.374 mmol) of pentanic acid 0-tritylhydroxyamide was treated sequentially with 0.119 mL (0.745 mmol) of triethylsilane and 0.225 mL (2.92 mmol) of trifluoroacetic acid at 0 ° C. After 10 minutes, the solution was concentrated with nitrogen gas at 0 ° C. and the residue was triturated with 5 ml of diethyl ether. The product was recovered by vacuum filtration and dried to give (2R)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (1,3-dioxo-1,3-dihydroisoindole-) as a white solid. 162.3 mg (82%) of 2-yl) pentanoic acid hydroxyamide were obtained: mp 204-206 ° C. (decomposition); NMR (DMSO-d ₆ ) 1.24-1.33 (br m, 1H), 1.37-1.50 (br m, 3H), 3.39-3.47 (m, 2H), 3.52-3.62 (m, 1H), 7.53 (d, 2H , J = 8.3), 7.70 (d, 2H, J = 8.3), 7.80 (br s, 8H), 8.12 (d, 1H, J = 8.5), 8.82 (br s, 1H), 10.56 (s, 1H) ; IR 1772, 1341, 1159; ESI-MS 528 (M ⁺ +1)
Example 3
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid
The title compound was obtained as a white solid similar to that described in Example 1: mp 177-179 ° C .; NMR (CDCl ₃ ) 1.70-1.83 (m, 1H), 1.88-2.00 (m, 3H), 3.77 (q, 2H, J = 6.3), 4.05-4.13 (m, 1H), 5.36 (d, 1H, J = 8.6), 7.42 (d, 2H, J = 8.4), 7.52 (d, 2H, J = 8.4), 7.65 (d, 2H, J = 8.5), 7.80-7.92 (m, 3H), 7.91 (d, 2H, J = 8.2), 8.02 (d, 1H, J = 7.2); IR 1776, 1733, 1338, 1188; ESI-MS 547 (M ^_ -1), 549 (M ⁺ +1).
Example 4
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) Pentanic acid
The title compound was obtained as a white solid similar to that described in Example 1: mp 188-191 ° C .; NMR (DMSO-d ₆ ) 1.44-1.68 (m, 4H), 3.47 (s, 3H), 3.67-3.78 (m, 1H), 3.79-3.89 (m, 2H), 7.27 (t, 1H, J = 7.5 ), 7.40 (d, 1H, J = 8.6), 7.52 (d, 2H, J = 8.6), 7.71 (d, 2H, J = 8.5), 7.67-7.79 (m, 1H), 7.81 (s, 4H) , 8.01 (d, 1H, J = 6.8), 8.20 (d, 1H, J = 8.8), 12.62 (br s, 1H); IR 1734, 1702, 1627, 1337, 1164; ESI-MS 540 (M ^_ -1) 542 (M ⁺ +1).
1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline was prepared as follows.
A mixture of 4.95 g (30 mmol) methyl 2-methylaminobenzoate, 3.9 g (60 mmol) sodium isocyanate and 30 mL acetic acid was stirred at room temperature for 24 hours. The precipitated product was recovered by vacuum filtration, washed with water, diethyl ether and dried to give 3.25 g (62%) of white solid 1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin. Got.
Example 5
(2R)-(4-biphenylsulfonylamino) -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) pentanoic acid
The title compound was obtained as a white solid similar to that described in Example 1: mp 222-224 ° C .; IR 1737, 1700, 1652, 1328, 1160; ESI-MS 506 (M ^- 1).
Example 6
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) pentanoic acid
The title compound was obtained as a white solid similar to that described in Example 1: mp 68-71 ° C .; NMR (CDCl ₃ ) 1.34 (s, 6H), 1.55-1.81 (m, 4H), 2.84 (s, 3H), 3.50-3.56 (br m, 2H), 4.10 (q, 2H, J = 7.2), 5.52 (d, 1H, J = 8.8), 7.42 (d, 2H, J = 8.4), 7.52 (d, 2H, J = 8.4), 7.65 (d, 2H, J = 8.3), 7.89 (d, 2H, J = 8.3); IR 1772, 1341, 1159; ESI-MS 528 (M ⁺ +1).
3,4,4-trimethyl-2,5-dioxoimidazolidine is prepared according to the known methods described in US Pat. No. 1,337,269.
Example 7
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (4-methylbenzenesulfonylamino) pentanoic acid
The title compound was obtained as a white solid similar to that described in Example 1: mp 62 ° C .; IR 1725, 1596, 1327, 1160; ESI-MS 535 (M ^- 1).
Example 8
(2R)-[4- (pyridin-4-yloxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid
The title compound was obtained similarly as described in Example 1.
Example 9
(2R)-[4- (4-imidazol-1-ylphenoxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazole-2- (1) pentanoic acid
The title compound was obtained similarly as described in Example 1.
Example 10
(2R)-[4- (4-chlorophenyloxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid
The title compound was obtained similarly as described in Example 1.
Example 11
(2R)-(4-methylpiperazin-1-ylbenzenesulfonylamino) -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid
The title compound was obtained similarly as described in Example 1.
Example 12
(2R)-[4- (4-methoxybenzoylamino) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid
The title compound was obtained similarly as described in Example 1.
Example 13
(2R)-[4- (4-phenylpiperidin-1-yl) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazole-2- (1) pentanoic acid
The title compound was obtained similarly as described in Example 1.
Example 14
(2R)-(4-benzenesulfonylthiophen-2-sulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid
The title compound was obtained similarly as described in Example 1.
Example 15
(2R)-(5-benzenesulfonylthiophen-2-sulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid
The title compound was obtained similarly as described in Example 1.
Example 16
(2R)-[5- (5-trifluoromethylpyridine-2-sulfonyl) thiophene-2-sulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzo Isothiazol-2-yl) pentanoic acid
The title compound was obtained similarly as described in Example 1.
Example 17
(2R)-(4'-chlorobiphenyl-4-sulfonylamino) -3-{[(1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) methyl] Thio} propionic acid
The title compound was obtained similarly as described in Example 1.
Example 18
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid hydroxy amides
The title compound was obtained similarly as described in Example 2: mp 200-205 ° C. (decomposition); IR 1730, 1668, 1336, 1162; ESI-MS 564 (M ⁺ + l).
Example 19
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) Pentanic acid hydroxyamide
The title compound was obtained similar to that described in Example 2: mp 235 ° C .; IR 1702, 1658, 1336, 1160; ESI-MS 557 (M ⁺ + l).
Example 20
(2R)-(4-biphenylsulfonylamino) -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) pentanoic acid hydroxyamide
The title compound was obtained similarly as described in Example 2: mp 202-203 ° C .; IR 1704, 1660, 1336, 1160; ESI-MS 523 (M ⁺ + l).
Example 21
(2R)-[4- (pyridin-4-yloxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid Hydroxyamide
The title compound was obtained similarly as described in Example 2.
Example 22
(2R)-[4- (4-imidazol-1-ylphenoxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazole-2- (1) pentanoic acid hydroxyamide
The title compound was obtained similarly as described in Example 2.
Example 23
(2R)-[4- (4-chlorophenyloxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydro-benzoisothiazol-2-yl) pentanoic acid Hydroxyamide
The title compound was obtained similarly as described in Example 2.
Example 24
(2R)-[4- (methylpiperazin-1-ylbenzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid Hydroxyamide
The title compound was obtained similarly as described in Example 2.
Example 25
(2R)-[4- (4-methoxybenzoylamino) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid Hydroxyamide
The title compound was obtained similarly as described in Example 2.
Example 26
(2R)-[4- (4-phenylpiperidin-1-yl) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazole-2- (1) pentanoic acid hydroxyamide
The title compound was obtained similarly as described in Example 2.
Example 27
(2R)-(4-benzenesulfonylthiophen-2-sulfonyl-amino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid hydroxide Oxyamide
The title compound was obtained similarly as described in Example 2.
Example 28
(2R)-(5-benzenesulfonylthiophen-2-sulfonylamino) -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid hydroxy amides
The title compound was obtained similarly as described in Example 2.
Example 29
(2R)-[5- (5-trifluoromethylpyridine-2-sulfonyl) thiophen-2-sulfonylamino] -5-1,1,3-trioxo-2,3-dihydrobenzoiso Thiazol-2-yl) pentanoic acid hydroxyamide
The title compound was obtained similarly as described in Example 2.
Example 30
(2R)-(4'-chlorobiphenyl-4-sulfonylamino) -3-{[(1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) methyl] Thio} propionic acid hydroxyamide
The title compound was obtained similarly as described in Example 2.
Example 31
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -6- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline-3- 1) hexanoic acid
A. 3- (4-Bromobutyl) -1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin and 3- (4-chlorobutyl) -1,2,3 , 4-tetrahydro-1-methyl-2,4-dioxoquinazoline
A stirred solution of 1.60 g (9.08 mmol) of 1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin in 25 mL of DMF was added to 0.40 g of sodium hydride (60% in mineral oil, 10.0). mmol) in one batch. The mixture was stirred for 1 hour at room temperature and 30 minutes at 50 ° C, then 4.19 mL (36.4 mmol) of 1-bromo-4-chlorobutane was added at 50 ° C in one portion, and the resulting solution was stirred at 80 ° C for 16 hours. It was. The reaction mixture was poured into 100 mL of water to precipitate a white solid which was extracted three times with 50 mL of ethyl acetate. The combined organic phases were washed three times with 25 ml brine, dried over anhydrous MgSO ₄ and concentrated to give 3- (4-bromobutyl) -1,2,3,4-tetrahydro-1-methyl-2, as a waxy white solid. 2.35 g (81%) of a 1: 1 mixture of 4-dioxoquinazoline and 3- (4-chlorobutyl) -1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline ) Obtained: mp 128 ° C .; NMR (CDCl ₃ ) 1.80-1.97 (m, 4H), 3.44 (t, 1H, J = 6.4), 3.56-3.59 (m, 1H), 3.60 (s, 3H), 4.12 (t, 2H, J = 6.9 ), 7.18-7.28 (m, 2H), 7.67 (td, 1H, J = 1.6, 7.9), 8.21 (dd, 1H, J = 1.5, 7.9); IR 1699, 1662; ESI-MS 267 (M ⁺ + l), 269 (M ⁺ +3), 311 (M ⁺ + I), 313 (M ⁺ +3).
B. 3- (4-iodobutyl) -1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline
Title A compound, 3- (4-bromobutyl) -1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline and 3- (4-chloro in 30 ml of methyl ethyl ketone Butyl) -1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline solution of 2.35 g (1: 1 mixture, 8.13 mmol) was dissolved in 2.64 g (17.62 mmol) of sodium iodide at room temperature. Treated. The reaction was heated to reflux for 16 h and then cooled to evaporate the solvent under reduced pressure. The residue was partitioned between 200 ml of ethyl acetate and 5 ml of water. The organic solution was washed with 10 ml of 1% aqueous sodium sulfite solution and 10 ml of brine, dried over anhydrous MgSO ₄ , and concentrated to give 3- (4-iodobutyl) -1,2,3,4-tetrahydro-1 as a white solid. 3.10 g (100%) of -methyl-2,4-dioxoquinazoline were obtained: mp 105-107 ° C .; NMR (CDCl ₃ ) 1.75-1.95 (m, 4H), 3.22 (t, 2H, J = 6.8), 3.59 (s, 3H), 4.11 (t, 2H, J = 7.1), 7.17-7.28 (m, 2H ), 7.67 (dt, 1 H, J = 1.6, 7.9), 8.21 (dd, 1H, J = 1.5, 7.9); IR 1702, 1658; ESI-MS 359 (M ⁺ +1).
C. 2- (benzhydrylideneamino) -6- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) hexanoic acid t-butyl ester
A solution of 1.30 g (4.40 mmol) of N- (diphenylmethylene) glycine t-butyl ester in 10 mL of DMF was treated with 0.250 g of sodium hydride (60% in mineral oil, 6.25 mmol) at 25 ° C. to give a red orange solution. . After 1 hour the temperature was raised to 60 ° C. and the title B compound, 3- (4-iodobutyl) -1,2,3,4-tetrahydro-1-methyl-2,4-dioxo, in 10 mL DMF A solution of 1.58 g (4.41 mmol) of quinazoline was added dropwise over 10 minutes. After stirring for 5 h at 60 ° C. for 58 h at 25 ° C., the solvent was evaporated under reduced pressure and the residue was partitioned between 75 ml of ethyl acetate and 25 ml of water. The organic solution was washed three times with 25 ml brine, dried over anhydrous MgSO ₄ and concentrated to give 2- (benzhydrylideneamino) -6- (1,2,3,4-tetrahydro-1-methyl-2 in yellow oil. 2.15 g of, 4-dioxoquinazolin-3-yl) hexanoic acid t-butyl ester were obtained.
D. 2-Amino-6- (1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) hexanoic acid t-butyl ester
Title C compound, 2- (benzhydrylideneamino) -6- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) in 80 ml of acetonitrile A 2.15 g solution of hexanoic acid t-butyl ester was treated with 8 mL of water and 0.800 g (4.21 mmol) of p-toluenesulfonic acid hydrate, and the clear solution was stirred at 25 ° C. for 16 h. The solvent was evaporated under reduced pressure and the residue was partitioned between 150 ml of diethyl ether and 100 ml of 0.1 N HCl aqueous solution. The aqueous phase was added dropwise to 15 ml (15.0 mmol) of 0.1 N aqueous NaOH solution to precipitate an oily solid, which was extracted twice with 60 ml of methylene chloride. The combined organic extracts were dried over anhydrous MgSO ₄ and concentrated. Chromatography on silica gel (eluent: ethyl acetate) to give 2-amino-6- (1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) hexanoic acid as a colorless oil. 448 mg (30%) of t-butyl ester were obtained: NMR (CDCl ₃ ) 1.46 (s, 9H), 1.51-1.79 (m, 6H), 3.32 (dd, 1H, J = 7.0, 5.4), 3.61 (s , 3H), 4.1 1 (t, 2H, J = 7.4), 7.20 (d, 1H, J = 8.3), 7.25-7.29 (m, 1H), 7.69 (td, 1H, J = 8.6, 1.5), 8.23 (dd, 1H, J = 7.9, 1.5); IR 1702, 1656; MS 362 (M ⁺ + I).
E. (2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -6- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline- 3-yl) hexanoic acid t-butyl ester
Title D compound in 2 mL THF, 2-amino-6- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) hexanoic acid t-butyl ester 129 The mg (0.357 mmol) solution was treated with 50.8 mg (0.502 mmol) triethylamine and 110 mg (0.383 mmol) 4'-chlorobiphenyl-4-sulfonyl chloride at 0 ° C. The clear solution was warmed to room temperature over 2 hours and partitioned between 25 ml of dichloromethane and 10 ml of brine. The organic phase was dried over anhydrous MgSO ₄ and concentrated. Chromatography on silica gel (eluent: 30% to 50% gradient of ethyl acetate in hexane) gave (2R, S)-(4'-chlorobiphenyl-4-sulfonylamino) -6- (1,2, 190 mg (87%) of 3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) hexanoic acid t-butyl ester were obtained: NMR (CDCl ₃ ) 1.24 (s, 9H) , 1.47 (q, 2H, J = 7.6), 1.66-1.79 (m, 4H), 3.61 (s, 3H), 3.79-3.90 (m, 1H), 4.07 (t, 2H, J = 7.4), 5.28 ( d, 1H, J = 9.2), 7.21 (d, 1H, J = 8.2), 7.25-7.29 (m, 1H), 7.44 (d, 2H, J = 8.4), 7.50 (d, 2H, J = 8.4) , 7.65 (d, 2H, J = 8.4), 7.69 (t, 1H, J = 7.2), 7.91 (d, 2H, J = 8.4), 8.23 (dd, 1H, J = 7.8, 1.3); IR 1727, 1702, 1658, 1349, 1166; MS 612
(M ⁺ + l).
F. (2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -6- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline- 3-yl) hexanoic acid
The title compound was obtained similarly as described in Example 1: mp 208-21O <0>C; NMR (1: 100 CD30D / CDCl ₃ ) 1.36-1.47 (m, 2H), 1.58-1.69 (m, 2H), 1.69-1.86 (m, 2H), 3.57 (s, 3H), 3.90 (dd, 1H , J = 6.8, 5.1), 4.00 (td, 2H, J = 7.0, 2.0). 7.20 (d, 1H, J = 8.3), 7.23-7.28 (m, 1H), 7.40 (d, 2H, J = 8.5), 7.50 (d, 2H, J = 8.5), 7.68 (td, 1H, J = 7.0, 0.7), 7.89 (d, 2H, J = 8.3), 8.17 (dd, 1H, J = 7.7, 1.1); IR 1727, 1700, 1635, 1334, 1157; ESI-MS 554 (M ^- 1).
Example 32
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -6- (4,4-dimethyl-2,5-dioxoimidazolidin-1-yl) hexanoic acid
The title compound was obtained as a white solid similar to that described in Example 31: mp 78-80 ° C .; IR 1714, 1598, 1166; ESI-MS 509 (M ⁺ + l).
Example 33
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -6- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-quinazolin-3 -Yl) hexanoic acid hydroxyamide
The title compound was obtained as a white solid similar to that described in Examples 2 and 31.
Example 34
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -6- (4,4-dimethyl-2,5-dioxoimidazolidin-1-yl) hexanoic acid hydroxyamide
The title compound was obtained as a white solid similar to that described in Examples 2 and 31.
Example 35
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -4- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) -butyric acid
A. D-aspartic acid b-methyl ester hydrochloride
A suspension of 10.0 g (75.1 mmol) of D-aspartic acid in 50 mL of methanol was treated with 8.94 g (75.1 mmol) of thionyl chloride at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 2 hours. The resulting clear solution was diluted with 200 mL of diethyl ether with rapid stirring. A white precipitate formed which was collected by vacuum filtration, washed with diethyl ether and dried to give 10.7 g (78%) of D-aspartic acid b-methyl ester hydrochloride.
B. D-N- (4'-chlorobiphenyl-4-sulfonyl) aspartic acid b-methyl ester
A solution of 10.7 g (58.33 mmol) of the title A compound, D-aspartic acid b-methyl ester hydrochloride, in 400 mL of 1/1 dioxane / water containing 23.61 g (233.3 mmol) of triethylamine was obtained at room temperature. Treated with 17.0 g (58.33 mmol) of chlorobiphenyl-4-sulfonyl chloride. After 16 hours the mixture was concentrated to half the original volume and acidified to pH = 1 to 2 by addition of aqueous 1N HCl solution. The product was dissolved in EtOAc (2 x 200 mL), the combined organic extracts were washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated to give DN- (4'-chlorobiphenyl-4-sulfonyl) aspartic acid b 20.24 g (87%) of methyl ester were obtained.
C. D-N- (4'-chlorobiphenyl-4-sulfonyl) aspartic acid a-t-butyl, b-methyl ester
The title B compound DN- (4'-chlorobiphenyl-4-sulfonyl) aspartic acid b-methyl ester suspension in N, N-dimethylformamide di-t-butyl acetal in 60 ml of toluene over 40 minutes at 75 ° C Dropped in The resulting clear solution was heated at 80 ° C. for an additional 2 hours. The reaction solution was cooled to room temperature and the reaction was stopped with water. The organic solution was washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. Chromatography (eluent: 2 / 5-EtOAc / hexanes) on silica gel to give 11.41 g (49%) of aspartic acid at-butyl, b-methyl ester of DN- (4'-chlorobiphenyl-4-sulfonyl) aspartic acid as a yellow solid. )
D-N-t-butyloxycarbonyl-N- (4'-chlorobiphenyl-4-sulfonyl) aspartic acid a-t-butyl, b-methyl ester
30 ml of di-t-butyl dicarbonate solution in 30 ml of tetrahydrofuran was added over 30 minutes at 0 ° C. via the addition funnel to the title C compound, DN- (4′-chlorobiphenyl-4-sulfonyl) aspartic acid. To a mixture of at-butyl, b-methyl ester 11.41 g (25.14 mmol), 7.63 g (75.4 mmol) triethylamine and 3.07 g (25.14 mmol) 4-dimethylaminopyridine were added dropwise. The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature for 3 hours. The solvent was evaporated and the residue was partitioned between 150 mL EtOAcc and 150 mL 0.5N HCl aqueous solution. The organic solution was washed with saturated aqueous NaHCO ₃ and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give DNt-butyloxycarbonyl-N- (4'-chlorobiphenyl-4-sulfonyl) aspartic acid at yellow foam. 11.47 g (83%) of -butyl and b-methyl esters were obtained.
E. (2R)-[t-butoxycarbonyl (4'-chlorobiphenyl-4-sulfonyl) amino] -4-hydroxybutyric acid t-butyl ester
A solution of lithium borohydride 2 M in 9 mL (18.07 mmol) of THF was dissolved at 0 ° C. in the title D compound, DNt-butyloxycarbonyl-N- (4′-chlorobiphenyl-4-sulfonyl) -aspart in 40 mL THF. To a solution of 4.0 g (7.23 mmol) of acid at-butyl, b-methyl ester. The resulting yellow solution was stirred at 0 ° C. for 2 hours and treated with 0.63 g (18.07 mmol) of methanol. The reaction mixture was further stirred at 0 ° C. for 1 hour and gradually warmed to room temperature. After 24 hours, the reaction solution was cooled back to 0 ° C. and the reaction was stopped with saturated aqueous sodium carbonate (Na ₂ CO ₃ ) solution. The mixture was partitioned between EtOAc and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The product was chromatographed on silica gel (eluent: 1/4-EtOAc / hexanes) to give 2.0 g (53%) of the product.
F. (2R)-[t-butyloxycarbonyl (4'-chlorobiphenyl-4-sulfonyl) amino] -4-iodobutyric acid t-butyl ester
Title E compound, 50 g of dichloromethane, (2R)-[t-butoxycarbonyl (4'-chlorobiphenyl-4-sulfonyl) amino] -4-hydroxybutyric acid t-butyl ester 2.0 g (9.58 mmol) The solution was treated sequentially with 2.88 g (14.37 mmol) of iodine, 3.72 g (14.37 mmol) of triphenylphosphine and 0.97 g (14.37 mmol) of imidazole at room temperature. After 2 hours 20 ml of methanol were added and the reaction mixture was stirred for 30 minutes at room temperature. The solvent was evaporated and the product was purified by chromatography on silica gel (eluent: 1 / 19-EtOAc / hexanes) to give (2R)-[t-butyloxycarbonyl (4'-chlorobiphenyl-4-sulfonyl) amino ] 2. 46 g (78%) of iodobutyric acid t-butyl ester were obtained.
G. (2R)-[t-butyloxycarbonyl (4'-chlorobiphenyl-4-sulfonyl) amino] -4- (3,4,4-trimethyl-2,5-dioxoimidazolidine -1-yl) butyric acid t-butyl ester
Title F compound, 10 g of DMF, (2R)-[t-butyloxycarbonyl (4'-chlorobiphenyl-4-sulfonyl) amino] -4-iodobutyric acid t-butyl ester 0.6 g (0.94 mmol) To the solution was added 3,4,4-trimethyl-2,5-dioxoimidazolidine and 0.65 g (4.72 mmol) of potassium carbonate and 2 mg of 18-crown-6. The reaction mixture was stirred at rt for 3 h and partitioned between water and EtOAc. The organic solvent was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. Chromatography on silica gel (eluent: 1/19 EtOAc / hexanes) gave 0.25 g (41%) of the title compound as a white foam.
H. (2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -4- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) butyric acid
The title compound was obtained as a white solid similar to that described in Example 1: mp 430 ° C .; IR 1762, 1737, 1700, 1157; ^{ESI-MS (M + +1)} , 493 (M _ -1).
Example 36
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -4-[(1,3-dioxo-1,5,10, (10aS) -tetrahydroimidazo- [1,5- b] isoquinolin-2-yl)] butyric acid
The title compound was obtained as a white solid similar to that described in Example 35: mp 70 ° C .; IR 1764, 1706, 1162; ESI-MS 553 (M ^_ -1).
1,3-dioxo-1,5,10, (10aS) -tetrahydroimidazo- [1,5-b] isoquinoline is described in J. Chem. Pharm. Sci., 67, 718 (1978).
Example 37
(2R)-(4'-chlorobiphenyl-4-sulfonylamino) -4- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) Butyric acid
The title compound was obtained as a white solid similar to that described in Example 35: IR 1735, 1708, 1648, 1155; ^{ESI-MS (M _ -1)} .
Example 38
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -4- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) butyric acid hydroxyamide
The title compound was obtained as a white solid similar to that described in Examples 2 and 35: mp 117-120 ° C .; ^{ESI-MS (M _ -1)} .
Example 39
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) propanoic acid
A. Benzhydrylideneaminoacetic acid t-butyl ester
A solution of 10 g (59.65 mmol) glycine t-butyl ester hydrochloride in 250 mL dichloromethane was treated with 10.8 g (59.6 mmol) benzophenoneimine at room temperature. After 16 hours, the mixture was washed with brine, dried over anhydrous MgSO ₄ and concentrated to give 16.1 g (91%) of benzhydrylideneaminoacetic acid t-butyl ester as a white solid.
B. (2R, S) -Amino-3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) propanoic acid t-butyl ester
A solution of the title A compound, benzhydrylideneaminoacetic acid t-butyl ester, 1.36 g (4.59 mmol) in 15 mL of DMF was added to a sodium hydride suspension in 5 mL of DMF at room temperature. After 1 hour, 1.08 g (4.59 mmol) of 3-bromomethyl-1,5,5-trimethylimidazolidine-2,4-dione (prepared according to the known method disclosed in US Pat. No. 1,337,269) at a time Was added and the reaction was heated at 60 ° C. for 16 h. The mixture was partitioned between EtOAc and water, and the organic solution was washed with water and brine, dried over anhydrous MgSO ₄ and concentrated. The residue was dissolved in 20 ml of acetonitrile and 2 ml of water, treated with 1.39 g (7.33 mmol) of p-toluenesulfonic acid monohydrate, and the mixture was stirred for 16 hours at room temperature. The solvent was evaporated and the residue was partitioned between diethyl ether and 1N HCl aqueous solution. The combined organic solutions were extracted with 1N HCl aqueous solution and the aqueous extracts were combined and basified to pH = 12 by addition of solid potassium hydroxide (KOH). The product was treated with ethyl acetate, dried over anhydrous MgSO ₄ and concentrated to give (2R, S) -amino-3- (3,4,4-trimethyl-2,5-dioxoimidazolidine-1- in colorless oil. I) 810 mg (62%) of propanoic acid t-butyl ester were obtained.
C. (2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) propane Acid t-butyl ester
A solution of 810 mg (2.84 mmol) of the title B compound and 430 mg (4.26 mmol) of triethylamine in 15 mL of dichloromethane was treated with 815 mg (2.84 mmol) of 4'-chlorobiphenyl-4-sulfonyl chloride at room temperature. After 16 hours, the reaction mixture was washed with water and the organic solution was dried over anhydrous MgSO ₄ and concentrated. Chromatography on silica gel (eluent; 1% MeOH in dichloromethane) to (2R, S)-(4'-chlorobiphenyl-4-sulfonylamino) -3- (3,4,4-trimethyl-2,5 960 mg (63%) of dioxoimidazolidin-1-yl) propanoic acid t-butyl ester were obtained.
D. (2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) propane mountain
Title D compound in 20 mL EtOAc, (2R, S)-(4'-chlorobiphenyl-4-sulfonylamino) -3- (3,4,4-trimethyl-2,5-dioxoimidazoli A solution of 960 mg (1.79 mmol) of din-1-yl) propanoic acid t-butyl ester was saturated with hydrogen chloride gas for 15 minutes. The reaction solution was sealed and stirred at room temperature for 16 hours. The solvent was evaporated and the residue was triturated with petroleum ether to give a white solid of (2R, S)-(4'-chlorobiphenyl-4-sulfonylamino) -3- (3,4,4-trimethyl-2,5- 680 mg (79%) of dioximidazolidin-1-yl) propanoic acid were obtained: mp 198-201 ° C .; ESI-MS 478 (M ^_ -1).
Example 40
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -3- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3- I) propionic acid
The title compound was obtained as a white solid similar to that described in Example 39. mp 218 ° C. (decomposition); ESI-MS 512 (M ^_ -1).
3-Bromomethyl-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline was prepared as described in US Pat. No. 3,781,288.
Example 41
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) propanoic acid hydroxide Oxyamide
The title compound was obtained as a white solid similar to that described in Examples 2 and 39: mp 130 ° C. (decomposition); ^{ESI-MS 493 (M _ -1} ).
Example 42
(2R)-(4-phenyloxybenzenesulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid
A. (2R)-(t-butyloxycarbonylamino) -4-morpholin-4-yl-4-oxobutyric acid benzyl ester
A solution of 2.53 g (7.82 mmol) of DNt-butyloxycarbonylaspartic acid benzyl ester in 30 mL of DMF was added to 4.15 g (9.38 mmol) of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, Treatment was performed sequentially with 1.28 g (9.38 mmol) of 1-hydroxy-7-azabenzotriazole, 2.5 g (19.6 mmol) of diisopropylethylamine and 0.82 g (9.38 mmol) of morpholine. The mixture was stirred at rt for 16 h and partitioned between EtOAc and water. The organic solution was washed with water and brine, dried over anhydrous MgSO ₄ and concentrated. 2.91 g (2R)-(t-butyloxycarbonylamino) -4-morpholin-4-yl-4-oxobutyric acid benzyl ester of pale oil by chromatography on silica gel (eluent: 5% MeOH in dichloromethane). 95%).
B. (2R) -Amino-4-morpholin-4-yl-4-oxobutyric acid benzyl ester hydrochloride
2.91 g (7.42 mmol) solution of the title A compound, (2R)-(t-butyloxycarbonylamino) -4-morpholin-4-yl-4-oxobutyric acid benzyl ester, in 50 mL of ethyl acetate was added with hydrogen chloride gas. Saturate for minutes. The reaction solution was sealed and stirred at room temperature for 3 hours. The solvent was evaporated to afford 2.27 g (93%) of (2R) -amino-4-morpholin-4-yl-4-oxobutyric acid benzyl ester hydrochloride as a white solid.
C. (2R)-(4-phenyloxybenzenesulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid benzyl ester
A solution of 420 mg (1.28 mmol) of the title B compound, (2R) -amino-4-morpholin-4-yl-4-oxobutyric acid benzyl ester hydrochloride, in 5 ml of dichloromethane was diluted with 345 mg (2.82 mmol) of triethylamine. Treatment was followed by 345 mg (1.28 mmol) of 4-phenoxybenzenesulfonyl chloride in 2 ml of dichloromethane. The reaction was stirred for 16 h and partitioned between dichloromethane and water. The organic solution was washed with brine, dried over anhydrous MgSO ₄ and concentrated. 430 mg of (2R)-(4-phenyloxybenzenesulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid benzyl ester of white foam by chromatography on silica gel (eluent; 3% MeOH in dichloromethane) (64%) was obtained.
D. (2R)-(4-phenyloxybenzenesulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid
Title C compound in 10 ml EtOAc, 430 mg (0.82 mmol) of (2R)-(4-phenyloxybenzenesulfonylamino) -4-morpholin-4-yl-oxobutyric acid benzyl ester and 100 mg 10% Pd on carbon The mixture of was stirred under hydrogen (H ₂ ) atmosphere (1 atm) for 2 hours. The catalyst was removed by vacuum filtration through celite and the filtrate was concentrated to give 330 mg (2R)-(4-phenyloxybenzenesulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid as a white solid ( 100%) was obtained: mp 147-149 ° C; ^{ESI-MS (M _ -1)} .
Example 43
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid
The title compound was obtained as a white solid similar to that described in Example 42: mp 144-146 ° C .; ESI-MS 452 (M ^_ -1).
Example 44
(2R)-(4-phenyloxybenzenesulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid hydroxyamide
The title compound was obtained as a white solid similar to that described in Examples 2 and 42: mp 161-163 ° C .; ESI-MS 448 (M ^- l).
Example 45
(2R)-(4'-chlorobiphenyl-4-sulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid hydroxyamide
The title compound was obtained as a white solid similar to that described in Examples 2 and 42: mp 139-141 ° C .; ESI-MS 466 (M ^- 1).
Example 46
(2R)-(4-phenoxy-benzenesulfonylamino) -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid
A. (2R) -t-butoxycarbonylamino-5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2yl) pentanoic acid t-butyl ester
0.311 g (7.78 mmol) of sodium hydride was added to a solution of 1.73 g (9.44 mmol) of saccharin and 0.025 g of 18-crown-6 in 10 mL of DMF. After stirring for 30 minutes at room temperature, 2.78 g (6.96 mmol) of (2R)-(t-butyloxycarbonylamino) -5-iodopentanoic acid t-butyl ester in 10 ml of DMF was added and the solution was stirred at room temperature. Stirred for 30 minutes at 60 ° C. for 6 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 0.05M HCl aqueous solution. The organic phase was washed with water and brine, dried over anhydrous MgSO ₄ and concentrated. The crude material was purified by silica gel chromatography (hexane / ethyl acetate = 4/1 to 3/1) to give 1.98 g (63%) of the title compound: NMR (40OMHz, CDCl ₃ ) 1.44 (s, 9H), 1.46 ( s, 9H), 1.68-1.96 (m, 4H), 3.81 (t, 2H, J = 7.0 Hz), 4.19-4.29 (m, 1H), 5.09 (br d, 1H, J = 7.9 Hz), 7.82- 7.93 (m, 3 H), 8.06 (d, 1 H, J = 7.3 Hz).
B. (2R) -Amino-5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid t-butyl ester
A solution of 0.677 g (1.45 mmol) of the title A compound in 10 mL of methylene chloride was treated with 0.89 mL (10.0 mmol) of trifluoroacetic acid (TFA) at 0 ° C. The reaction was completed by stirring at 0 ° C. for 30 minutes and then at room temperature for 2 hours and adding 0.4 ml of TFA to the solution. The mixture was then stirred at rt for 1.5 h. The solvent was removed under reduced pressure without heating and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous MgSO ₄ and concentrated to give 0.494 g (yield 94%) of the title compound: NMR (40OMHz, CDCl ₃ ) 1.47 (s, 9H), 1.79-1.99 (m, 4H), 3.62 (t, 1H , J = 5.7 Hz), 3.82 (t, 2H, J = 6.6 Hz), 7.94-8.01 (m, 2H), 8.06-8.10 (m, 2H).
C. 4-phenoxybenzenesulfonyl chloride
A solution of 4.3 ml (64.6 mmol) of chlorosulfonic acid in 20 ml of dichloromethane was added dropwise to a solution of 10 g (58.8 mmol) of diphenyl ether in 20 ml of dichloromethane at 0 ° C. under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. To the mixture was added 6.5 mL (76.4 mmol) of oxalyl chloride followed by 1.5 mL of DMF at room temperature. After heating at 40 ° C. for 1 hour, the reaction mixture was stirred at room temperature for 15 hours. The mixture was poured into ice-water and extracted with ether. The organic layer was dried over MgSO ₄ and evaporated in vacuo to yield the title compound quantitatively: NMR (CDCl ₃ ) 7.10 (t, 4H, J = 8.6 Hz), 7.22-7.30 (m, 1H), 7.46 (t, 2H, J = 8.6 Hz), 7.98 (d, 2H, J = 9.1 Hz).
D. (2R)-(4-Phenoxy-benzenesulfonylamino) -5- (l, 1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) -pentanoic acid t- Butyl ester
To a solution of 0.500 g (1.41 mmol) of the title B compound in 15 mL of dioxane and 7.5 mL of water was added 0.30 mL (2.12 mmol) of triethylamine at 0 ° C., followed by 0.492 g (1.83 4-phenoxybenzenesulfonylchloride) in succession. mmol) was added and the reaction mixture was allowed to warm to room temperature. After stirring for 2 hours at room temperature, water and 1 M HCl were added to the solution and the organics were extracted with ethyl acetate. The organic phase was separated and washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate 2/1) to give 0.571 g (69% yield) of the title compound: NMR (40OMHz, CDCl ₃ ) 1.29 (s, 9H), 1.68-2.05 (m, 4H) ), 3.75-3.89 (m, 3H), 5.21 (d, 1H, J = 9.0 Hz), 7.00 (d, 2H, J = 8.6 Hz), 7.03 (d, 2H, J = 7.6 Hz), 7.20- 7.26 (m, 1H), 7.40 (t, 2H, J = 7.9 Hz), 7.79 (d, 2H, J = 9.1 Hz), 7.81-7.94 (m, 3H), 8.06 (d, 1H, J = 7.1 Hz ).
E. (2R)-(4-Phenoxy-benzenesulfonylamino) -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid
0.301 g (0.513 mmol) of the title D compound were treated with 3.49 mL (39.5 mmol) of TFA at room temperature and the mixture was stirred at this temperature for 1 hour. The solution was concentrated under reduced pressure, then the residue was dissolved in ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous MgSO ₄ and concentrated. The product was lyophilized with dioxane to give 0.300 g (quantitative yield) of the title compound: NMR (40OMHz, CDCl ₃ ) 1.67-1.91 (m, 4H), 3.70-3.76 (m, 2H), 3.88-3.91 (m, 1H), 7.00 (d, 2H, J = 9.1 Hz), 7.05 (d, 2H, J = 7.6 Hz), 7.21 (t, 1H, J = 7.5 Hz), 7.40 (t, 2H, J = 8.0 Hz) 7.81 (d, 2H, J = 8.8 Hz), 7.91-8.00 (m, 2H), 8.04-8.09 (m, 2H).
Example 47
(2R)-[4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) Pentanic acid
A. 4- (4-fluorophenoxy) benzenesulfonyl chloride
The title compound was obtained from 4-fluorodiphenyl ether similarly as described in Example 46C: NMR (CDCl ₃ ) 7.00-7.20 (m, 6H), 7.98 (d, 2H, J = 8.6 Hz).
B. (2R)-[4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazole-2- (1) pentanoic acid
The title compound was obtained similarly as described in Example 46: NMR (40OMHz, CDCl ₃ ) 1.62-1.93 (m, 4H), 3.70-3.77 (m, 2H), 3.87-3.91 (m, 1H), 7.00 (d , 2H, J = 9.1 Hz), 7.06-7.17 (m, 4H), 7.81 (d, 2H, J = 8.6 Hz), 7.91-8.00 (m, 2H), 8.07 (t, 2H, J = 8.0 Hz) .
Example 48
(2R)-[4- (4-fluorophenoxy) benzenesulfonylamino] -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3- (1) pentanoic acid
A. (2R) -t-butoxycarbonylamino-5- (l, 2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3yl) pentanoic acid t-butyl ester
0.408 g (10.2 mmol) of sodium hydride was added to 2.17 g (12.4 mmol) of 1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline and 0.045 g of 18-crown-6 in 25 ml of DMF. To the solution. After stirring for 30 minutes at room temperature, 3.60 g (9.02 mmol) of (2R)-(t-butyloxycarbonylamino) -5-iodopentanoic acid tbutyl ester in 15 ml of DMF were added and the solution was stirred for 30 minutes at room temperature. Then it was stirred at 60 ° C. for 6 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 0.05M HCl aqueous solution. The organic phase was washed with water and brine, dried over MgSO ₄ and concentrated. The crude material was purified by silica gel chromatography (hexane / ethyl acetate 3/1 to 2/1) to give 3.81 g (95% yield) of the title compound: NMR (40OMHz, CDCl ₃ ) 1.42 (s, 9H), 1.45 ( s, 9H), 1.60-1.88 (m, 4H), 3.60 (s, 3H), 4.08-4.21 (m, 3H), 5.06 (br d, 1 H, J = 8.1 Hz), 7.19-7.31 (m, 2H), 7.68 (dt, 1H, J = 7.84, 1.56 Hz), 8.22 (dd, 1H, J = 7.88, 1.52 Hz).
B. (2R) -Amino-5- (1,2,3,4-tetrahydro-l-methyl-2,4-dioxoquinazolin-3-yl) -pentanoic acid t-butyl ester
3.81 g (8.52 mmol) of the title A compound in 20 mL of methylene chloride were treated with 5.09 mL (57.5 mmol) of TFA at 0 ° C. After stirring for 5 hours at 0 ° C. to room temperature, the mixture was cooled to 0 ° C. and carefully neutralized with aqueous NaHCO ₃ until pH 7-8. The product was extracted three times with ethyl acetate and the combined organic phases were combined, dried over MgSO ₄ and concentrated under reduced pressure to give 2.72 g (92% yield) of the title compound: NMR (40OMHz, CD ₃ 0D) 1.47 (s, 9H), 1.60- 1.81 (m, 4H), 3.40 (t, 1H, J = 5.8 Hz), 3.60 (s, 3H), 4.06-4.12 (m, 2H), 7.30 (t, 1H, J = 7.5 Hz), 7.43 (d , 1H, J = 8.4 Hz), 7.74-7.78 (m, 1H), 8.14 (d, 1H, J 7.8 Hz).
C. (2R)-[4- (4-fluorophenoxy) benzenesulfonylamino] -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin- 3-yl) pentanoic acid t-butyl ester
To a solution of 2.98 g (8.59 mmol) of the title B compound in 90 mL of dioxane and 45 mL of water, 1.80 mL (12.9 mmol) of triethylamine was added continuously, and 4- (4-fluorophenoxy) benzenesulfur at 0 ° C. 3.20 g (11.2 mmol) of polyvinylchloride were added and the reaction mixture was allowed to warm to room temperature. After stirring for 3 hours at room temperature, the mixture was cooled to 0 ° C. and water and 1 M HCl were added. The organic material was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over MgSO ₄ and concentrated under reduced pressure to give crystalline product which was triturated with ether, filtered and dried to give 4.65 g (91% yield) of the title compound: NMR (40OMHz, CDCl ₃ ) 1.28 ( s, 9H), 1.57-1.90 (m, 4H), 3.61 (s, 3H), 3.83-3.92 (m, 1H), 4.08-4.11 (m, 2H), 5.23 (d, 1H, J = 9.4 Hz) , 6.95-7.28 (m, 8H), 7.69 (t, 1H, J = 7.8 Hz), 7.78 (d, 2H, J = 8.7 Hz), 8.22 (d, 1H, J8.0 Hz).
D. (2R)-[4- (4-Fluorophenoxy) benzenesulfonylamino] -5- (1,2,3,4-tetrahydro-l-methyl-2,4-dioxoquinazoline- 3-yl) pentanoic acid
The title compound was obtained similarly as described in Example 46E: NMR (40OMHz, CDCl ₃ ) 1.59-1.80 (m, 4H), 3.60 (s, 3H), 3.85-3.87 (m, 1H), 4.03-4.05 (m , 2H), 6.98-7.16 (m, 6H), 7.32 (t, 1H, J = 7.3 Hz), 7.43 (d, 1H, J = 8.4 Hz), 7.76-7.80 (m, 3H), 8.14 (dd , 1H, J = 7.9, 1.4 Hz).
Example 49
(2R)-(4-phenoxybenzenesulfonylamino) -5- (1,2,3,4-tetrahydro-l-methyl-2,4-dioxoquinazolin-3-yl) pentanoic acid
The title compound was obtained similarly as described in Example 48: NMR (40OMHz, CD ₃ 0D) 1.59-1.80 (m, 4H), 3.60 (s, 3H), 3.85-3.88 (m, 1H), 4.02-4.07 ( m, 2H), 7.00 (d, 2H, J = 9.1 Hz), 7.03 (d, 2H, J = 8.6 Hz), 7.20 (t, 1H, J = 7.6 Hz), 7.30 (t, 1H, J = 7.6 Hz), 7.37-7.44 (m, 3H), 7.74-7.79 (m, 1H), 7.79 (d, 2H, J = 8.6 Hz), 8.14 (dd, 1H, J = 8.1, 1.5 Hz).
The following additional compounds can be prepared using the methods described above or variations thereof.

权利要求:
Claims (22)
[1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt thereof.
<Formula I>

Where
W is -OH or -NHOH;
X is
a) pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thia Diazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, oxadizolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- Oxopyrrolodinyl, 2-oxoazinyl, azepinyl, 4-piperidinyl, pyridyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl Sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-l, l-dioxothienyl, benzothiazolyl, benzoxazolyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl , Isoquinolinyl, benzimidazolyl, benzopyranyl, indolinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, synol Linyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydrobenzoisothiazolyl, dihydroquinazolinyl, tetrahydroquinazolinyl and a 10-15 membered tricyclic ring system (bicyclic system) May have one or more heteroatoms in the ring comprising one or more carbon atoms and each ring of the heterocyclic radical comprising the hetero atoms may have one, two or three heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms Substituted or unsubstituted heterocyclic radicals selected from the group consisting of: wherein X is a heterocyclic radical comprising nitrogen, the heterocyclic radical is attached to the (CH ₂ ) m moiety by a ring nitrogen, Nitrogen and sulfur hetero atoms of the heterocyclic radical may be oxidized);
b) —NR ₁ SO ₂ R ₂ , wherein R ₁ is hydrogen, alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl, and R ₂ is hydrogen, alkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl , Aryl or heteroaryl;
c) heterocyclylalkylthio;
d) -CONR ₂ R ₃ , wherein R ₂ and R ₃ together with the nitrogen atom to which they are attached form a 5-7 membered ring which may optionally include another hetero atom selected from oxygen, nitrogen and sulfur ; or
e) -NR ₁ COR ₂ , wherein R ₁ is hydrogen, alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl, and R ₂ is hydrogen, heterocyclylalkyl, aralkyl, heteroarylalkyl or aryl ego;
Y is carbon, nitrogen, oxygen or sulfur, where n is 2 when Y is carbon;
Z is alkyl, aryl, alkoxy, aryloxy, aralkoxyaryl, alkoxyheteroaryl, heteroaryl, heterocyclyl, heteroaryloxy, -CONR ₂ R ₃ , -NR ₁ COR ₂ , -NR ₁ CONR ₂ R ₃ , -OCONR ₂ R ₃ , -NR ₁ COOR ₄ or -SO ₂ R ₂ , wherein R ₁ is hydrogen, alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl, and R ₂ and R ₃ are independently hydrogen , Alkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, aryl or heteroaryl or R ₂ and R ₃ together with the nitrogen atom to which they are attached may optionally include another hetero atom selected from oxygen, nitrogen and sulfur Forms a 5-7 membered ring, R ₄ is alkyl, heterocyclylalkyl, aralkyl, aryl or heteroaryl;
m is an integer from 1 to 6;
n is an integer of 1 or 2.
[2" claim-type="Currently amended] The method of claim 1,
W is -OH or -NHOH;
X is pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, Furyl, tetrahydrofuryl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazinyl, azepinyl, 4-piperidinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro- l, l-dioxothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzopyranyl, indolinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, Cinnaolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydrobenzoisothiazolyl, dihydroquinazoli , Tetrahydroquinazolinyl and a 10 to 15 membered tricyclic ring system, which has at least one heteroatom in a ring comprising at least one carbon atom and each ring of a heterocyclic radical comprising a heteroatom is nitrogen A substituted or unsubstituted heterocyclic radical selected from the group consisting of atoms, which may have one, two or three hetero atoms selected from atoms, oxygen atoms and sulfur atoms;
The remaining symbols and radicals have the meaning as described in claim 1 or a pharmaceutically acceptable salt thereof.
[3" claim-type="Currently amended] The method of claim 1,
X is pyrazolyl, oxetanyl, pyrazolinyl, imidazolinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, iso Thiazolidinyl, furyl, tetrahydrofuryl, oxadiazolyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxoazinyl, pyridyl, pyrazinyl, pyridazinyl, tetra Hydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-l, l-dioxothienyl, benzothiazolyl, benz Oxazolyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzopyranyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnaolinyl, quinoxalinyl, indazolyl , Pyrrolopyridyl, furopyridinyl, dihydrobenzoisothiazolyl, dihydroquinazolinyl, tetrahydrate Quinazolinyl and a 10 to 15 membered tricyclic ring system, which has one or more heteroatoms in the ring containing one or more carbon atoms and each ring of a heterocyclic radical comprising a hetero atom is a nitrogen atom, oxygen A substituted or unsubstituted heterocyclic radical selected from the group consisting of one or two or three hetero atoms selected from atoms and sulfur atoms;
The remaining symbols and radicals are compounds having the meaning as described in claim 1 or a drug thereof.
Scholarly acceptable salts.
[4" claim-type="Currently amended] The method of claim 1,
W is -OH or -NHOH;
X is a nitrogen containing heterocyclic radical;
Y is carbon;
n is 2;
Z is aryl, aryloxy, heteroaryl or heteroaryloxy;
m is an integer from 2 to 4
Phosphorus compounds or pharmaceutically acceptable salts thereof.
[5" claim-type="Currently amended] The method of claim 1,
W is -OH or -NHOH;
X is 1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-quinazolinyl, 3,4,4-trimethyl-2,5-dioxoimidazolinyl, 4-methyl Benzenesulfonylamino or 1,1,3-trioxo-2,3-dihydrobenzoisothiazolyl;
Z is aryl, aryloxy, heteroaryl or heteroaryloxy;
N is 2 when Y is carbon, nitrogen, oxygen or sulfur but Y is carbon;
n represents an integer of 1 or 2;
m is an integer from 2 to 4
Phosphorus compounds or pharmaceutically acceptable salts thereof.
[6" claim-type="Currently amended] The method of claim 1,
W is -OH;
X is 1,2,3,4-tetrahydro-l-methyl-2,4-dioxo-quinazolinyl or 1,1,3-trioxo-2,3-dihydrobenzoisothiazolyl;
Y is carbon;
n is 2;
Z is aryl or aryloxy, where aryl is unsubstituted or substituted, respectively, with halogen;
m is an integer from 2 to 4
Phosphorus compounds or pharmaceutically acceptable salts thereof.
[7" claim-type="Currently amended] The method of claim 1,
W is -OH;
The remaining symbols and radicals have the meaning as described in claim 1 or a pharmaceutically acceptable salt thereof.
[8" claim-type="Currently amended] The method of claim 1,
W is -OH or -NHOH;
X is -CONR ₂ R ₃ , wherein R _{2 and} R ₃ together with the nitrogen atom to which they are attached form a 5 to 7 membered ring optionally containing oxygen as another hetero atom;
Y is carbon;
n is 2;
Z is aryl or aryloxy;
m is an integer from 1 to 2
Phosphorus compounds or pharmaceutically acceptable salts thereof.
[9" claim-type="Currently amended] The method of claim 1,
W is -OH or -NHOH;
X is -NR ₁ COR ₂ , wherein R ₁ is hydrogen and R ₂ is aralkyl or aryl;
Y is carbon;
n is 2;
Z is alkoxy or aryl;
m is an integer from 3 to 4
Phosphorus compounds or pharmaceutically acceptable salts thereof.
[10" claim-type="Currently amended] The method of claim 1,
W is -OH or -NHOH;
X is -NR ₁ S0 ₂ R ₂ , wherein R ₁ is hydrogen and R ₂ is alkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, aryl or heteroaryl;
Y is carbon;
n is 2;
Z is alkoxy or aryl;
m is an integer from 3 to 4
Phosphorus compounds and their pharmaceutically acceptable salts.
[11" claim-type="Currently amended] The method of claim 1,
(2R)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid;
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-quinazolin-3-yl ) Pentanoic acid;
(2R)-(4-biphenylsulfonylamino) -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) pentanoic acid;
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) -pentanoic acid;
(2R)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (4-methylbenzenesulfonylamino) pentanoic acid;
(2R)-[4- (pyridin-4-yloxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid ;
(2R)-[4- (4-imidazol-1-ylphenoxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazole-2- I) pentanoic acid;
(2R)-[4- (4-chlorophenyloxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid;
(2R)-(4-methylpiperazin-1-ylbenzenesulfonylamino) -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid;
(2R)-[4- (4-methoxybenzoylamino) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid ;
(2R)-[4- (4-phenylpiperidin-1-yl) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazole-2- I) pentanoic acid;
(2R)-(4-benzenesulfonylthiophen-2-sulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid;
(2R)-(5-benzenesulfonylthiophen-2-sulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid;
(2R)-[5- (5-trifluoromethylpyridine-2-sulfonyl) thiophene-2-sulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzo Isothiazol-2-yl) pentanoic acid;
(2R)-(4'-chlorobiphenyl-4-sulfonylamino) -3-{[(1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) methyl] Thio} propionic acid;
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid hydroxy amides;
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-quinazolin-3-yl ) Pentanoic acid hydroxyamide;
(2R)-(4-biphenylsulfonylamino) -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) pentanoic acid hydroxyamide ;
(2R)-[4- (pyridin-4-yloxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid Hydroxyamides;
(2R)-[4- (4-imidazol-1-ylphenoxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazole-2- I) pentanoic acid hydroxyamide;
(2R)-[4- (4-chlorophenyloxy) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid hydroxide Oxyamide;
(2R)-[(4-methylpiperazin-1-ylbenzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid Hydroxyamides;
(2R)-[4- (4-methoxybenzoylamino) benzenesulfonylamino] -5- (l, l, 3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid Hydroxyamides;
(2R)-[4- (4-phenylpiperidin-1-yl) benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazole-2- I) pentanoic acid hydroxyamide;
(2R)-(4-benzenesulfonylthiophen-2-sulfonyl-amino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid hydroxide Oxyamide;
(2R)-(5-benzenesulfonylthiophen-2-sulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid hydroxy amides;
(2R)-[5- (5-trifluoromethylpyridine-2-sulfonyl) thiophene-2-sulfonylamino] -5- (l, 1,3-trioxo-2,3-dihydrobenzo Isothiazol-2-yl) pentanoic acid hydroxyamide;
(2R)-(4'-chlorobiphenyl-4-sulfonylamino) -3-{[(1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) methyl] Thio} propionic acid hydroxyamide;
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -6- (1,2,3,4-tetrahydro-1 -methyl-2,4-dioxoquinazolin-3- I) hexanoic acid;
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -6- (4,4-dimethyl-2,5-dioxoimidazolidin-1-yl) -hexanoic acid;
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -6- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-quinazolin-3 -Yl) hexanoic acid hydroxyamide;
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -6- (4,4-dimethyl-2,5-dioxoimidazolidin-1-yl) hexanoic acid hydroxyamide ;
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -4- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) -butyric acid;
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -4-[(1,3-dioxo-1,5,10, (l0aS) -tetrahydroimidazo- [1,5- b] isoquinolin-2-yl)] butyric acid;
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -4- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-quinazolin-3-yl ) Butyric acid;
(2R)-(4'-Chlorobiphenyl-4-sulfonylamino) -4- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) -butyric acid hydroxyamide ;
(2R, S)-(4'-chlorobiphenyl-4-sulfonylamino) -3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) propanoic acid;
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -3- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3- (1) propanoic acid;
(2R, S)-(4'-Chlorobiphenyl-4-sulfonylamino) -3- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) propanoic acid hydroxide Oxyamide;
(2R)-(4-phenyloxybenzenesulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid;
(2R)-(4'-chlorobiphenyl-4-sulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid;
(2R)-(4-phenyloxybenzenesulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid hydroxyamide; or
(2R)-(4'-chlorobiphenyl-4-sulfonylamino) -4-morpholin-4-yl-4-oxobutyric acid hydroxyamide
Phosphorus compounds or pharmaceutically acceptable salts of said compounds.
[12" claim-type="Currently amended] The method of claim 1,
(2R)-(4-phenoxybenzenesulfonylamino) -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl) pentanoic acid;
(2R)-[4- (4-fluorophenoxy) benzenesulfonylamino] -5- (1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3- I) pentanoic acid;
(2R)-[4- (4-Fluorophenoxy) -benzenesulfonylamino] -5- (1,1,3-trioxo-2,3-dihydrobenzo-isothiazol-2-yl) Pentanic acid; or
(2R)-(4-phenoxybenzenesulfonylamino) -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid
Phosphorus compounds or pharmaceutically acceptable salts of said compounds.
[13" claim-type="Currently amended] The method of claim 1,
Compound which is (2R)-(4'-chlorobiphenyl-4-sulfonylamino) -5- (1,1,3-trioxo-2,3-dihydrobenzoisothiazol-2-yl) pentanoic acid Or a pharmaceutically acceptable salt thereof.
[14" claim-type="Currently amended] A pharmaceutical composition comprising a matrix-degrading metalloproteinase inhibitory effective amount of a compound of formula (I) according to any one of claims 1 to 13 together with one or more pharmaceutically acceptable carriers.
[15" claim-type="Currently amended] A pharmaceutical for the treatment of a tumor of a warm-blooded animal, including a human, comprising an anti-tumorally effective amount of a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt of said compound together with a pharmaceutically acceptable carrier. Composition.
[16" claim-type="Currently amended] Use of a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt of said compound for the manufacture of a pharmaceutical composition for the chemotherapy of a tumor.
[17" claim-type="Currently amended] Use of a compound of formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt of said compound for chemotherapy of a tumor.
[18" claim-type="Currently amended] A matrix-degrading metalloproteinase in a mammal comprising administering to the mammal in need thereof an inhibitory amount of the matrix-degrading metalloproteinase inhibition of the compound of formula (I) according to claim 1. Method of inhibiting deactivation.
[19" claim-type="Currently amended] 15. A stromelysin or collagenase in a mammal comprising administering to the mammal in need thereof an inhibitory effective amount of stromelysin or collagenase of the compound of formula (I) according to claim 1. How to inhibit activity.
[20" claim-type="Currently amended] A matrix-degrading metalloproteinase in a mammal comprising administering to the mammal in need thereof an inhibitory effective amount of the matrix-degrading metalloproteinase of the compound of formula (I) according to claim 1. How to treat dependent disease.
[21" claim-type="Currently amended] A constant temperature, including a human, comprising administering an anti-tumorally effective amount of a compound of Formula (I) according to any one of claims 1 to 13 or a pharmaceutically acceptable salt of said compound to a warm-blooded animal, including a person with tumor disease Method of treatment of animals.
[22" claim-type="Currently amended] Reacting a compound of formula IV with sulfonyl chloride of formula V to form a compound of formula VI and optionally treating the compound of formula VI with anhydrous acid to form a compound of formula I wherein W is hydroxyl Sulfonylamino acids or sulfonylamino of formula (I), comprising reacting a compound of formula (I) wherein W is hydroxyl with a protected hydroxylamine and removing a protecting group to form a compound of formula (I) wherein W is hydroxylamino Process for the preparation of hydroxamic acid or salts thereof.
<Formula I>

<Formula IV>

<Formula V>

<Formula VI>

Where
W is -OH or -NHOH;
X is pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thia Diazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, oxadizolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- Oxopyrrolodinyl, 2-oxoazinyl, azepinyl, 4-piperidinyl, pyridyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl Sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-l, l-dioxothienyl, benzothiazolyl, benzoxazolyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl , Isoquinolinyl, benzimidazolyl, benzopyranyl, indolinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, shin Linyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydrobenzoisothiazolyl, dihydroquinazolinyl, tetrahydroquinazolinyl and a 10-15 membered tricyclic ring system (bicyclic system) May have one or more heteroatoms in the ring comprising one or more carbon atoms and each ring of the heterocyclic radical comprising the hetero atoms may have one, two or three heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms Substituted or unsubstituted heterocyclic radicals selected from the group consisting of: wherein X is a heterocyclic radical comprising nitrogen, the heterocyclic radical is attached to the (CH ₂ ) m moiety by a ring nitrogen, Nitrogen and sulfur hetero atoms of the heterocyclic radical may be oxidized); or
Heterocyclylalkylthio;
Y is carbon, nitrogen, oxygen or sulfur, where n is 2 when Y is carbon;
Z is alkyl, aryl, alkoxy, aryloxy, aralkoxyaryl, alkoxyheteroaryl, heteroaryl, heterocyclyl, heteroaryloxy, -CONR ₂ R ₃ , -NR ₁ COR ₂ , -NR ₁ CONR ₂ R ₃ , -OCONR ₂ R ₃ , -NR ₁ COOR ₄ or -SO ₂ R ₂ , wherein R ₁ is hydrogen, alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl, and R ₂ and R ₃ are independently hydrogen , Alkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, aryl or heteroaryl or R ₂ and R ₃ together with the nitrogen atom to which they are attached may optionally comprise another hetero atom optionally selected from oxygen, nitrogen and sulfur. Form a 5 to 7 membered ring, R ₄ is alkyl, heterocyclylalkyl, aralkyl, aryl or heteroaryl;
m is an integer from 1 to 6;
n represents an integer of 1 or 2.

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公开号 | 公开日 | 专利标题

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US9447033B2|2016-09-20|Potassium channel blockers

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同族专利:

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公开号 | 公开日

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SK11692000A3|2001-02-12|

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HU0101176A2|2001-09-28|

---

PL342009A1|2001-05-07|

---

WO1999042443A1|1999-08-26|

---

NO317977B1|2005-01-17|

---

EP1918278A1|2008-05-07|

---

ID24957A|2000-08-31|

---

CA2318145C|2009-10-27|

---

RU2208609C2|2003-07-20|

---

TR200002224T2|2000-12-21|

---

IL137465D0|2001-07-24|

---

EP1053226A1|2000-11-22|

---

AU747911B2|2002-05-30|

---

JP2002503720A|2002-02-05|

---

AU2923599A|1999-09-06|

---

US6277987B1|2001-08-21|

---

CA2318145A1|1999-08-26|

---

NZ505968A|2003-03-28|

---

CN1195735C|2005-04-06|

---

NO20003565D0|2000-07-11|

---

HU0101176A3|2002-06-28|

---

JP4750272B2|2011-08-17|

---

CN1290250A|2001-04-04|

---

NO20003565L|2000-10-03|

---

BR9909322A|2000-12-05|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1998-02-04|Priority to US1881998A

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1998-02-04|Priority to US09/018,819

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1999-02-02|Application filed by 한스 루돌프 하우스, 헨리테 브룬너, 베아트리체 귄터, 노파르티스 아게

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1999-02-02|Priority to PCT/EP1999/000646

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2001-05-15|Publication of KR20010040698A

优先权:

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申请号 | 申请日 | 专利标题

---

US1881998A| true| 1998-02-04|1998-02-04|

---

US09/018,819|1998-02-04|

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PCT/EP1999/000646|WO1999042443A1|1998-02-04|1999-02-02|Sulfonylamino derivatives which inhibit matrix-degrading metalloproteinases|