GB2391547A - Hydroxy-succinamide compounds for the treatment of alzheimer's disease - Google Patents
Hydroxy-succinamide compounds for the treatment of alzheimer's disease Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being saturated and containing rings
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
A compound of formula (I) <EMI ID=1.1 HE=32 WI=110 LX=701 LY=572 TI=CF> <PC>wherein ```R<1> is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, any of which is optionally substituted with R<4>; ```R<2> is alkyl, alkenyl, alkoxy or alkylthio, any of which is optionally substituted with R<5>; ```R<3> is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, any of which is optionally substituted with R<6>; ```each R<4> is the same or different and is alkyl, alkenyl, alkoxy, aryl, -alkyl-aryl, -alkoxy-aryl, -C(O)O- or -C(O)NH-R<6>; ```each R<5> is the same or different and is alkylthio, aryl, heteroaryl, -NHC(O)-R<6>, -NHC(O)O-R<6>, -C(O)NH-R<6>, -C(O)O-R<6> or -heteroaryl-aryl; ```each R<6> is the same or different and is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl or -alkyl-aryl; or a pharmaceutically acceptable salt thereof. Preferred compounds feature R<3>= hydrogen or cyclopentylmethyl. These compounds act as BACE inhibitors and thus may be useful in the treatment of Alzheimer's Disease.
Description
COMPOUNDS AND THEIR USE
Field of the Invention
This invention relates to compounds and their therapeutic use.
Background to the Invention
5 Alzheimer's disease (AD) is the most common form of dementia among older people, and affects parts of the brain that control thought, memory and language. Susceptibility to Alzheimer's disease increases with age, but the disease is not a normal part of the ageing process.
Alzheimer's disease is associated with regions of accumulated proteins 10 in the brain. These dense regions, termed "amyloid plaques" and "neurofibrilliary tangles", contain,6-amyloid precursor protein (,B-APP)., B-APP is degraded by p-amyloid converting enzyme (BACK, also known as,B secretase) to produce,B-amyloid peptide A,B 40/42, which accumulates in the plaques. Research has shown that the activity of BACK is an early step in the 15 pathogenesis pathway common to all familial and sporadic forms of Alzheimer's disease; thus inhibitors of BACK may have therapeutic utility in the treatment of this disease.
Summary of the Invention
According to a first aspect of the invention, a compound has the formula 20 (1)
25 R2'N R' ()
wherein R' is alkyl, alkenyl, cycloalkyl7 cycloalkenyl, heterocycloalkyl, 30 heterocycioalkenyl, aryl or heteroaryl, any of which is optionally substituted with 4. R.
R2 is alkyl, alkenyl, alkoxy or alkylthio, any of which is optionally substituted with R5; R3 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, any of which is optionally substituted with 5 R6; each R4 is the same or different and is alkyl, alkenyl, alkoxy, aryl, -alkyl-
aryl, -alkoxy-aryl, -C(O)O- or-C(O)NH-R6; each R5 is the same or different and is alkylthio, aryl, heteroaryl, -NHC(0)-
R6, -NHC(0)0-R6, -C(0)NH-R6, -C(0)0-R6 or -heteroaryl-aryl; 10 each R6 is the same or different and is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl or-alkyl-aryl; or a pharmaceutically acceptable salt thereof.
Compounds of the invention are inhibitors of BACK and as a consequence may have utility in the treatment or prevention of diseases or 15 conditions in which BACK is implicated. In particular, the present invention may have utility in the treatment of diseases or conditions associated with the deposition and/or elevated levels of amyloid beta peptide (A,B), for example Alzheimer's disease.
Another aspect of the invention is a pharmaceutical composition 20 comprising a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
A further aspect of the invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of a disease or condition associated with the deposition and/or elevated levels of amyloid 25 beta peptide (A,8).
DescriDtion of the Invention For the present invention, certain compounds and combinations of substituents are preferred; in particular see the subclaims. With regard to formula (I), R' is preferably alkyl, -arylalkyl, -aryl-alkoxy, -aryl-alkyl-aryl, -aryl 30 alkoxy-aryl, -CH(aryl)2 or-alkyl-C(O)O-alkyl-aryl. R2 is preferably -alkyl-aryl, -alkyl-C(O)NHaryl, -alkyl(alkylthio)-C(O)NH-aryl, -CH(aryl)2, -alkyl-NHC(O)O
alkyl-aryl, -alkyl(aryl)-C(O)NH-cycloalkyl, -alkyl(aryl)C(O)O-alkyl or alkyl-
heteroaryl-aryl. R3 is preferably hydrogen, alkyl or -alkyl-cycloalkly.
The term "alkyl" as used herein refers to a straight or branched chain alkyl moiety having from 1 to 8 carbon atoms, and includes, for example, methyl, ethyl, 5 propyl, isopropyl, n-butyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, hept-2-yl and octyl. "Coo alkyl" has the same meaning.
The term "alkenyl" refers to a straight or branched chain alkyl moiety having 2 to 8 carbon atoms and having in addition at least one double bond., and includes, for example, vinyl, 1-propenyl, 1- and 2- butenyl and 2- methyl-2 10 propenyl. "C2 alkenyl" has the same meaning.
The term "alkoxy" as used herein refers to a straight or branched chain alkoxy moiety having from 1 to 8 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy. "C, 8 alkoxy" has the same meaning.
15 The term "alkylthio" as used herein refers to a straight or branched chain alkylthio moiety having from 1 to 8 carbon atoms, and includes, for example, methylthio, ethylthio and propylthio. ''C'4 alkylthio" has the same meaning.
The term "aryl" as used herein refers to optionally substituted aromatic ring systems comprising 6 to 14 ring atoms, and optionally substituted polycyclic 20 ring systems having two or more cyclic rings at least one of which is aromatic.
This term includes for example, phenyl and naphthyl. The group may be optionally substituted with the substituents being the same or different in each occurrence and selected from nitro and halogen.
The term ''heteroaryl" as used herein refers to an optionally substituted 25 aromatic monocyclic or bicyclic ring moiety comprising 5 to 15 ring atoms and optionally substituted heteropolycyclic ring systems having two or more rings, at least one of which is aromatic. The group comprises of at least one of which is selected from O. N. P and S. and includes for example furanyl, thiophenyl, pyridyl, indolyl, piperonyl and quinolyl. The substituents may be the same or 30 different in each occurrence and selected from alkyl and halogen.
The term "cycloalkyl" as used herein refers to a saturated alicyclic moiety having from 3 to 8 carbon atoms and includes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyi.
The term "cycloalkenyl" as used herein refers to an alicyclic moiety having 5 from 3 to 8 carbon atoms and having in addition at least one double bond, and includes for example cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. The term "heterocycloalkyl" as used herein refers to a saturated heterocyclic moiety having from 3 to 8 carbon atoms and one or more 10 heteroatoms selected from the group N. 0, S and P. and includes for example azetidinyl, pyrrolidinyl, tetrahydrofuranyl and piperidinyl.
The term "heterocycloalkenyl" as used herein refers to a unsaturated heterocyclic moiety having from 3 to 8 carbon atoms and one or more heteroatoms selected from N. 0, S and P. 15 The term "halogen" as used herein refers to F. Cl, Br or 1.
Preferred compounds of the invention include: N'-benzol1,3]dioxcl-5ylmethyl-N4-(4-butyl-phenyl)-2(S)-hydroxy succinamide; N4-(4-benzyloxyphenyl)-2(S)-hydroxy-N'-[2(S)-methyl-1 (S)-(4-nitro 20 phenylcarbamoyl)butyl]-succinamide; 2(S)-hydroxy-N'-[2(S)-methyl-1 (S)-(4nitrohenylcarbamoyl)-butyl]-N4-(4 pentyloxy-phenyl)-succinamide; N4-(4benzyl oxy-phenyl)-2(S)-hydroxy-N'-[3-methylsulphanyl-1 (S) (naphthalene2-ylcarbamoyl)-propyl]-succinamide; 25 2(S)-hydroxy-N4-( 1 (R/S)-methylhexyl)-N'-l3-methylsulphanyl-1 (S) (naphthalene-2-ylcarbamoyl)-propyl]succinamide; N4-(4-benzyloxy-phenyl)-N'{(R/S)-(4 chloro-phenyl)-phenylmethyl]-2(S) hydroxy-succinamide; {4-[3-(4-benzyl-phenylcarbamoyl)-2(S)hydroxy-propionylamino]-butylY 30 carbamic acid benzyl ester; {4-[3-(4sec-butyl-phenylcarbamoyl)-2(S)ydroxy-propionylamino]-butyl} carbamic acid benzyl ester;
N4-[(4-chloro-phenyl)-phenyl-methyl]-N'-(1 (S)-cyclohexylcarbamoyl-2-
phenyl-ethyl)-2(S)-cyclopentylmethyl-3(S)-hydroxy-succinamide; 2(R)-[3-( 1 -benzyloxycarbonyl-ethylcarbamoyl)-2(S)-cyclopentylmethyl-
3(S)-hydroxy-propionylamino]-3-(4-chloro-phenyl)-propionic acid methyl ester; 5 and 2(S)-{4-cyclopentyl-2(S)-hydroxy-3(S)-[(5-methyl-3-phenylisoxazol4-
ylmethyl)-carbamoyl]-butyrylamino}-propionic acid benzyl ester.
Compounds of the invention are chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate. The conformation of the 10 chiral centre adjacent to the hydroxyl group is preferably S. The compounds of the invention may be prepared in racemic form, or prepared in individual enantiomeric form by specific synthesis or resolution as will be appreciated in the art. The compounds may, for example, be resolved into their enantiomers by standard techniques, such as the formation of 15 diastereomeric pairs by salt formation with an optically active acid followed by fractional crystallization and regeneration of the free base. Alternatively, the enantiomers of the novel compounds may be separated by HPLC using a chiral column. A compound of the invention may be in a protected amino, protected 20 hydroxy or protected carboxy form. The terms "protected amino", "protected hydroxy" and "protected carboxy" as used herein refer to amino, hydroxy and carboxy groups which are protected in a manner familiar to those skilled in the art. For example' an amino group can be protected by a benzyloxycarbonyl, tert-
butoxycarbonyl, acetyl or like group, or in the form of a phthalimido or like group.
25 A carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester.
Some compounds of the formula may exist in the form of solvates, for example hydrates, which also fall within the scope of the present invention.
Compounds of the invention may be in the form of pharmaceutically 30 acceptable salts, for example, addition salts of inorganic or organic acids. Such inorganic acid addition salts include, for example, salts of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid and sulphuric acid. Organic acid
addition salts include, for example, salts of acetic acid, benzenesulphonic acid, benzoic acid, camphorsulphonic acid, citric acid, 2-(4-chlorophenoxy)-2 methylpropionic acid, 1,2-ethanedisulphonic acid, ethanesulphonic acid, ethylenediaminetetraacetic acid (EDTA), fumaric acid, glucoheptonic acid, 5 gluconic acid, glutamicacid, Nglycolylarsanilicacid, 4-hexylresorcinol, hippuric acid, 2-(4hydroxybenzoyl)benzoic acid, 1 -hydroxy-2-naphthoic acid, 3-hydroxy 2naphthoic acid, 2-hydroxyethanesulphonic acid, lactobionic acid, ndodecyl sulphuric acid, maleic acid, malic acid, mandelic acid, methanesulphonic acid, methyl sulphuric acid, mucic acid, 2naphthalenesulphonic acid, pamoic acid, 10 pantothenic acid, phosphanilic acid ((4-aminophenyl)phosphonic acid), picric acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, terephthalic acid, p-toluenesulphonic acid and 1 0-undecenoic acid.
Salts may also be formed with inorganic bases. Such inorganic base salts include, for example, salts of aluminium, bismuth, calcium, lithium, magnesium, 15 potassium, sodium, zinc and the like. Organic base salts include, for example, salts of N. N'-dibenzylethylenediamine, choline (as a counterion), diethanolamine, ethanolamine, ethylenediamine, N,N' bis(dehydroabietyl)ethylenediamine, N-methylglucamine and procaine, tris(hydroxymethyl)aminoethane ("TRIS").
20 It will be appreciated that such salts, provided that they are pharmaceutically acceptable, may be used in therapy. Such salts may be prepared by reacting the compound with a suitable acid or base in a conventional manner.
A compound of the invention may be prepared by any suitable method 25 known in the art and/or by the following processes:
Scheme 1 OH 1) TFM OH DCC/HOBT/DMF OH
HO C CO2H CO2H MeO2C CONHR 2 2) MeOH MeO2C R1NH NaOH/aq THF OH PYBOP/DIEA/DMF OH CONHR1 R2HNOC
Scheme 2 OH1) TFM F3C 3 R2NH2/ dioxan OH HO2C; 2) Evaporste O:o R2HNOCCO2H PYBOP/DIEAIDMF OH
R'NH2 R HNOC
R3
Scheme 3 00: i) "Bul i omen - Bu2BOTf omen R3 63 2) R3CH2COCI 63 NE
O O Ac2O/Pyndine,_ REDO O O o O O OFF ET2O at_ a\ CO2tBu HO O. 1 R3 HO2C CO2tBu >:o::CC13 - R3 EDC/HOBT HO 1) TFA HO
- R1HNOC CO2tBu R1HNOC CONHR2 R1NH2 R3 2) EDCIHOBTIR2NH2 R3
It will be understood that the processes detailed above are solely for the 5 purpose of illustrating the invention and should not be construed as limiting. A process utilising similar or analogous reagents and/or conditions known to one skilled in the art may also be used to obtain a compound of the invention.
Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known 10 manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances.
The activity and selectivity of the compounds may be determined by any suitable assay known in the art.
The compounds of the invention may be used in the treatment of various ailments, conditions and diseases in which p-amyloid peptide (AM is implicated), 5 including, but not limited to, Alzheimer's disease.
In therapeutic use, the active compound may be administered orally, rectally, parenterally, by inhalation (pulmonary delivery), topically, ocularly, nasally, or to the buccal cavity. Thus, the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical 10 compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art. The 15 compositions of the invention may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, a unit dose comprises the active ingredient in an amount of 1- 500 mg. The excipients used in the preparation of these compositions are the excipients known in the art.
20 Appropriate dosage levels may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of 25 excretion, drug combination and the severity of the disease undergoing treatment. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard 30 or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more
agents selected from the group consisting of sweetening agents' flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients 5 which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating 10 agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
15 Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
20 Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may 25 be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example 30 polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p
hydroxybenzoate, one or more colouring agents, one or more flavouring agents' and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or 5 in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
10 Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present.
15. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for 20 example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
25 Syrups and elixirs may beformulatedwith sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the 30 known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, for example as a solution in 1,3 butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending 5 medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid, find use in the preparation of injectables.
The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be 10 prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compositions for topical administration are also suitable for use in the 15 invention. The pharmaceutically active compound may be dispersed in a pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as light liquid paraffin, dispersed in a aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as 20 a mineral oil or wax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
25 The following Examples illustrate the invention.
In the Examples, the following abbreviations are used: TFM = Trifluoroacetic anhydride DCC = Dicyclohexyl carbodiimide HOST = 1Hydroxybenzotriazole 30 DMF = N,N-Dimethylformamide THE = Tetrahydrofuran
PYBOP = Benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexaf I uorophosphate DIEA = Diisopropylethylamine EDC = 1-[3-(Dimethylamino) propyll-3-ethylcarbodiimide 5 hydrochloride TEA = Trifluoroacetic acid Samples were purified with a Waters mass-directed purification system utilising a Waters 600 LO pump, Waters Xterra C18 column (5,um 19 mm x 50 mm) and Micromass ZQ mass spectrometer, operating in positive ion 10 electrospray ionisation mode. Mobile phases A (0.1% formic acid in water) and B (0.1% formic acid in acetonitrile) were used in a gradient; 5% B to 100% B over 7 minutes, held for 1 minute, at a flow rate of 20 ml/mint Analytical hpic was carried out with a Spectra System P4000 pump and Jones Genesis C18 column (4 m, 50 mm x 4.6 mm). Mobile phases A (0.1% 15 Formic acid in water) and B (acetonitrile) were used in a gradient of 5% B for 1 minute rising to 98% B aRer 5 minutess, held for 3 minutes at a flow rate of 2 ml/minute. Detection was by a TSP UV 6000LP detector at 254 nm UV and range 21000 nm PDA. The mass spectrometerwas a Finnegan LCQ operating in positive ion electrospray mode.
20 Thin Layer Chromatography (TLC) was performed on Merck Silica Gel 60, F254, aluminium plates.
Intermediate 1: 2(S)-Hydroxy-N-(4-benzyloxyphenyl)succinamic acid 2(S)Hydroxysuccinic acid 1- methyl ester was synthesised according to Miller et al, J Org Chem 1982, 47, 4928. (S)-Malic acid (5.3 9) was added 25 portionwise to trifluoroacetic anhydride (15 ml) with cooling in an ice bath. The mixture was then stirred at 0 C for 3 hours giving a clear solution. The solution was evaporated to dryness giving a white solid that was dried under vacuum.
The solid was redissolved in methanol (50 ml) with ice cooling and allowed to stand overnight at room temperature. Evaporation of solvent gave a crude 30 product thatwas recrystallisedfrom ethyl acetate/hexane. 2(S)-Hydroxy-succinic acid-1- methyl ester was obtained as a white crystalline solid, 4 9, mp 72-73 C (softening at 70 C) (lit 79-80 C).
2(S)-Hydroxy-succinic acid-1-methyl ester (1.481 9) and N hydroxybenzotriazole (1.53 9) were dissolved in DMF (30 ml). A solution of N,N dicyclohexylcarbodiimide (2.26 9) in THF (30 ml) was added dropwise with stirring. 4-Benzyloxyaniline hydrochloride (2.585 9) was then added followed by 5 N,N,-Diisopropylethylamine (1.92 ml). The mixture was stirred at room temperature overnight.
The mixture was filtered and the filtrate concentrated under reduced pressure and then partitioned between water (50 ml) and ethyl acetate (100 ml).
The organic phase was washed with 1 M HCI, aqueous sodium bicarbonate and 10 saturated brine. Drying (MgSO4) and evaporation gave a crude solid that was crystallized from a small volume of dichloromethane. 2(S)Hydroxy-N-(4 benzylaxyphenyl)succinamic acid methyl ester was obtained as a white solid, 368 mg (11%), hpic/ me Rt 3.77 min. m/z 330.
2(S)-Hydroxy-N-(4-benzyloxyphenyl)succinamic acid methyl ester (368 15 mg) was dissolved in THF (4 ml) and 1M NaOH (1.23 ml) was added. The solution was then left to stir overnight at room temperature. The solution was concentrated under vacuum, acidified by addition of 1M HCI (2 ml) and partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried (MgSO4) and evaporated to dryness under vacuum 20 giving 2(S)-hydroxy-N-(4-benzyloxyphenyl)succinamicacid as awhite solid, 318 mg, (91 %) hpic/ms Rt 3.61 min. m/z 316.
Intermediate 2: 2(S)-hydroxy-N-(4-pentyloxyphenyl)succinamic acid 2(S)Hydroxy-succinic acid-1- methyl ester (889 mg) (prepared as in Intermediate 1), and N-hydroxybenzotriazole (920 mg) were dissolved in DMF 25 (15 ml). A solution of N,N-dicyclohexylcarbodiimide (1.36 9) in THF (15 ml) was added with stirring followed by 4-pentyloxyaniline (1.21 ml). The mixture was stirred at room temperature overnight and the white precipitate was removed by filtration and washed with a small volume of THF. The filtrate was concentrated under reduced pressure and partitioned between ethyl acetate and 1 N HCI. The 30 organic phase was then washed again with 1N HCI, with aqueous sodium bicarbonate and with brine. Drying (MgSO4) and evaporation gave a light brown solid that was recrystallized from ethyl acetate/hexane to give 2(S)-hydroxy-N-(4
pentyloxyphenyl)succinamic acid methyl ester as a grey solid, 980 mg (52%) , hpicims Rt 3.96 min. m/z 310.
2(S)-Hydroxy-N-(4-pentyloxyphenyl)succinamic acid methyl ester (620 mg) was dissolved in THF (15 ml) and 1 N NaOH (2.2 ml) added. The solution 5 was stirred at RT overnight and acidified by addition of 1 N HCI (2.2 ml). The solution was concentrated under reduced pressure and the resulting solid partitioned between water and ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and evaporated to dryness giving 2(S)hydroxy-N-(4-
pentyloxyphenyl)succinamic acid as a white solid, 540 mg (91%), hpic/ms Rt 10 3.78 min. m/z 296.
Intermediate 3 2(S)-hydroxy-N-(1(R]S)-methylhexyl)-succinamic acid 2(S)Hydroxy-succinic acid-1- methyl ester (889 mg), prepared as in Intermediate 1, and N-hydroxybenzotriazole (920 mg) were dissolved in DME (15 ml). A solution of N,N-dicyclohexylcarbodiimide (.36 g) in THF (15 ml) was 15 added followed by 2-heptylamine (1 ml). The solution was stirred overnight at room temperature and the solid removed by filtration. The filtrate was partitioned between water and ethyl acetate and the organic phase washed with 1M HCI, with aqueous sodium bicarbonate and with brine. Drying (MgSO4) and evaporation gave a crude solid that was recrystallized from ethyl acetate/ hexane 20 to give 2(S)-hydroxy-N-(1-methylhexyl) succinamic acid methyl ester as white crystals, 870 mg (59%), tic ethyl acetate/hexane (1:1) Rf 0.16.
2(S)-Hydroxy-N-(1-methylhexyl)succinamic acid methyl ester (861 mg) was dissolved in THF (15 ml) and 1 M NaOH (3.86 ml) added. The solution was stirred at RT for 3 hours, concentrated under reduced pressure, acidified by 25 addition of 1 M HCI (4 ml) and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4) and evaporated to give 2(S)hydroxy-N (1(RJS)-methylhexyl)succinamic acid as a thick gum, 817 mg (quantitative), hpic/ms Rt 3.40 min. m/z 232 Intermediate 4: 2(S)-hydroxyN-(4-benzylphenyl)succinamic acid 30 2(S)-Hydroxy-succinic acid-1- methyl ester (889 mg), prepared as in Intermediate 1, and N-hydroxybenzotriazole (920 mg) were dissolved in DMF (15 ml) and a solution of N,Ndicyclohexylcarbodiimide (1.36 9) in THF (15 ml)
added. A solution of 4-benzylaniline (1.2 9) in DMF (5 ml) was added dropwise and the mixture stirred at room temperature over the weekend. The precipitated solid was removed by filtration and the filtrate was concentrated by evaporation under reduced pressure and partitioned betweenwater and ethyl acetate. The 5 organic phase was washed with 1 N HCI, with aqueous sodium bicarbonate and with brine. Drying (MgSO4) and evaporation gave a crude solid that was recrystallized from ethyl acetate/hexane. 2(S)-Hydroxy-N-(4-
benzylphenyl)succinamic acid methyl ester was obtained as an off-white solid, 1.15 9 (61%), hpic/ms Rt 3.84 min m/z 314.
10 2(S)-Hydroxy-N-(4-benzylphenyl)succinamic acid methyl ester (1.15 9) was dissolved in THE (15 ml) and 1 M NaOH (4.03 ml) was added. The solution was stirred at room temperature and monitored by hpic. After ca 2 hours the mixture was acidified by addition of 1M HCI (4.5 ml) and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate 15 and the organic phase was washed with brine. Drying (MgSO4) and evaporation gave a white solid that was recrystallized from ethyl acetate/ hexane to give 2(S) hydroxy-N-(4-benzylphenyl) succinamic acid as a white solid, 660 mg (60%), hpic/ms Rt 3.68 min. and m/z 300.
Intermediate 5: 2(S)-hydroxy-N-(4-sec-butylphenyl)succinamic acid 20 2(S)Hydroxy-succinic acid-1- methyl ester (889 mg), prepared as in Intermediate 1, and N-hydroxybenzotriazole (920 mg) were dissolved in DMF (15 ml). A solution of N,N-dicyclohexylcarbodiimide (1.35 9) in THF(15 ml) was added with stirring followed by 4-sec-butylaniline (1.04 ml). The mixture was stirred overnight at room temperature and then filtered to remove precipitated 25 solid. The filtrate was concentrated in a rotary evaporator and then partitioned between ethyl acetate and water. The organic phase was washed with 1 M HCI, aqueous sodium bicarbonate and with brine. Drying (MgSO4) and evaporation gave a crude solid that was purified by silica gel chromatography, eluting with ethyl acetate/hexane (1:1). Fractions having Rf 0.13 were combined and 30 evaporated to dryness giving 2(S)-hydroxy-N-(4-sec-butylphenyl)succinamic acid methyl ester as a white solid, 1.18 9 (70%), hpic/ms Rt 3.89 min. m/z 280.
2(S)-Hydroxy-N-(4-sec-butylphenyl)succinamic acid methyl ester (1.18 9) was dissolved in THE (20 ml) and 1 M NaOH (4.65 ml) was added. The solution was stirred for 2 hours at RT and monitored by hpic. The solution was then acidified by addition of 1M HCI (5 ml) and concentrated under vacuum. The 5 residue was partitioned between water and ethyl acetate and the organic phase washed with water, with brine and dried (MgSO4). Evaporation of solvent gave 2(S)-hydroxy-N-(4-sec-butylphenyl) succinamic acid as a yellow solid,1.13 9 (quantitative), hpic/ms Rt 3.69 min. m/z 266.
Intermediate 6: 4(S)-benzyl-3-(3-cyclopentyl-propionyl)-oxazolidin-2 1 0 one 4(S)-Benzyl-2-oxazolidinone (25 g, 0.14 mol) was dissolved in anhydrous THE under nitrogen and cooled to-78 C in an acetone/dry-ice bath. A 1.6M solution of n-butyl lithium in hexane (88 ml, 0.14 mol) was added to the stirred solution via a syringe during 30 minutes. 3cyclopentyl propionyl chloride 15 (23.5ml, 0.154mol) was added drop wise over 30 minutes via syringe. The resultant solution was stirred at -78 C for 1 hour, then allowed to warm to room temperature over 1 hour.
The reaction was quenched with saturated aqueous ammonium chloride (90 ml) and the organic solvents removed under reduced pressure. The 20 remaining slurry was extracted with dichloromethane (2 x 90 ml) and the combined extracts washed with 1 M sodium hydroxide solution ( 120 ml) and brine (120 ml). The solution was dried over magnesium sulphate, filtered, evaporated and the residue crystallized from cold hexane to give 4(S)benzyl-3-(3-
cyclopentyl-propionyl)-oxazolidin-2-one (37.2 9, 88%) as a white solid. TLC (1: 1 25 ethyl acetate/hexane) RF 0.62.
Intermediate 7: 4(S)-benzyl-3-(2(S)-cyclopentylmethyl-3(R)-hydroxy-
hex"-enoyl)-oxazolidin-2-one A solution of 4(S)-benzyl-3-(3-cyclopentylpropionyl)-oxazolidin-2-one (37 9' 0.12 mol) in anhydrous dichloromethane (260 ml) under nitrogen was stirred 30 and cooled to 0 C in an ice-bath. A 1 M solution of dibutyl boron trifluoromethane sulphonate (141 ml, 0.14 mol) in dichloromethane was added via syringe during 30 minutes, keeping the temperature below 3 C. The solution
was kept at 0 C for 10 minutes then treated drop wise with triethylamine (22 ml, 0.158 mol) keeping the temperature below 3 C. The solution was cooled to -70 C in an acetone/dry-ice bath and treated drop wise during 1 hour with but-2-
enal (10.93 ml, O.132 mol) keeping the temperature below 8 C. The reaction 5 mixture was kept below 8 C for 1 hour, then at 0 C for 1 hour. The reaction mixture was quenched with pH 7 phosphate buffer (120 ml) and methanol (400 ml). A2:1 mixture of methanol and 30% hydrogen peroxide (400 ml) was added drop wise over 90 minutes, keeping the temperature below 1 0 C, then left at this temperature for 1 hour. Organic solvents were removed under reduced pressure 10 and the remaining slurry extracted with diethyl ether (3 x 500 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate (500ml) and brine (500 ml), dried over magnesium sulphate, filtered and evaporated to give 4(S)-benzyl-3(2(S)-cyclopentylmethyl-3(R)-hydroxy-hex4-enoyl)-oxazolidin-2-
one (449, 98%) as an oil. TLC (7:3 hexane/ethyl acetate) RF 0.16.
15 Intermediate 8: 4S)-benzy1-343(R)-acetoxy-2(S)<yclopentylmethyl-hex 4enoyl)-oxazolidin-2-one A solution of 4(S)-benzyl-3-(2(S)cyclopentylmethyl-3(R)-hydroxy-hex4-
enoyl)-oxazolidin-2-one (44 9, 0.12 mol) in pyridine (500 ml) under nitrogen was treated with 4-dimethylamino-pyridine (1.46 9, 0.012 mol). The solution was 20 cooled in an ice-bath and treated drop wise with acetic anhydride (12.45 ml, 0.132 mol) maintaining a temperature below 5 C. The temperature was allowed to rise to room temperature and the mixture stirred for 2 hours. The reaction mixture was cooled in an icebath and a further portion of acetic anhydride ( 12.45 ml, 0.132 mol) added as previously. After stirring at room temperature for 25 1 hour, methanol (20 ml) was added cautiously and the mixture stirred for 2 hours. The mixture was concentrated under reduced pressure, the residue treated with a 2M aqueous solution of copper sulphate (100 ml) and extracted with ethyl acetate (3 x 200ml). The combined extracts were reduced in volume to 300 ml under reduced pressure and washed with water (20 ml), brine (20 ml), 30 dried over magnesium sulphate, filtered and evaporated. Flash chromatography of the residue on silica gel eluted with 4:1 hexane/ethyl acetate and concentration of the fractions under reduced pressure gave 4(S)benzyl-3-(3(R)
acetoxy-2(S)-cyclopentylmethyl-hex=-enoyl)-oxazolidin-2-one (48.89, 99%) as a viscous oil. TLC (1:1 ethyl acetate/hexane) RF 0.63.
Intermediate 9: 2(S)-acetoxy - -(4(S)-benzyl-2-oxo-oxazolidin-yl)-3(S) cyclopentylmethyl-oxo-butync acid 5 A solution of 4(S)-benzyl-3-(3(R)acetoxy-2(S)-cyclopentylmethyl-hex-4 enoyl)-oxazolidin-2-one (48 9, 0.118 mol) was dissolved in a 1:1 mixture of acetonitrile/carbon tetrachloride (400 ml) and cooled to 0 C in an ice-bath.
Ruthenium bichloride monohydrate (4.05 9, 0.018 mol) was added portionwise and the reaction mixture kept at 0 C for 10 minutes. A solution of sodium 10 periodate (49.2 9, 0.23 mol) in water (150 ml) was added drop wise over 90 minutes keeping the temperature below 1 0 C. The reaction mixture was stirred at O0C for 2 hours then warmed to room temperature during i hour. The mixture was cooled to 0 C and treated with a solution of sodium periodate (509, 0,234 mol) in water (150 ml) keeping the temperature below 10 C. After warming to 15 room temperature overnight, the reaction was quenched by the addition of isopropanol (5ml). Volatile solvents were removed under reduced pressure and the residue partitioned between ethyl acetate (1L) and water (600ml). The organic phase was washed with water (3 x 300 ml), dried over magnesium sulphate, filtered and concentrated in vacua to give 50 g of a dark oil. Flash 20 chromatography on silica gel elated with 3% methanol/dichloromethane gave 2(S)-acetoxy-4-(4(S)-benzyl-2-oxo-oxazolidin-3-yl)-3(S)cyclopentylmethyl-4 oxo-butyric acid (20.79, 42%) as a viscous oil. TLC (10% methanol/dichloromethane) RF 0.15.
Intermediate 10: 2(S)-acetoxy-444(S)-benzyl -2-oxo-oxazolidin-3-yl)-3(S) 25 cyclopentylmethyl - -oxo-butyric acid tert-butyl ester A solution of 2, 2,2-trichloro-acetimidic acid tet-butyl ester (10 ml, 0.056 mol) in hexane (200 ml) was added drop wise to a stirred solution of 2(S) acetoxy4-(4(S)-benzyl-2-oxo-oxazolidin-3-yl)-3(S)-cyclopentylmethyl-4-oxo butyric acid (10 g, 0.024 mol) in dichloromethane (100 ml) and the mixture stirred 30 at room temperature for go minutes. The mixture was cooled in an ice-bath and diluted with hexane (400 ml). The suspension was filtered and the filtrate concentrated under reduced pressure. Flash chromatography of the residue on
silica gel eluted with a gradient of 15% ethyl acetate/hexane to 40 /O ethyl acetate/hexane gave 2(S)-acetoxy4-(4(S)-benzyl-2-oxo-oxazolidin-3yl)-3(S)-
cyclopentylmethyl=-oxo-butyric acid tert-butyl ester (10.14 9, 89%) as a pale yellow oil.
5 Intermediate 11: 2(S)-cyclopentylmethyl-3(S)-hydroxy-succinic acid 4-
tert-butyl ester A stirred solution of 2(S)-acetoxy4-(4(S)-benzyl-2-oxooxazolidin-3-yl)-
3(S)-cyclopentylmethyl4-oxo-butyricacid tert-butyl ester(10g,0.021 mol) in 4:1 tetrahydrofuran/water (125 ml) was treated with 30% aqueous hydrogen peroxide 10 (9 ml, 0.097 mol) and a solution of lithium hydroxide (27 9, 1.12 mol) in water (100 ml). The mixture was stirred for 75 minutes then treated with 30% aqueous hydrogen peroxide (4.5 ml, 0.048 mol) and stirred for a further 30 minutes.
Sodium sulphite (20 9, 0.195 mol) in water (100 ml) was added and the tetrahydrofuran removed under reduced pressure. The aqueous solution was 15 washed with dichloromethane (3 x 80 ml) and the combined dichloromethane extracts back extracted with 5% aqueous lithium hydroxide (2 x 50 ml). All aqueous fractions were combined, acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (4 x 80 ml). The ethyl acetate fractions were concentrated under reduced pressure and passed through a silica 20 gel plug in 2:3 ethyl acetate/hexane. Evaporation of the filtrate gave 2(S) cyclopentylmethyl-3(S)-hydroxysuccinic acid 4-tert-butyl ester (1.839,32%) as a white solid. m/z (negative ion mode) 271 (M-H).
Example 1: N'-benzol1,3]dioxol-5-ylmethyl-N4-(4-butyl-phenyl)-2(S) hydroxy succinamide 25 To a solution of N-Benzol1,3]dioxol-5-ylmethyl-3(S) -hydroxy-succinamic acid (0.05 mmol) in DMF (0.1 ml) was added a solution of 4-n-butylaniline (0.055 mmol) in DMF (0.11 ml)and a solution of PyBOP (0.075 mmol) in DMF (0.15 ml).
DIEA (0.15 mmoles) was added and the reaction mixture was allowed to stand overnight at room temperature.
30 The reaction mixture was diluted with a saturated solution of sodium bicarbonate (0.5 ml) and extracted with dichloromethane (1 ml). The aqueous phase was diluted with water (0.5 ml) and extracted again with dichloromethane
(0.5 ml). The crude product obtained from this extract was purified by preparative hpic (see methods) to give N'-benzo[1,3]dioxol-5-ylmethyl-N4(4 butyl-phenyl)-2(S)-hydroxy succinamide, 2.2 mg (11%), hpic/ms Rt 4.42 min. m/z 399. 5 The N-benzo[1,3]dioxol-5-ylmethyl-3(S)-hydroxysuccinamicacid used as the starting material was prepared as follows (Ref: P Lorenz et a/, J prakt Chem, 1998, 340, 733):
(S)-malic acid (1.34 g) was added portionwise to trifluoroacetic anhydride (12 ml) with cooling in an ice bath. The mixture was then stirred at 0 C for 2.5 10 hours and then evaporated to dryness giving a white solid that was dried under vacuum. The solid was redissolved in dioxan (20 ml), cooled in an ice bath and a solution of N-benzo[1, 3ldioxol-5-ylmethylamine (3.32 g) in dioxan (10 ml) was added dropwise with stirring. The reaction was then allowed to warm to room 15 temperature overnight.
The reaction mixture was evaporated to dryness and the residue chromatographed on silica gel eluting with ethyl acetate/hexane, ethyl acetate, and ethyl acetate/methanol. N-Benzo[1,3]dioxol-5-ylmethyl-3(S)hydroxy succinamic acid was obtained as an orange solid, 1.4 g (52%), hpic/ms Rt 3.01 20 min. m/z 267.
Example 2: N4-(4-benzylOxy-phenyl)-2(S)-hydroxy-N'-t2(S)-methyl-1(S)-(4 nitro-phenylcarbamoyl)-butyl]-succinamide A DMF solution of 2(S)-hydroxyN-(4-benzyloxyphenyl)succinamic acid (0.05 mmol) and iso-leucine pnitroanilide (0.055 mmol) was treated with PyBOP 25 and DIEA as described in Example 1.
Workup and purification by preparative hpic gave N4-(4-benzyloxy phenyl)2(S)-hydroxy-N'-[2(S)-methyl-1 (S)-(4-nitro-phenylcarbamoyl)-butyll succinamide, 5.3 mg (19%), hpic/ms Rt 4.70 min. mIz 549.
Example 3: 2(S)-hydroxy-N'-12(S)-methyl-1(S)-(4-nitro-phenyl-carbamoyl) 30 butyl]-N4-(4-pentylaxy-phenyl)-succinamide A DMF solution of 2(S)hydroxy-N-(4-pentyloxyphenyl)succinamic acid (0.05 mmol) and iso-leucine p-nitroanilide (0.055 mmol) was treated with PyBOP
and DIEA as described in Example 1. Workup and purification by preparative hpic gave 2(S)-hydroxy-N'-[2(S)-methyl-1 (S)-(4-nitrophenylcarbamoyl)-butyl] N4-(4-pentyloxy-phenyl)-succinamide, 6.6 mg (25%), hpic/ms Rt 4.93 min. m/z 529. 5 Example 4: N4-(4-benzyloxy-phenyl)-2(S)hydroxy-N'-t3-methylSulphanyl 1(S)-(naphthalene-2-ylcarbamoyl)-propyllsuccinamide A DMF solution of 2(S)-hydroxy-N-(4-benzyloxyphenyl) succinamic acid (0.05 mmol), prepared as in Intermediate 1, and Lmethionine beta naphthylamide (0.055 mmol) was treated with PyBOP and DIEA as described in 10 Example 1. Workup and purification by preparative hpic gave N4-(4-benzyloxy phenyl)-2(S)-hydroxy-N'-[3-methylsulphanyl-1 (S) -(naphthalene-2-ylcarbamoyl) propyl]-succinamide, 5.6 mg (19%), hpic/ms Rt 4.76 min. m/z 572.
Example 5: 2(SJ-hydroxy-N4-(1(R/S)-methyl-hexyl)-N'-l3-methylSulphanyl.
1 (S)-(naphthalene-2-ylcarbamoyl)-propyll-succinamide 15 A DMF solution of 2(S)-hydroxy-N-(1(R]S)-methylhexyl)succinamic acid (0.05 mmol) and Lmethionine beta-naphthylamide (0.055 mmol) was treated with PyBOP and DIEA as described in Example 1. Workup and purification by preparative hpic gave 2(S)-hydroxy-N4-(1 (R/S)-methyl-hexyl)-N'-[3 methylsulphanyl-1 (S)-(naphthalene-2-ylcarbamoyl)-propyl]-succinamide, 9.6 mg 20 (39%), hpic/ms Rt 4.77 min. m/z 488.
Example 6: N4(4-benzyloxy-phenyl)-N'-[(R/S)-(4-chloro-phenyl)-phenyl methyl]-2(S)-hydroxy-succinamide A DMF solution of 2(S)-hydroxy-N-(4benzyloxyphenyl)succinamic acid (0.05 mmol), prepared as in Intermediate 1, and 4-chlorobenzhydrylamine 25 hydrochloride (0.055 mmol) was treated with PyBOP and DIEA as described in Example 1. Workup and purification by preparative hpic gave N4-(4-benzyloxy phenyl)-N1-[(RJS)-(4-chloro-phenyl)phenyl-methyl]-2(S)-hydroxy-succinamide, 5.9 mg (23%), hpic/ms Rt 4.92 min. m/z 515.
Example7: {4-t3-(4-benzyl-phenylcarbamoyl)-2(S)-hydroxy propionylaminolbutyl}-carbamic acid benzyl ester A DMF solution of 2( S)hydroxy-N-(4-benzylphenyl)succinamic acid (0.05 mmol) and Nbenzyloxycarbonyl-1,4-diaminobutane hydrochloride (0.055 mmol) 5 was treated with PyBOP and DIEA as described in Example 1. Workup and purification by preparative hpic gave the amide, 1.2 mg (4%), hpic/ms Rt 4.36 min. m/z 504.
Example 8: {4-[3-(4-sec-butyl-phenylcarbamoyl)-2(S)-hydroxy propionylaminolbutyl}-carbamic acid benzyl ester 10 A DMF solution of 2(S) -hydroxy-N-(4-sec-butylphenyl)succinamic acid (0.05 mmol) and Nbenzyloxycarbonyl-1,4-diaminobutane hydrochloride (0.055 mmol) was treated with PyBOP and DIEA as described in Example 1. Workup and purification by preparative hpic gave {4-[3-(4-sec-Butyl-phenylcarbamoyl) 2(S)-hydroxy-propionylamino]-butyl}-carbamic acid benzyl ester, 10.5 mg (44%), 15 hpic/ms Rt 4.38 min. m/z 470.
Examples: N4-l(4-chloro-phenyl)-phenyl-methyl]-N'-(1(S) cyclohexylcarbamoyl-2-phenylthyl)-2(S)-cyclopentylmethyl 3(S)-hydroxysuccinamide A solution of N-(1-cyclohexylcarbamoyl-2-phenyl-ethyl)-3 20 cyclopentylmethyl-2-hydroxy-succinamic acid (21 mg, 0.047 mmol) in dichloromethane (0.5 ml) under nitrogen was treated with 4-chloro benzhydrylamine hydrochloride (18 mg, 0.07 mmol). N-ethyl morpholine (27, ul, 0.21 mmol), HOST (6.4 mg, 0.047 mmol) and EDC (13.6 me, 0.07 mmol) were added and the mixture stirred at room temperature overnight. The reaction 25 mixture was diluted with dichloromethane (2 ml) and washed with 1M hydrochloric acid (3 ml), brine (2 ml) then passed through a hydrophobic frit.
Purification by preparative hpic gave N4-[(4-chloro-phenyl)-phenyl-methyl] -N' (1 (S)-cyclohexylcarbamoyl-2-phenyl-ethyl)-2(S)-cyclopentylmethyl-3tS) -hydroxy succinamide (11 mg, 37%) as a white solid. Hpicims Rt 5.24 min, m/z 644 (M+t 1).
30 The N-(1-cyclohexylcarbamoyl-2-phenyi-ethyl)-3-cyclopentylmethyl-2 hydroxy-succinamic acid used as starting material was prepared as follows:
2(S)-cyclopentylmethyl-3(S)-hydroxy-succinic acid 4-tert-butyl ester (Intermediate 11,125 mg, 0.46 mmol) was dissolved in dichloromethane (2 ml) and treated with (S)-phenylalanine cyclohexylamide (170 mg, 0.69 mmol) under nitrogen. N-ethyl morpholine (145,ul, 1.14mmol), HOST (68 mg, 0.5 mmol) and 5 EDC (100 mg, 0.5 mmol) were added and the reaction mixture stirred at room temperature overnight. The solution was diluted with dichloromethane (3 ml) and washed with 1M hydrochloric acid (3 ml), brine (3 ml), dried over sodium sulphate, filtered and evaporated. The residue was subjected to flash chromatography on silica gel elating with 2:3 ethyl acetate/hexane and product 10 containing fractions evaporated to give N-(1-cyclohexylcarbamoyl-2-phenyl ethyl)-3-cyclopentylmethyl-2hydroxy-succinamic acid fort butyl ester (163 mg, 71 %) as a white solid.
The N-(1-cyclohexylcarbamoyl-2-phenyl-ethyl)-3-cyclopentylmethyl-2 hydroxy-succinamic acid test butyl ester (160 mg, 0.32 mmol) was stirred in 15 trifluoroacetic acid (2.5 ml) at 0 C under nitrogen for 2 hours. Solvent was evaporated under reduced pressure and the residue reevaporated with toluene (10 ml). The residue was subjected to flash chromatography on silica gel eluting first with 1:1 ethyl acetate/hexane, then with ethyl acetate. Product containing fractions were evaporated to give N-(1-cyclohexylcarbamoyl-2-phenyl-ethyl)-3 20 cyclopentylmethyl-2hydroxy-succinamic acid (131 mg, 92%) as a white solid.
Example 10:2(R)-[3(1-benzylaxycarbonyl-ethylcarbamoyl)-2(S) cyclopentylmethyl-3(S)-hydroxy-propionylaminol(4-chloro phenyl)-propionic acid methyl ester In a manner analogous to Example 9, starting from N-[2(4-chloro-phenyl) 25 1-methoxycarbonyi-ethyl]-3-cyclopentylmethyl-2hydroxy-succinamic acid (27 my, 0.066 mmol) and (S)-alanine benzyl ester hydrochloride (21.2 mg, 0.098mmol) were obtained 2(R)-[3-(1 benzyloxycarbonyl-ethylcarbamoyl)-2(S) cyclopentylmethyl-3(S)-hydroxypropionylamino]-3-(4-chloro-phenyl)-propionic acid methyl ester (1 9.3mg, 51 %) as a white solid. Hpic/ms Rt 4.75 min. m/z 573 30 (M+H)
The N-[2-(4<hloro-phenyl)-1-methoxycarbonyl-ethyl]cyclopentylmethyl 2hydroxy-succinamic acid used as starting material was prepared as in Example
9 replacing (S)-phenylalanine cyclohexylamide with (R)4-chlorophenylalanine methyl ester.
ExamnIe 11: 2(S)-{4-cyclopentyl-2(S)-hydroxy-3(S)-[(5-methyl-3-phenyl isoxazol-ylmethyl)<arbamoyl]-butyrylamino}-propionic acid 5 benzyl ester In a manner analogous to Example 9, starting from 3-cyclopentylmethyl-2 hydroxy-N-(5-methyl-3-phenyl-isoxazol=-ylmethyl)-succinamic acid (20mg, 0. 052 mmol) and (S)-alanine benzyl ester hydrochloride (16.7 mg, 0.078 mmol) were obtained 2(S)-{4-cyclopentyl-2(S)-hydroxy-3(S)-l(5-methyl-3-phenyl 10 isoxazol4-ylmethyl) carbamoyl]-butyrylamino}-propionicacid benzyl ester(16.6 mg, 58%) as a white solid. Hpic/ms Rt 4.51 min' m/z 548 (M+H).
The 3-cyclopentylmethyl-2-hydroxy-N-(5-methyl-3-phenyl-isoxazol4 ylmethyl) -succinamic acid used as starting material was prepared as in Example 9 replacing (S)-phenylalanine cyclohexylamide with 5-methyl-3-phenylisoxazol 1 5 4-yl-methylamine.
ExamnIe 12: activity assay The compounds of Examples 1 to 11 were tested for their inhibitory activity towards BACK.
All enzyme assays were performed at 20 C on an AlphaFusion (Packard 20 Instruments) using 384 well plates (Greiner Bio-One Ltd). The assay volume was 30,ul. Inhibitors were dissolved in dimethyl sulphoxide (DMSO) and added into a well with 50 mM sodium acetate buffer pH 4.5 and 10 M EDANS EVNLDAEFK-DABCYL peptide substrate. The DMSO concentration was set at 10% in the assay.
25 The reaction was started with the addition of 1 g/ml recombinant human soluble BACK-1. After 3 hours the fluorescence increase was measured in the plate reader at 365ex/485em. The EDANS-DABCYL peptide substrate becomes slightly fluorescent upon enzymatic cleavage due to disruption of the resonance energy transfer between the EDANS donor and DABCYL quenching acceptor in 30 the intact substrate.
The activities (ICso values in,uM) of the Example compounds are shown in Table 1.
Table 1
_ Example IC50 (pM) 1 162
5 2 82
3 95 4 73 5 103
6 73 10 7 75
8 102
9 44 10 50
11 _ 48
The results show that Compounds of the invention have a desirable inhibitory activity to BACK.
Claims (14)
1. A compound of formula (I) OH O R2'N jJN'Ri (1) O R wherein R' is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, any of which is optionally substituted with R4 15 R2 is alkyl, alkenyl, alkoxy or alkylthio, any of which is optionally substituted with R5; R3 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocyctoalkenyl, aryl or heteroaryl, any of which is optionally substituted with R6. 20 each R4 is the same or different and is alkyl, alkenyl, alkoxy, aryl, -alkyl aryl, -alkoxy-aryl, -C(O)O- or-C(O)NH-R6; each R5 is the same or different and is alkylthio, aryl, heteroaryl, -NHC(0) R6, -NHC(0)0-R6, -C(0)NH-R6, -C(0)0-R6 or heteroaryl-aryl; each R6 is the same or different and is alkyl, alkenyl, cycloalkyl, 25 cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl or-alkyl-aryl; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R' is alkyl, -aryl-alkyl, aryl alkoxy, -aryl-alkyl-aryl, -aryl-alkoxy-aryl, -CH(aryl), or-alkyl-C(O) O-alkyl-aryl.
3. A compound according to claim 2, wherein R' is 4-butylphenyl, 30 4benzyloxyphenyl, 4-pentoxyphenyl, hept-2-yl, 4-benzylphenyl, 4-(but-2-yl) phenyl, (4-chlorophenyl)-phenyl-methyl or 1-benzyloxycarbonyl-ethyl.
4. A compound according to any preceding claim, wherein R2 is -alkyl-aryl, -alkyl-C(O)NH-aryl, -alkyl(alkylthio)-C(O)NH-aryl, -CH(aryl)2, -alkylNHC(O)O-
alkyl-aryl, -alkyl(aryl)-C(O)NFI-cycloalkyl, -alkyl(aryl)C(O)O-alkyl or alkyl-
heteroaryl -aryl.
5 5. A compound according to claim 4, wherein RZ is 1-(naphth-2-yl-
carbamoyl)-3-th iomethylpropyl, 1 4(4-nitrophenyl)-carbamoyl]-2methylbutyl, benzol1,3]dioxol--yl-methyl, N-(benzyloxycarbonyl)butylamino, 1-
cyclohexylcarbamoyl-2-phenyl-ethyl, 3-(4-chlorophenyl)-propionic acid or 5-
methyl-3-phenyl-isoxazol-4-ylmethyl. 10
6. A compound according to any preceding claim, wherein R3 is hydrogen, alkyl or-alkyl-cycloalkyl.
7. A compound according to claim 6, wherein R3 is hydrogen.
8. A compound according to claim 6, wherein R3 is cyclopentylmethyl.
9. A compound according to claim 1, selected from 15. N -benzo[ 1, 3] dioxol-5-ylmethyl-N4-(4-butyl-phenyl)-2 ( S)-hydroxy succinamide; N4-(4benzyloxy-phenyl)-2(S)-hydroxy-N'-l2(S)-methyl-1 (S)-(4-nitro phenylcarbamoyl)-butyl]-succinamide; 2(S)-hydroxy-N'-[2(S)-methyl-1 (S)(4-nitro-phenylcarbamoyl)-butyl]-N4-(4 20 pentyloxy-phenyl)-succinamide; N4-(4-benzyloxy-phenyl)-2(S)-hydroxy-N'-I3-methylsulphanyl-1 (S) (naphthalene-2-ylcarbamoyl)-propyl]-succinamide; 2(S)-hydroxy-N4-(1 (R/S)methyl-hexyl)-N'-[3-methylsulphanyl-1 (S) (naphthalene-2-ylcarbamoyl)propyl]-succinamide; 25 N4-(4-benzyloxy-phenyl)-N'-[(R/S)-(4-chlorophenyl)-phenyl-methyl]-2(S) hydroxy-succinamide; {4-[3-(4-benzylphenylcarbamoyl)-2(S)-hydroxy-propionylamino]-butyl} carbamic acid benzyl ester; {4-[3-(4-sec-butyl-phenylcarbamoyl)-2(S)-hydroxy-propionylamino]butylY 30 carbamic acid benzyl ester.
N4-[(4-chloro-phenyl)-phenyl-methyl]-N'-(1 (S)-cyclohexylcarbamoyl-2 phenyl-ethyl)-2(S)-cyclopentylmethyl-3(S)-hydroxy-succinamide;
2(R)-[3-( 1 -benzylOxycarbonyl-ethylcarbamoyl)-2(S)-cyclopentylmethyl-
3(S)-hydroxy-propionylamino]-3-(4-chloro-phenyl)-propionic acid methyl ester; and 2(S)14-cyclopentyl-2(S)-hydroxy-3(S)-[(5-methyl-3-phenylisoxazol -
5 ylmethyl)-carbamoyll-butyrylamino}-propionic acid benzyl ester.
10. A compound according to any preceding claim, which is in the form of a single enantiomer or diastereomer.
11. A compound according to any preceding claim, for therapeutic use.
12. A pharmaceutical composition comprising a compound of any of claims 10 1 to 10 and a pharmaceutically acceptable carrier or diluent.
13. Use of a compound of any of claims 1 to 10, for the manufacture of a medicament for the treatment or prevention of a disease or condition associated with the deposition and/or elevated levels of amyloid beta peptide (Ap).
14. Use according to claim 13, for the manufacture of a medicament for the 15 treatment of Alzheimer's disease.
-
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| GBGB0218031.3A GB0218031D0 (en) | 2002-08-02 | 2002-08-02 | Compounds and their use |
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| GB0317864A Withdrawn GB2391547A (en) | 2002-08-02 | 2003-07-30 | Hydroxy-succinamide compounds for the treatment of alzheimer's disease |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006088694A1 (en) * | 2005-02-14 | 2006-08-24 | Wyeth | SUBSTITUTED THIENYL AND FURYL ACYLGUANIDINES AS β-SECRETASE MODULATORS |
| US8256089B2 (en) | 2005-07-05 | 2012-09-04 | Saipem S.A. | Method of covering inside surface of steel connection part |
-
2002
- 2002-08-02 GB GBGB0218031.3A patent/GB0218031D0/en not_active Ceased
-
2003
- 2003-07-30 GB GB0317864A patent/GB2391547A/en not_active Withdrawn
Non-Patent Citations (7)
| Title |
|---|
| Eur. J. Med. Chem., 1994, Vol.29(9), Langlois et al., pp.639-647. See whole document and CAS Abstract 122:161321. * |
| Helvetica Chimica Acta, 1961, Vol.44, Hardegger et al., pp.1413-1417. See whole document and CAS Abstract No.56:31318. * |
| JP 09286768 (FUJISAWA PHARMA) See whole document and CAS Abstract No.127:359520. * |
| JP 09286768 (FUJISAWA PHARMA) See whole document and CAS Abstract No.127:359520.:256686. * |
| Tet. Lett., 1995, Vol.36(47), Cousins et al., pp.8689-8692. See whole document and CAS Abstract No.124:176663. * |
| US 4782005 (EKLUND et al.) See whole document and CAS Abstract No.110:145029. * |
| US 6413914 (MEIER et al.) See whole document and CAS Abstract No.137:429994. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006088694A1 (en) * | 2005-02-14 | 2006-08-24 | Wyeth | SUBSTITUTED THIENYL AND FURYL ACYLGUANIDINES AS β-SECRETASE MODULATORS |
| US8256089B2 (en) | 2005-07-05 | 2012-09-04 | Saipem S.A. | Method of covering inside surface of steel connection part |
Also Published As
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| GB0218031D0 (en) | 2002-09-11 |
| GB0317864D0 (en) | 2003-09-03 |
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