Hydrazine derivatives

专利摘要:
The hydrazine derivatives of formula (I), or pharmaceutically acceptable salts thereof, inhibit the release of tumor necrosis factor (TNF-a) and transforming growth factor (TGF-a) from cells as well as keratinocyte proliferation : Formula I In this formula, Y signifies CO or SO 2 ; R 1 means lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl; R 2 means lower alkyl, halo-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl or aryl when Y signifies SO 2 and lower alkyl, halo-lower alkyl, lower alkoxy, lower alkoxycarbonyl, acyl, lower cycloalkyl, aryl, aryl-lower alkyl, aryl-represents lower alkoxy or NR 5 R 6, and; R 3 is hydrogen, Lower alkyl substituted or unsubstituted with cyano, amino, hydroxy, lower alkoxy, lower alkoxycarbonyl, heterocyclyl or heterocyclylcarbonyl, Lower alkenyl, lower alkynyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl, aryl or heterocyclyl; or R 2 and R 3 together form a moiety of a 5-, 6- or 7-membered cyclic amide, cyclic imide, cyclic sulfonamide or cyclic urethane group; R 4 is lower alkyl, hydroxy-lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or aryl formula X-, X- heteroaryl or - (CH 2) 1-2 -CH = CR 7 > R < 8 & gt ;; X represents a spacer group; R 5 and R 6 are each independently hydrogen, lower alkyl or aryl-lower alkyl; R 7 and R 8 together represent a lower alkylene group in which one methylene group is substituted or unsubstituted by a hetero atom. They are particularly useful as medicaments for the treatment of inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis.
公开号:KR20010014331A
申请号:KR1019997012477
申请日:1998-06-18
公开日:2001-02-26
发明作者:브로드허스트마이클존；존슨윌리암헨리；월터데릴시몬
申请人:프리돌린 클라우스너, 롤란드 비. 보레르；에프. 호프만-라 로슈 아게；
IPC主号:

专利说明:

[0001] HYDRAZINE DERIVATIVES [0002]
The present invention relates to novel hydrazine derivatives, a process for their preparation and medicaments containing them. The invention also relates to pharmaceuticals and the use of these derivatives for the manufacture of medicaments.
The novel hydrazine derivatives provided by the present invention are compounds of the general formula (I)
In this formula,
Y signifies CO or SO ₂ ;
R ¹ means lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl;
R ² means lower alkyl, halo-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl or aryl when Y signifies SO ₂ and lower alkyl, halo-lower alkyl, lower alkoxy, lower alkoxycarbonyl, acyl, lower cycloalkyl, aryl, aryl-lower alkyl, aryl-represents lower alkoxy or NR ⁵ R ^6, and;
R ³ is hydrogen,
Lower alkyl substituted or unsubstituted with cyano, amino, hydroxy, lower alkoxy, lower alkoxycarbonyl, heterocyclyl or heterocyclylcarbonyl,
Lower alkenyl, lower alkynyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl, aryl or heterocyclyl; or
R ² and R ³ together form a moiety of a 5-, 6- or 7-membered cyclic amide, cyclic imide, cyclic sulfonamide or cyclic urethane group;
R ⁴ is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a group of the general formula X-aryl, X-heteroaryl or - (CH ₂ ) _1-2 -CH = CR ⁷ R ⁸ Means;
X represents a spacer group;
R ⁵ and R ⁶ are each independently hydrogen, lower alkyl or aryl-lower alkyl;
R ⁷ and R ⁸ together represent a lower alkylene group in which one methylene group is substituted or unsubstituted by a hetero atom.
The hydrazine derivatives provided by the present invention are inhibitors of tumor necrosis factor (TNF-a) and transforming growth factor (TGF-a) release from cells. They also inhibit the proliferation of keratinocytes. Therefore, the hydrazine derivatives of the present invention can be used as medicines especially for the treatment of inflammation, fever, bleeding, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis and psoriasis.
In contrast to the structurally related hydroxamic acid derivatives, the hydrazine derivatives provided by the present invention are useful for the matrix metalloproteinase (MMP) classes of enzymes, such as collagenase, stromelysin and gelatinase But exhibit only mild inhibitory activity.
The term "lower alkyl" as used herein, alone or in combination, such as, for example, in "halo-lower alkyl" and "lower cycloalkyl-lower alkyl" Butyl, tert-butyl, n-pentyl, and n-pentyl, each of which is optionally substituted with one or more halogen atoms, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, - means hexyl. Trifluoromethyl is an example of a halo-lower alkyl group.
The term " lower alkoxy ", alone or in combination, such as in " lower alkoxycarbonyl ", refers to lower alkyl groups as defined above linked by an oxygen atom such as methoxy, ethoxy, n-propoxy , Isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Methoxycarbonyl, ethoxycarbonyl and the like are examples of a lower alkoxycarbonyl group.
The term " lower cycloalkyl ", alone or in combination, as in " lower cycloalkyl-lower alkyl ", refers to a cycloalkyl group containing from 3 to 7 carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl, Cycloheptyl. Cyclopropylmethyl, 2-cyclobutyl-ethyl and 3-cyclohexyl-propyl are examples of lower cycloalkyl-lower alkyl groups.
The term " lower alkenyl ", alone or in combination, as in " aryl-lower alkenyl ", means alkenyl groups containing from 2 to 7 carbon atoms such as allyl, vinyl and butenyl, &Quot; Lower alkynyl " means an alkynyl group containing from 2 to 7 carbon atoms, for example, propargyl or butynyl.
The term " lower alkylene " means an alkylene group containing from 2 to 6 carbon atoms, such as dimethylene, trimethylene, tetramethylene, and the like. Thus, R ⁷ and R ⁸ together with the carbon atoms to which they are attached may represent, for example, cyclopentane, cyclohexane or tetrahydropyranyl ring.
The term " acyl " denotes an acyl group derived from a lower alkanecarboxylic acid, i.e., from an alkanecarboxylic acid containing up to 6 carbon atoms, or from an aromatic carboxylic acid. Examples of the acyl group include acetyl, propionyl, butyryl, isobutyryl, pivaloyl, benzoyl, p-chlorobenzoyl and the like.
The term " aryl " refers to phenyl or naphthyl substituted or unsubstituted by halogen, i. E. Fluorine, chlorine, bromine or iodine, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, lower alkoxycarbonyl, Means, for example, phenyl, 1-naphthyl, 2-methylphenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 4-nitrophenyl and 4-methoxycarbonylphenyl. Benzyl, 4-chlorobenzyl, 4-bromobenzyl, 3-hydroxybenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-phenylethyl, Is a typical example of a group, and benzyloxy, 4-chloro-benzyloxy and 4-nitro-benzyloxy are typical examples of aryl-lower alkoxy groups. 2-phenylvinyl and 3-phenylallyl are examples of aryl-lower alkenyl groups.
The term " heterocyclyl " refers to a monocyclic or bicyclic heterocycle which is bound by a C atom or a secondary N atom (i.e., -NH-) and contains one or more heteroatoms selected from nitrogen, sulfur and oxygen, Means a 4-, 5- or 6-membered saturated or partially unsaturated, or 5- or 6-membered aromatic heterocyclic group optionally substituted with alkoxy and / or oxo and / or optionally benz-fused . Examples of heterocyclyl groups include pyrrolidinyl, pyrrolinyl, pyrazolinyl, piperidinyl, morpholinyl, thiamorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, furyl, thienyl, thiazolyl , Oxazolyl, isoxazolyl, oxetanyl, imidazolidinyl, dioxolanyl, pyrrolyl, pyridyl, pyrimidinyl, benzofuranyl, benzothienyl, benzthiazolyl, indolyl, isoindolyl, Quinolyl and isoquinolyl.
The term " heterocyclylcarbonyl " means a heterocyclyl group as defined above which is attached to C (O) by a secondary N atom. Morpholinocarbonyl is a typical example of the above-mentioned heterocyclylcarbonyl group.
The term " heteroaryl " means an aromatic heterocyclic group in the definition of " heterocyclyl ".
The cyclic amide, imide, sulfonamide or urethane group formed by R ² , R ³ and the atoms to which they are bonded, that is, the C or S atom of Y and the N atom, respectively, (a) to (g) wherein n represents 3, 4 or 5 and R ^a and R ^b together form the remaining part of the aromatic or cycloalkane ring.

A preferred spacer group represented by X of the general formula _{- (CH 2) 1-5 -,} -CH 2 -CH = CH-, -CH 2 -C≡C-, -CH 2 NHCO-, - (CH 2) 1 _{or 2 NHCONH-, - (CH 2)} 1-5 -S-, especially _{-CH 2 S-, -CH 2 NHSO 2} -, -CH 2 NHCH 2 -, - (CH 2) 1-5 -O-, - O- (CH _{2) 1-5} - and a group of -S-.
The compounds of formula I form pharmaceutically acceptable salts with bases such as alkali metal hydroxides, for example sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides, for example, calcium hydroxide, barium hydroxide and magnesium hydroxide. The compounds of formula I which are basic can be prepared by reacting a compound of formula I with an inorganic acid such as hydrohalic acid such as hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as acetic acid, tartaric acid, succinic acid, fumaric acid, , Salicylic acid, citric acid, methanesulfonic acid and p-toluenesulfonic acid with pharmaceutically acceptable salts.
Although the formulas shown herein depict each compound in its absolute stereochemistry, it will be appreciated that the present invention encompasses the stereoisomer as well as the corresponding racemate and diastereomer mixture. Furthermore, when the spacer group represented by X contains an olefinic double bond such as in -CH ₂ -CH = CH-, the spacer group has a structure of (E) or (Z), preferably a structure of .
Preferred compounds of formula I are those wherein Y signifies CO, R ² signifies lower alkoxy, in particular methoxy, or Y signifies SO ₂ and R ² signifies lower alkyl, in particular methyl. R ¹ preferably means lower alkyl, especially isobutyl. R ³ preferably means lower alkyl, especially isobutyl or 2-methylbutyl, lower alkenyl, especially 2-methylallyl, aryl-lower alkyl, especially unsubstituted benzyl or aryl, especially unsubstituted phenyl. R ⁴ preferably means a group of the formula X-aryl, especially when X means a spacer group of the general formula -CH ₂ -CH = CH- and aryl means an unsubstituted phenyl.
Particularly preferred compounds of formula (I) are:
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-( methanesulfonyl) Valero hydrazide;
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- Lohia Drazide;
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- (S) -methylbutyl) valerohydrazide;
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - methylallyl) valerohydrazide; And
Methyl (E) -3- [2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutylcarbazate .
According to the process provided by the present invention, the protecting group represented by R < ⁹ > is isolated from the compound of formula (II) and, if desired, converting the obtained compound of formula (I) into a pharmaceutically acceptable salt, Derivatives are prepared:
In this formula,
Y, R ¹ , R ² , R ³ and R ⁴ have the meanings indicated above,
R ⁹ means a protecting group.
The protecting group represented by R < ⁹ > in the compound of formula (II) may be any conventional protecting group, but is preferably tetrahydropyranyl, 4-methoxybenzyl, benzyl or tri Dimethylsilyl.
The separation of the protecting group represented by R ⁹ from the compound of formula (II) is carried out according to a method known per se. For example, the tetrahydropyranyl group can be isolated by treatment with a lower alkanol, e.g., a sulfonic acid such as methanesulfonic acid or p-toluenesulfonic acid in methanol. Separation of the 4-methoxybenzyl group can be carried out, for example, using trifluoroacetic acid. Benzyl protecting groups can be separated using a catalyst, for example, in the presence of palladium and hydrogenolysis in a lower alkanol, e.g., methanol. The tri (lower alkyl) silyl protecting group can be separated using water or low pH; The separation typically takes place in the preparation of each compound of formula II (i.e., separation takes place in situ) from the medium in which the compound of formula II is prepared.
The conversion of the obtained compound of formula I into a pharmaceutically acceptable salt is effected by treatment with a suitable acid or base in a known manner.
The compounds of formula (II) used as starting materials in the process described above are novel and are another object of the present invention. These are exemplified in the following reaction scheme (wherein Y, R ¹ , R ² , R ³ , R ⁴ and R ⁹ have the meaning indicated above, ^t Bu means tert-butyl and Me means methyl) And the like.
In relation to Scheme A, in a first step, the compound of formula (III) is condensed with a hydrazine of formula (IV) or a substituted hydrazine to give a hydrazide of formula (V). The condensation is carried out under known conditions of the peptide coupling reaction and in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, coupling reagents known per se for the coupling, For example, 1-hydroxybenzotriazole.
The hydrazide of formula (V) is then reacted with a chloride of formula (VI) or anhydride of formula (VII) to give a compound of formula (VIII). The reaction is carried out in a known manner, for example, in an organic solvent which is inert under the reaction conditions and in the presence of an organic base at about 0 ° C to about room temperature. Suitable solvents are halogenated hydrocarbons, for example dichloromethane. Examples of organic bases which can be used are tri (lower alkyl) amines, such as triethylamine, pyridine, 4-dimethylaminopyridine and the like. When the base is a liquid under the reaction conditions, the base can be used in excess and in this case can serve as the sole solvent.
Then, in the next step, the compound of formula VIII is deprotected with trifluoroacetic acid (TFA) to give the carboxylic acid of formula IX. The deprotection is carried out in a manner known per se, for example, in an organic solvent which is inert under the reaction conditions, for example at about room temperature, for example in halogenated hydrocarbons such as dichloromethane.
Finally, the carboxylic acid of formula (IX) is converted to the starting material of formula (II) by condensation with an O-protected hydroxylamine of formula (X). The condensation is carried out in a manner known per se for the peptide coupling reaction and in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride using conventional coupling reagents, Roxibenzotriazole is used.
Optionally, the compounds produced or produced by Scheme A may be interchanged or substituted.
Compounds of formula (V) in which R < ³ > represents hydrogen can then be converted into the corresponding compounds of formula (V) in which R < ³ > represents lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl or aryl- Lt; / RTI > For example, compounds of formula V, wherein R < ³ > represents hydrogen, may be reacted with a compound of formula R < ³⁰ > -CHO where R < ³⁰ > is lower alkyl, lower alkenyl, lower alkynyl, Alkyl, aryl-lower alkyl or aryl), and the resulting substituted imine can be condensed with an alkali metal cyanoborohydride, especially sodium cyanoborohydride, preferably in situ, . ≪ / RTI > Alternatively, compounds of formula (V) in which R ³ represents hydrogen can be conveniently prepared at elevated temperature, suitably at the reflux temperature of the reaction mixture, conveniently in the presence of an organic base such as tri (lower alkyl) amine such as triethylamine And in an organic solvent inert under the reaction conditions, for example an aromatic hydrocarbon such as benzene, toluene or the like, can be reacted with a cyclic anhydride of the formula XI wherein n has the meaning indicated above, for example, glutaric anhydride. have:
In this way, compounds of formula (VIII) are obtained wherein R ² , R ³ and the atoms to which they are attached signify a group of formula (c) above.
Compounds of formula II in which R < ³ > represents hydrogen are conveniently prepared in the presence of a base, for example an alkali metal carbonate such as sodium carbonate or potassium carbonate, and in an organic solvent which is inert under the reaction conditions, for example dimethylformamide Can be converted to the corresponding compound of formula (II) wherein R ³⁰ has the meaning indicated above by reaction with a known compound of formula R ³⁰ -X, wherein R ³⁰ has the meaning indicated above and X represents halogen.
The compounds of formula (VIII) wherein R <^4> is phthalimido-lower alkyl can also be conveniently converted into hydrazine hydrate in a lower alkanol, such as methanol or ethanol, conveniently in an inert organic solvent under reaction conditions can be processed, and the resulting product, i.e., R ⁴ is an amino-corresponding compound of formula (VIII) represents a lower alkyl is a suitable (two kinds in the presence of a coupling reagent in the presence of a base to introduce a desired group R ^4, which ) Aromatic carboxylic acid or sulfonic acid halide, (hetero) aromatic isocyanate or (hetero) aromatic carboxylic acid.
The carboxylic acid of formula IX in Scheme A is novel and another object of the present invention.
Compounds of formula (III) used in Scheme A can be prepared as described in the following examples or analogously, as long as they are not analogs of known or known compounds. In addition, the compounds of formulas IV, VI, VII and X as well as the aldehydes of general formula R ³⁰ -CHO and the cyclic anhydrides of general formula XI, which are also used in Scheme A, are known or analogous to known compounds.
In relation to Scheme B, Step 1 involves converting a carboxylic acid of formula (III) to the corresponding methyl ester of formula (XII). The process may be carried out in a known manner, for example by reaction with a tertiary organic base such as, for example, 4-dimethylaminopyridine, and a diisocyanate such as a condensing agent, for example 1-ethyl-3- (3- Meade in the presence of methanol.
The methyl ester of formula XII is then deprotected in the tert-butoxycarbonyl group by treatment with trifluoroacetic acid. The deprotection is carried out in a manner known per se, for example, in an organic solvent which is inert under the reaction conditions, for example at about room temperature, for example in halogenated hydrocarbons such as dichloromethane.
The resulting compound of formula (XIII) is subsequently condensed with an O-protected hydroxylamine of formula (X) to give a compound of formula (XIV). The condensation is carried out in a manner known per se for peptide coupling reactions using conventional coupling reagents such as 1-hydroxy-3-hydroxy-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, Benzotriazole. &Lt; / RTI &gt;
In the next step, the compound of formula XIV is reacted with trimethylaluminium and hydrazine of formula IV or substituted hydrazine to give the compound of formula XV. The reaction is conveniently carried out in an organic solvent which is inert under the reaction conditions, for example in halogenated hydrocarbons such as dichloromethane and at temperatures in the approximate range of from room temperature to 60 ° C.
Finally, the compound of formula (XV) is reacted with the chloride of formula (VI) or anhydride of formula (VII) to give the desired starting material of formula (II). The reaction is carried out in a known manner, for example, in an organic solvent which is inert under reaction conditions at from about 0 캜 to about room temperature and in the presence of an organic base. Suitable solvents are halogenated hydrocarbons, such as dichloromethane. Examples of organic bases which can be used are tri (lower alkyl) amines, such as triethylamine, pyridine, 4-dimethylaminopyridine, and the like. When the base is a liquid under the reaction conditions, the base can be used in excess and in this case can simultaneously act as a solvent.
In one step of Scheme C, the carboxylic acid of formula XVI is treated, for example, by treatment with oxalyl chloride, followed by reaction with a substituted hydrazine of formula XVII to give a compound of formula XVIII. The reaction is conveniently carried out at about 0 &lt; 0 &gt; C in the presence of a base, especially a tertiary organic amine such as triethylamine, and in an organic solvent which is inert under the reaction conditions, for example halogenated hydrocarbons such as dichloromethane.
Subsequently, the compound of formula (XVIII) is reacted with trimethylaluminium and the O-protected hydroxylamine of formula (X) to give the desired starting material of formula (II). The reaction is conveniently carried out in an organic solvent which is inert under the reaction conditions, for example halogenated hydrocarbons such as dichloromethane, and at temperatures from about room temperature to about 60 ° C.
The carboxylic acid of formula (XVI) used in Scheme C and the substituted hydrazine of formula (XVII) are known compounds or analogs of known compounds which may be prepared in analogous manner to known compounds.
As mentioned earlier, the hydrazine derivatives provided by the present invention inhibit the proliferation of keratinocytes as well as the release of TNF and TGF- [alpha]. These activities can be demonstrated using the in vitro tests described below.
Test A: inhibition of TNF-a release
THP1 cells were cultured in RPMI 1640 medium supplemented with antibiotics and 10% fetal calf serum, and harvested by centrifugation and then diluted to 5 x 10 ⁵ cells / ml in the medium supplemented with 20 mM HEPES buffer. An aliquot of the cell suspension (200 ml) was plated on 96-well culture plates and incubated at 37 占 폚 for 0.5 hour before addition of the test compound. The test compounds were dissolved in dimethyl sulfoxide (DMSO) at a storage concentration of 1.2 mM diluted in phosphate buffered saline / 10% DMSO solution to give the test compound at a final concentration of 10 ^-9 to 10 ^-5 M, Concentrations were tested in duplicate. Cells were incubated with the test compound for 0.5 hour at 37 ° C, then LPS (lipopolysaccharide of bacteria) was added at a concentration of 2 mg / ml and incubated at 37 ° C in an atmosphere containing 5% CO ₂ and at 95% Lt; 0 &gt; C for 3 hours. After centrifugation at 260 g for 10 min, an aliquot of each supernatant was taken and the amount of TNF-a was assessed by ELISA (R & D Systems Europe Ltd., Irvington, UK) . The concentration (IC ₅₀ ) of the test compound that resulted in about 50% inhibition of LPS-induced TNF-a release was calculated from the dose-response curve.
Test B: Suppression of TGF-a release
This test is a modification of the method described in RJ Coffrey, R. Derynk, JN Wilcox, TS Bringman, AS Goustin, HL Moses and MR Pittelkow, Nature, 328, 816-820 (1987). Standard human epidermal keratinocytes (neonatal and adult) were supplied by Clonetics Corporation, San Diego, CA, and in a third transition, 2 x 10 &lt; ³ &gt; to 10 &lt; ⁴ &gt; Cells / well and grown for 5 days in a humidified incubator with a 5% CO ₂ atmosphere at 37 ° C in serum-free keratosynthetic growth medium (KGM; Cronetics Corporation). The test compound was dissolved in DMSO and then diluted 10-fold in keratinocyte basic medium (KBM; Cronectics Corporation). A serial dilution of the test compound in 10% DMSO in KBM was prepared to provide a concentration 12 times higher than the final assay concentration. The test compound dilution (or only the vehicle as a control) was added to the cells, followed by incubation at 37 DEG C for 0.5 hour. Then, 10 ng / ml of TPA (phorbol 12-myristate 13-acetate) was added to stimulate the release of TGF-a. After further incubation at 37 DEG C for 24 hours, the TGF-alpha content of the culture medium was measured by TGF-alpha ELISA (Oncogene Science Inc., Uniondale, New York) (Igen Inc., Gattersburg, Md.) Based on electrochemiluminescence, formatted with human TGF- (AL &amp; D Systems Europe Limited). The concentration of the test compound (IC ₅₀ , n mol), which inhibited the release of TGF-a by 50% compared to the control, was then calculated.
Test C: inhibition of keratinocyte proliferation
This test is described in T. Karashima, H. Hachisuka and Y. Sasai, J. Dermatol. Sci., 12, 246-254 (1996); and A. Olaniran, BS Baker, JJ Garioch, AV Powles and L. Fry, Arch. Dermatol. Res., 287, 231-236 (1995). Normal human epidermal keratinocytes (NHEK) (neonatal and adult) were plated for 2 x 10 ³ cells / well on 96-well culture plate. The cells were cultured in a humidified incubator with a 5% CO ₂ atmosphere at 37 ° C in serum-free KGM (see above) for 24 hours to attach the cells to the culture plate. Then, the medium was incubated with KBM ) For 4 days. The test compound was dissolved in DMSO and then diluted 10-fold in KBM. A serial dilution of the test compound in 10% DMSO in KBM was prepared to provide a concentration 11 times higher than the final assay concentration. Cells were then returned to KGM and test compound dilutions (or vehicle only as a control) were added immediately. After 3 days of incubation, for the final 16 hours, 1 μCi / well of ³ H-thymidine with intrinsic activity of 5 Ci / millimolar (Amersham International plc, Little Rock Font, Buckinghamshire, UK) ). The cells were then separated and harvested using trypsin-EDTA. ³ H-thymidine incorporation was measured by scintillation counting as a measure of proliferation. The concentration (IC ₅₀ , n mol) of the test compound that inhibited ³ H-thymidine incorporation by 50% compared to the control was calculated.
The results obtained in the above tests with representative compounds of formula I are tabulated in the following table.
compound The IC ₅₀ (n mol) The IC ₅₀ (n mol) The IC ₅₀ (n mol) A 437 210 1300 B 515 255 1100 C 365 N / T N / T D 408 N / T N / T E 531 N / T N / T F 1516 N / T N / T G 428 N / T N / T H 381 N / T N / T I 881 N / T N / T J 933 N / T N / T N / T means not tested.
In the above table,
A was prepared from (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Phenyl valerohydrazide,
B was prepared from (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Methoxyphenyl) -4-methylvalerohydrazide, &lt; / RTI &gt;
C was prepared from (E) -2 ' -benzyl-2 (R) - [1 (S) - (hydroxycarbamoyl) Methyl valerohydrazide,
D was prepared from (E) -2 &apos;-( cyclohexylmethyl) -2 &^apos;-( R) - [1 (S) - (hydroxycarbamoyl) &Lt; / RTI &gt; 4-methylvalerohydrazide,
E was prepared from (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- - methylvalerohydrazide, &lt; / RTI &gt;
F is a mixture of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-N- (2,6-dioxopiperidino) Valeramide,
G was prepared by reacting (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) [2 (S) -methylbutyl] valerohydrazide,
H can be obtained from (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) (2-methylallyl) valerohydrazide,
I was prepared by reacting methyl (E) -3- [2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- It's Jay,
J was prepared by reacting (E) -2 (R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( isobutyl) -2 '-( isopentanoyl) Methyl valerohydrazide.
The hydrazine derivatives provided by the present invention can be used, for example, as medicaments in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, they may also be administered rectally, for example, in the form of suppositories, or parenterally, in the form of injection solutions.
In the preparation of pharmaceutical preparations, the hydrazine derivatives may be formulated with a therapeutically inert, inorganic or organic carrier. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as such carriers for, for example, tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. However, depending on the nature of the active ingredient, a carrier is generally not required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, saccharides, phosgene, glucose and the like. Suitable carriers for the preparation of injection solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils and the like. Natural and hardened oils, waxes, fats, semi-liquid polyols and the like are suitable carriers for the manufacture of suppositories.
The pharmaceutical preparations may also contain preservatives, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for controlling osmotic pressure, buffers, coatings or antioxidants.
Methods for preparing such medicaments as well as medicaments containing hydrazine derivatives and therapeutically acceptable carriers as described above are also an object of the present invention. The method comprises preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, in a galenical administration form together with a therapeutically inert carrier material and optionally one or more additional therapeutically active substances.
Another object of the present invention includes the use of the hydrazine derivatives provided by the present invention for the treatment of diseases, particularly inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis and psoriasis. The dosage can vary within wide limits and will, of course, be tailored to the individual requirements in each particular case. In general, when administered to an adult, a daily dosage of about 5 to about 30 mg, preferably about 10 to about 15 mg is appropriate, but the upper limit may be exceeded if found beneficial. The daily dose may be administered in a single dose or in divided doses.
The following examples illustrate the invention. The structures of the products and critical intermediates were confirmed by NMR spectroscopy.
Example 1
2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide
(S) - (carboxy) -4-phenylbutyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydra A solution of 0.165 g of zid was cooled to 0 占 폚 while stirring under nitrogen and 0.09 g of 1-hydroxybenzotriazole and 0.09 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were continuously added The After stirring at 0 C for 40 min, the solution was treated with 0.18 g of O- (tert-butyldimethylsilyl) hydroxylamine and the mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The ethyl acetate layer was washed successively with water, 2 M sulfuric acid, water and brine, then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a pink rubber which was crystallized from ether to give 0.05 g of 2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -2 ' -methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a gray solid.
MS: 476 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO, 353K)} : 10.73 (1H, s); 10.30 (1H, broad singlet); 8.46 (1H, broad singlet); 7.50-7.44 (2H, m); 7.42-7.34 (2 H, m); 7.30-7.21 (3 H, m); 7.18-7.06 (3H, m); 3.17 (3 H, s); 2.64-2.54 (1 H, m); 2.50-2.30 (2 H, m); 2.25-2.11 (1 H, m); 1.59-1.23 (6 H, m); 1.10-1.02 (1 H, m); 0.84 (1H, d, J = 6.5 Hz); 0.76 (1H, d, J = 7 Hz).
HPLC: gradient elution using Solvent A containing 10% Solvent B for 5 minutes and increasing to 90% Solvent B from 5 minutes to 15 minutes; Flow rate of 1 ml / min. Retention time: 16.77 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The 2 (R) - [1 (S) - (carboxy) -4-phenylbutyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide used as a starting material was Were prepared as follows:
(i) A solution of 2 (R) - [1 (S) - (tert-butoxycarbonylamino) -2-methylpyridine, prepared by a method similar to that described in Example 2, -4-phenylbutyl] -4-methylvaleric acid in 10 ml of tetrahydrofuran was cooled to 0 &lt; 0 &gt; C and 0.1 ml of N-methylmorpholine, 0.16 g of 1-hydroxybenzotriazole, 0.16 g of phenylhydrazine And 0.27 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The solution was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium hydrogen carbonate solution. The ethyl acetate layer was washed successively with water, 5% citric acid solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (6: 1) to elute. 0.41 g of a yellow oil which was crystallized from hexane / ether and then 0.255 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenylbutyl] -2 &apos; -phenylvalerohydrazide in the form of a white solid.
MS: 439 (M + H) &lt; ⁺ & gt ^; .
(ii) A solution of 0.19 g of the product of part (i) in 3 ml of pyridine was cooled to 0 &lt; 0 &gt; C and 0.15 g of methanesulfonyl chloride was added. The solution was allowed to stand at room temperature and the solvent was evaporated. The residue was partitioned between ethyl acetate and 2M sulfuric acid and the ethyl acetate layer was washed successively with 2M sulfuric acid, water, 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography using hexane / ethyl acetate (6: 1) to elute. To a solution of 0.19 g of 2 (R) - [1 (S) - (tert-butoxycarbonyl) -4-phenylbutyl] -2 &apos;-( methanesulfonyl) -4-methyl-2-phenylvalerohydra The zide was obtained in the form of a white solid.
MS: 517 (M + H) &lt; ⁺ & gt ^; .
(iii) A solution of 0.19 g of the product of part (ii) was dissolved in a mixture of 8 ml of dichloromethane and 4 ml of trifluoroacetic acid and left at room temperature for 5 hours. The solvent was evaporated and the residue was re-evaporated from toluene. The procedure was repeated two more times to obtain a residue. The residue was triturated with ether and the solid was filtered. (S) - (carboxy) -4-phenylbutyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide as a white solid Lt; / RTI &gt;
MS: 461 (M + H) &lt; ⁺ & gt ^; .
Example 2
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- Lohia Dragaj
To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in 10 ml of tetrahydrofuran was treated with 0.043 mg of 4-toluenesulfonic acid. The mixture was stirred at room temperature for 3 hours and then the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was triturated with ether to give 0.051 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) 4-methyl-2 ' -phenylhydrazide in the form of a white solid.
MS: 474 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO, 353K)} : 10.80 (1H, s); 10.30 (1H, broad singlet); 8.48 (1H, broad singlet); 7.51-7.45 (2 H, m); 7.42-7.34 (2 H, m); 7.32-7.23 (5 H, m); 7.21-7.14 (1 H, m); 6.22 (1H, doublet, J = 15.5 Hz); 6.08-5.96 (1 H, m); 3.20 (3H, s); 2.70-2.60 (1 H, m); 2.42 - 2.12 (3 H, m); 1.58-1.48 (1 H, m); 1.46-1.35 (2H, m); 1.14-1.05 (1H, m); 0.85 (3H, d, J = 6.5 Hz); 0.76 (3H, d, J = 7.5 Hz).
HPLC: gradient elution using Solvent A containing 10% Solvent B for 5 minutes and increasing to 90% Solvent B from 5 minutes to 15 minutes; Flow rate of 1 ml / min. Retention time: 16.76 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide was prepared as follows:
(i) A solution of 5.19 g of 4-tert-butylhydrogen 2 (R) -isobutyl-succinate in 50 mL anhydrous tetrahydrofuran was cooled to -78 C with stirring under nitrogen. 25 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran was added dropwise, and the mixture was stirred at -78 DEG C for 15 minutes. Then a solution of 5.55 g of cinnamylbromide in 25 ml anhydrous tetrahydrofuran was added dropwise and the mixture was slowly warmed to room temperature. After stirring overnight, the tetrahydrofuran was evaporated and the residue partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate layer was washed with an additional two portions of 5% citric acid solution, water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to give an orange oil. This was dissolved in 100 ml of hexane, and 2.35 g of cyclohexylamine was added thereto. The mixture was allowed to stand for 2 hours and the resulting solid was collected by filtration. The solid was suspended in ethyl acetate and shaken with two portions of 2M sulfuric acid to give a clear solution. The ethyl acetate solution was washed twice with water, then with saturated sodium chloride solution and successively dried over anhydrous magnesium sulfate. After evaporation of the solvent, 6.41 g of (E) -2 (R) - [1 (R) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid Obtained as a pale cream colored solid.
(ii) The product obtained in part (i) was dissolved in 50 mL anhydrous tetrahydrofuran, cooled to -78 ° C with stirring, and 20.5 mL of a 2M solution of lithium diisopropylamide in tetrahydrofuran was added dropwise. After stirring at -78 &lt; 0 &gt; C for 1.75 hours, 8 ml of methanol was added dropwise. The mixture was allowed to warm slowly to room temperature and stirred overnight. The tetrahydrofuran was evaporated and the residue partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate layer was washed successively with two additional portions of citric acid solution, two portions of water and saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After evaporation, 1 (S), 2 (R) and 1 (R) of E-2- [1- (tert-butoxycarbonyl) 2 &lt; / RTI &gt; (R) isomer. The epimerization procedure was repeated three times to obtain a mixture having substantially 1 (S), 2 (R) isomers. The crude product was dissolved in 100 mL of hexane and the solution was treated with 1.9 g of cyclohexylamine. After standing for 3 hours, the precipitated salt was filtered off and dried. 5.53 g of a light cream solid was obtained, which was converted to the free acid by a procedure similar to that described in (i). (E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid as a yellow solid Respectively.
(E) -2 (R) -1 (S) -thiazole-2-carboxylic acid starting from 0.7 g of the carboxylic acid prepared in part (ii) of this example in a similar manner to that described in Example 1, part (i) ) - (tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylhydrazide in the form of a white solid.
MS: 437 (M + H) &lt; ⁺ & gt ^; .
(iv) In a similar manner to that described in Example 1, Part (ii) and (iii), 0.15 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) (R) - [1 (S) - (carboxy) -4-methyl-2 ' -phenylvalerohydrazide to yield 0.14 g of (E) Phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a white solid.
(v) The carboxylic acid prepared in the preceding paragraph was dissolved in 3 ml of dimethylformamide, cooled to 0 C and treated with 0.064 g of O- (tetrahydro-2H-pyran-2 (RS) -yl) Was treated successively with 0.061 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between 5% citric acid solution and ethyl acetate. The ethyl acetate layer was washed with water, 5% sodium hydrogencarbonate solution and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated. The resulting white solid was triturated with ether and filtered to give 0.095 g of (E) -2 (R) - [1 (S) - [(tetrahydro-2- (RS) -pyranyloxy) carbonyl] -4- Phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a white powder.
MS: 558 (M + H) &lt; ⁺ & gt ^; .
Example 3
Benzyl 3- [2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methylvaleryl] -2-phenylcarbazate
(RS) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] (S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methylvaleryl] -2-phenylcarbazate was prepared 0.032 g of benzyl 3- [2 (R) Phenylbutyl] -4-methylvaleryl] -2-phenylcarbazate in the form of a light cream solid.
MS: 532 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO, 353K)} : 10.83 (1H, s); 10.47 (1H, broad singlet); 8.62 (1H, broad singlet); 7.64 (2 H, m); 7.54 (7 H, m); 7.41 (3 H, m); 7.33 (1 H, m); 7.24 (2 H, m); 5.40 (2 H, s); 2.76-2.30 (4 H, m); 1.75-1.45 (6 H, m); 1.22 (1 H, m); 0.97 (3H, d, J = 7 Hz); 0.90 (3H, d, J = 6.5 Hz).
HPLC: gradient elution using solvent A containing 10% solvent B for 10 minutes and increasing to 80% solvent B from 10 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 19.71 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(RS) - (pyranyloxy) carbamoyl] -4-phenylbutyl] -4-methylvaleryl] piperazine used as a starting material, -2-phenylcarbazate was prepared as follows:
(i) 2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenylbutyl] -4-methyl- 2'-phenylvalerohydrazide (0.5 g) was dissolved in 10 ml of diethyl ether, and the mixture was stirred with 10 ml of a saturated aqueous sodium hydrogencarbonate solution and 1.0 ml of benzyl chloroformate. After 24 hours, the ether layer was separated, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (9: 1) to elute. 4-Methylvaleryl] -2-phenylcarbazate was prepared as a white solid (0.477 g) from benzyl 3- [2 (R) - [1 (S) - (tert-butoxycarbonyl) Lt; / RTI &gt;
MS: 573 (M + H) &lt; ⁺ & gt ^; .
(ii) In a manner similar to that described in Example 2, Part (iv) and (v) starting with 0.115 g of the phenylcarbazate prepared in the previous paragraph, 0.115 g of benzyl 3- [2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy)] - 4-phenylbutyl] -4-methylvaleryl] -2-phenylcarbazate in the form of a colorless gum .
MS: 616 (M + H) &lt; ⁺ & gt ^; .
Example 4
(S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methyl-2 ' -phenylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] (R) - [1 (S) - (hydroxycarbamoyl) -4-phenylbutyl] -4-methyl-2 ' -phenylvalerohydrazide, 0.062 g of 2 ' -Phenylbutyl] -4-methyl-2 ' -phenylvalerohydrazide in the form of a white solid.
MS: 440 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution with solvent B containing 25% solvent B for 5 minutes followed by increasing to 60% solvent B from 5 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 14.97 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenylbutyl] -4-methyl-2 Apos; -phenylvalerohydrazide was prepared as follows:
(i) 2 (R) - [1 (S) - (tert-Butylcarbonyl) -4-phenylbutyl] propionic acid, prepared as described in Example 1, part (i), in 2 ml of dichloromethane, -4-methyl-2'-phenylvalerohydrazide, 0.3 ml of acetic anhydride and 0.35 ml of N-methylmorpholine was left at room temperature for 3 days. The dichloromethane was evaporated and the residue was partitioned between ethyl acetate and 5% sodium bicarbonate solution. The ethyl acetate solution was washed with 5% sodium hydrogencarbonate solution, water, 5% citric acid solution, water and saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (1: 1) to elute. (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenylbutyl] -4-methyl-2 ' -phenylvalerohydrazide as white Obtained as a solid.
MS: 481 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 2, parts (iv) and (v), starting with 0.21 g of the hydrazide prepared in the preceding paragraph, 0.09 g of 2'-acetyl- 4-phenylbutyl] -4-methyl-2 ' -phenylvalerohydrazide was prepared in the form of a white solid &lt; RTI ID = 0.0 &gt; .
MS: 524 (M + H) &lt; ⁺ & gt ^; .
Example 5
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - pyridyl) valero hydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 2-ethoxy-4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 2-pyridyl) valerohydrazide, (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' - (methanesulfonyl) -4-methyl-2 '- (2-pyridyl) valerohydrazide in the form of a white solid.
MS: 475 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO, 353K)} : 10.86 (1H, s); 10.27 (1H, broad singlet); 8.45 (1H, broad singlet); 8.35 (1 H, m); 7.30 (1 H, m); 7.34-7.12 (7 H, m); 6.32 (1H, doublet, J = 15.5 Hz); 6.13-6.04 (1H, m); 3.51 (3 H, s); 2.79-2.69 (1 H, m); 2.50-2.30 (3 H, m); 1.53-1.50 (2 H, m); 1.19-1.10 (1H, m); 0.91 (3H, d, J = 7.0 Hz); 0.83 (3H, d, J = 6.5 Hz).
HPLC: gradient elution using Solvent A containing 10% Solvent B for 5 minutes and increasing to 90% Solvent B from 5 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 16.20 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -4-methyl-2 '- (2-pyridyl) valerohydrazide was prepared as follows:
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3 2 (R) - [1 (S) - (tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -carbamic acid ethyl ester and starting from 2-hydrazinopyridine ] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 2-pyridyl) valerohydrazide in the form of a white solid.
MS: 559 (M + H) &lt; ⁺ & gt ^; .
Example 6
(E) -2 '-( 2-benzothiazolyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl ) -4-methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.086 g of (E) -2 '- (2-benzothiazolyl) -2 (R) - [1 (S) - [(tetrahydro- Starting from (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide, After washing with an aqueous solution of sodium hydrogencarbonate, 0.045 g of (E) -2 '-( 2-benzothiazolyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -Butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 531 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution using solvent A containing 5% solvent B for 5 minutes and increasing to 95% solvent B from 5 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 18.16 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4 -Phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3 - (2-benzothiazolyl) -2 (R) - [1 (S) - (2-benzothiazolyl) Phenyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide was obtained in the form of a white solid Respectively.
Example 7
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - quinolyl) valero hydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.05 g of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) Starting from 2-ethoxy-4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 2-quinolyl) valerohydrazide, After washing with an aqueous sodium hydrogen solution, 0.026 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' ) -4-methyl-2 '-( 2-quinolyl) valerohydrazide in the form of a white solid.
MS: 524 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution using Solvent A containing 10% Solvent B for 5 minutes and increasing to 90% Solvent B from 5 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 17.90 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -4-methyl-2 '-( 2-quinolyl) valerohydrazide was prepared as follows:
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3 2 (R) - [1 (S) - (tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -carbamic acid tert- ] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 2-quinolyl) valerohydrazide in the form of a white solid.
Example 8
2 '- (methanesulfonyl) -2' - (4-methoxyphenyl) -3-butenyl] -2 &apos;-( methanesulfonyl) Phenyl) -4-methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.195 g of 1 (E) - (4-methoxy-phenyl) -3-butenyl] -2 '-( methanesulfonyl) -2 '-( methanesulfonyl) -2 '-( 4-methoxyphenyl) -4-phenyl- Methylvalerohydrazide in the form of a cream colored solid.
MS: 504 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution using solvent A containing 5% solvent B for 5 minutes and increasing to 95% solvent B from 5 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 16.53 minutes. Solvent A: H ₂ O / 0.01% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -2 '-( 4-methoxyphenyl) -4-methylvalerohydrazide was prepared as follows:
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3 2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) -pentanoyl] -4-methylvaleric acid and 4-methoxyphenylhydrazide. ) Carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 '-( 4-methoxyphenyl) -4- methylvalerohydrazide in the form of a white solid Respectively.
Example 9
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - methylphenyl) valerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.192 g of (E) -2 (R) - (4-methyl- ) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 2-methylphenyl) valerohydra The zide was obtained in the form of a cream solid.
MS: 488 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.37 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -4-methyl-2 '-( 2-methylphenyl) valerohydrazide was prepared as follows:
(i) In a similar manner to that described in Example 1, part (i), 0.7 g of (E) -2 (R) - [1 (S) - (tert-butoxycarbonyl) Starting from 0.5 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-methylvaleric acid and o-tolylhydrazine -Phenyl-3-butenyl] -4-methyl-2 '-( 2-methylphenyl) valerohydrazide in the form of a cream colored solid.
MS: 451 (M + H) &lt; ⁺ & gt ^; .
(ii) To a solution of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl- (2-methylphenyl) valerohydrazide in 50 ml of tetrahydrofuran was treated with 0.09 g of pyridine and 0.1 g of methanesulfonic anhydride. After stirring for 1.5 hours, 0.05 g of pyridine and 0.06 g of methanesulfonic anhydride were further added and the mixture was stirred for an additional 2 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate solution was washed with water, a 5% aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (6: 1) to elute. (E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl -2 '-( 2-methylphenyl) valerohydrazide in the form of a yellow gum.
(iii) The hydrazide prepared in the preceding paragraph was treated in a manner similar to that described in Example 1, Part (iii) and then treated in a similar manner to that described in Example 2, Part (v) to give (E) -2 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl-4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4- Methyl-2 '-( 2-methylphenyl) valerohydrazide in the form of a cream colored solid.
MS: 572 (M + H) &lt; ⁺ & gt ^; .
Example 10
(R) - [1 (S) - (hydroxycarbonyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - naphthyl) valero hydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.053 g of (E) -2 ((4-methyl-2-naphthyl) Methyl-2 '-( 1-naphthyl) valero &lt; / RTI &gt; Hydrazide was obtained in the form of a cream solid.
MS: 524 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.83 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -4-methyl-2 '- (1-naphthyl) valerohydrazide was prepared as follows:
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3 2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -carbamic acid valerate and 1-naphthyl hydrazine, ] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 1-naphthyl) valerohydrazide in the form of a cream colored solid.
MS: 608 (M + H) &lt; ⁺ & gt ^; .
Example 11
(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 '-( 3-hydroxybenzyl) -2 ) -4-methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.375 g of (E) -2 '-( 3-hydroxybenzyl) -2 (R) - [1 (S) - [(tetrahydro- (RS) -pyranyloxy) carbonyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide, 0.29 g of (E) - (3-hydroxybenzyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] Valero hydrazide in the form of a white solid.
MS: 503 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO, 353K)} : 10.23 (1H, br s); 10.09 (1H, s); 8.98 (1 H, s); 8.41 (1H, broad singlet); 7.30 (4 H, m); 7.18 (1 H, m); 7.09 (1 H, m); 6.83-6.73 (2H, m); 6.67 (1 H, m); 6.24 (1H, doublet, J = 15.5 Hz); 6.05-5.94 (1 H, m); 4.56-4.48 (2 H, m); 3.14 (3 H, s); 2.55-2. 45 (1H, m); 2.33-2.18 (2 H, m); 2.16-2.02 (1 H, m); 1.50-1.40 (1H, m); 1.38-1.21 (1 H, m); 1.05-0.95 (1H, m); 0.75 (3H, d, J = 7 Hz); 0.71 (3H, d, J = 7 Hz).
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.95 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbonyl] -4 -Phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3 -2 (R) - [1 (S) - [(tetrahydro-furan-2-ylmethoxy) -benzaldehyde] -2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 588 (M + H) &lt; ⁺ & gt ^; .
Example 12
(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( Methanesulfonyl) -4-methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, starting from 0.13 g of (E) -2 '- (2,4-difluorophenyl) -2 (R) - [1 (S) - [ Phenyl) -3-butenyl] -2 '-( methanesulphonyl) -4-methylvalerohydrazide, 0.083 g of (E -2 '-( methanesulphonyl) -2 '-( 2,4-difluorophenyl) -2 (R) - [1 (S) - (hydroxycarbonyl) Trifluoromethyl-phenyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 510 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.37 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2 '-( 2,4- difluorophenyl) -2 ] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3 -2 '- (2,4-difluorophenyl) -2 (R) - [1 (S) -pyrrolidinecarboxylic acid dihydrochloride ) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide as a white solid Lt; / RTI &gt;
Example 13
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -Nitrophenyl) valerohydrazide &lt; / RTI &gt;
(E) -2 (R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3 Starting from 0.06 g of (E) -2 (R) - [1 ((R) -2-methoxy- S '- (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 4-nitrophenyl) valerohydrazide as a yellow solid Lt; / RTI &gt;
MS: 519 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.54 min. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.
(R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 4-nitrophenyl) valerohydrazide was prepared as follows:
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3 -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -carbamic acid valerate ] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 4-nitrophenyl) valerohydrazide as a yellow solid.
Example 14
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 '-( 2-pyridyl) Valero Hydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.1 g of (E) -2'-acetyl-2 (R) - [1 (S) - [(tetrahydro- Oxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2 '-( 2-pyridyl) valerohydrazide, the ethyl acetate solution of the product was treated with 2% aqueous sodium bicarbonate solution (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4 -Methyl-2 '-( 2-pyridyl) valerohydrazide in the form of a cream solid.
MS: 439 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution using Solvent A containing 5% Solvent B for 5 minutes and increasing to 95% Solvent B from 5 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 15.67 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- -Thienyl] -4-methyl-2 '- (2-pyridyl) valerohydrazide was prepared as follows:
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3 (R) - [1 (S) - [(tetrahydro-naphthalen-2-ylmethyl) -2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2 '-( 2-pyridyl) valerohydrazide in the form of a white solid.
Example 15
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 ' Dragged
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.033 g of (E) -2 (R) - [1 (S) -tetrahydroisoquinolin- - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 ', 4-dimethylvalerohydrazide in the form of a gray solid.
MS: 412 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO): 10.56} (1H, s); 10.46 (1H, s); 8.75 (1H, s); 7.35-7.25 (4 H, m); 7.23-7.15 (1 H, m); 6.31 (1 H, d, J = 15.5 Hz); 6.10-6.00 (1 H, m); 3.06 (3 H, s); 3.04 (3 H, s); 2.55-2. 45 (1H, m); 2.37 (3 H, m); 1.54-1.36 (2 H, m); 1.02-0.93 (1H, m); 0.84 (3H, d, J = 7 Hz); 0.81 (3H, d, J = 7.5 Hz).
HPLC: gradient elution using Solvent A containing 10% Solvent B for 5 minutes and increasing to 90% Solvent B from 5 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 14.72 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2- (Methanesulfonyl) -2 ', 4-dimethylvalerohydrazide was prepared as follows:
(i) A mixture of 11 g of pentafluorophenol and 4.12 g of 1,3-dicyclohexylcarbodiimide in 50 ml of hexane was stirred at room temperature for 5 minutes. The resulting solid was filtered, washed with hexane, dried and then added to a solution of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) 3-butenyl] -4-methylvaleric acid. The mixture was left at 4 &lt; 0 &gt; C overnight, and then filtered to remove dicyclohexylurea. The filtrate was evaporated, the residue was dissolved in 50 mL of dichloromethane and 3 mL of hydrazine hydrate was added to the resulting solution. The mixture was stirred for 6 hours and then washed successively with 5% citric acid solution, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with hexane / ethyl acetate (4: 1) and the resulting solid was filtered. 4.68 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide was obtained as a gray solid Lt; / RTI &gt;
MS: 361 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 9, Part (ii) and (iii), 8.96 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) (RS) - [(S) - [(tetrahydro-2 (RS) - 4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 482 (M + H) &lt; ⁺ & gt ^; .
(iii) A solution of 0.34 g of hydrazide prepared in part (ii) in 7 ml dimethylformamide was treated with 0.126 g of methyl iodide and 0.293 g of anhydrous potassium carbonate. The mixture was stirred at room temperature for 3 hours and the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate phase was washed with water and saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (4: 1) followed by hexane / ethyl acetate (2: 1) to elute. (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl-4-phenyl-3-butenyl] -2 '-( methane Sulfonyl) -2 ', 4-dimethylvalerohydrazide in the form of a white solid.
Example 16
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.06 g of (E) -2 (R) - [1 (S) - (2-methyl- Hydroxy-carbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a gray solid.
MS: 398 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO): 10.55} (1H, s); 10.34 (1H, s); 9.52 (1H, s); 8.85 (1H, s); 7.36-7.25 (4 H, m); 7.23-7.16 (1 H, m); 6.30 (1H, doublet, J = 15.5 Hz); 6.08-5.98 (1 H, m); 2.96 (3 H, s); 2.56-2.46 (1 H, m); 2.39-2.13 (3 H, m); 1.53-1.33 (2 H, m); 1.01-0.93 (1 H, m); 0.83 (3H, d, J = 6.5 Hz); 0.80 (3H, d, J = 7 Hz).
HPLC: gradient elution increasing from 5 min to 20 min with 90% solvent B using solvent A containing 10% solvent B for 5 min; Flow rate of 1 ml / min. Retention time: 14.13 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 17
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Lohia Dragaj
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyl 4-methylvalerohydrazide there was obtained 0.142 g of (E) -2 ' -benzyl-2 '-( 2-methoxy- R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a gray solid .
MS: 488 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO, 353K)} : 10.22 (1H, br s); 10.1 (1H, s); 8.40 (1H, broad singlet); 7.40-7.24 (9 H, m); 7.22-7.15 (1 H, m); 6.23 (1H, doublet, J = 15 Hz); 6.05-5.94 (1 H, m); 4.63 (2 H, m); 3.15 (3 H, s); 2.54-2.44 (1 H, m); 2.31-2.17 (2 H, m); 2.14-2.01 (1 H, m); 1.51-1.49 (1H, m); 1.34-1.18 (1 H, m); 1.04-0.95 (1 H, m); 0.74 (3H, d, J = 6.5 Hz); 0.70 (3H, d, J = 7.0 Hz).
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.18 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Benzyl-2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2 (R) - [1 (S (2 H) -quinolinone &lt; ) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide Benzyl bromide. &Lt; / RTI &gt;
Example 18
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 '-( 4-methoxybenzyl ) -4-methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] (4-methoxybenzyl) -4-methylvalerohydrazide, 0.061 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 '-( 4- methoxybenzyl) Valero hydrazide in the form of a white solid.
MS: 518 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution using solvent A containing 35% solvent B for 5 minutes and increasing to 85% solvent B from 5 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 7.20 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -2 '-( 4-methoxybenzyl) -4-methylvalerohydrazide was prepared in analogy to example 15, part (iii) from ) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methylsulfonyl) Lt; / RTI &gt; was prepared by reaction with 4-methoxybenzylbromide starting from hydrazide.
Example 19
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Lohia Dragaj
(RS) - [(S) - [(tetrahydro-2 (RS) -pyranyl 4-methylvalerohydrazide, 0.013 g of (E) -2'-allyl-2 ((4-methoxy- R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide as a white solid .
MS: 438 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO, 353K)} : 10.26 (1H, br s); 10.08 (1H, s); 8.44 (1H, broad singlet); 7.35-7.25 (4 H, m); 7.22-7.15 (1 H, m); 6.33 (1H, d, J = 15.5 Hz); 6.13-6.03 (1H, m); 5.90-5.78 (1 H, m); 5.28 (1 H, m); 5.18 (1 H, m); 4.05 (1 H, m); 3.06 (3 H, s); 2.63-2.53 (1H, m); 2.44-2.25 (3 H, m); 1.59-1.45 (2 H, m); 1.14-1.03 (1H, m); 0.85 (3H, d, J = 7 Hz); 0.82 (3H, d, J = 6.5 Hz).
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.36 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2 (R) - [1 (S (2 H) -quinolinone &lt; ) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide Lt; / RTI &gt; with allyl bromide.
Example 20
(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 '-( 4-bromobenzyl) -2 ) -4-methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.215 g of (E) -2 '-( 4-bromobenzyl) -2 (R) - [1 (S) - [(tetrahydro- (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide, 0.147 g of (E) - (4-bromobenzyl) -2 '- (methanesulfonyl) -4-methyl- Valero hydrazide in the form of a white solid.
MS: 566/568 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.90 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(RS) -pyranyloxy) carbamoyl] -4 &lt; RTI ID = 0.0 &gt; (R) -2 (R) -phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide was prepared in analogy to example 15, part (iii) ) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbonyl] -4-phenyl-3-butenyl] -2 &apos;-( methanesulfonyl) Prepared by reaction with 4-bromobenzyl bromide starting from hydrazide.
Example 21
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) - nitrobenzyl) valero hydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.085 g of (E) -2 ((4-nitrobenzyl) valerohydrazide Methyl-2 '- (4-nitrobenzyl) valero-2'- Hydrazide was obtained in the form of a white solid.
MS: 533 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.14 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -4-methyl-2 '- (4-nitrobenzyl) valerohydrazide was prepared in a manner similar to that described in Example 15, Part (iii) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Lt; RTI ID = 0.0 &gt; 4-nitrobenzyl &lt; / RTI &gt; bromide.
Example 22
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Valero Hydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.04 g of (E) -2 (R) - [4-methyl-2 '-( 2-methanesulfonyl- 1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' - propargyl valero hydrazide as a white solid .
MS: 436 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO): 10.57} (1H, s); 10.54 (1H, s); 8.84 (1H, broad singlet); 7.35-7.25 (4 H, m); 7.22-7.16 (1 H, m); 6.30 (1H, doublet, J = 15.5 Hz); 6.09 - 5.99 (1 H, m); 4.32-4.17 (2 H, m); 3.44 (1 H, s); 3.11 (3 H, s); 2.63-2.54 (1 H, m); 2.41-2.17 (3 H, m); 1.56-1.41 (2 H, m); 1.03-1.93 (1 H, m); 0.85 (3H, d, J = 7.0 Hz); 0.81 (3H, d, J = 6.5 Hz).
HPLC: gradient elution gradient from solvent A containing 40% solvent B to 60% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.04 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -4-methyl-2'-propargyl valerohydrazide was prepared in a similar manner as described in Example 15, Part (iii) from (E) S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide And was prepared by reaction with propargyl bromide.
Example 23
(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) - 4-methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) - ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide, 0.124 g of (E) (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydra The zide was obtained in the form of a white solid.
MS: 437 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO): 10.94} (1H, s); 10.56 (1H, s); 8.56 (1H, broad singlet); 7.37-7.25 (4 H, m); 7.23-7.15 (1 H, m); 6.33 (1H, d, J = 15.5 Hz); 6.10 - 5.99 (1 H, m); 4.65 (2 H, m); 3.17 (3 H, s); 2.61-2.52 (1 H, m); 2.40-2.19 (3 H, m); 1.55-1.41 (2 H, m); 1.06-0.95 (1H, m); 0.85 (3H, d, J = 7 Hz); 0.82 (3H, d, J = 6.5 Hz).
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.90 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl -2 (R) - (3-methylbutanoyl) -2 '-( methanesulphonyl) -4-methylvalerohydrazide was prepared in a similar manner as described in example 15, part (iii) Phenyl] -3-butenyl] -2 '-( methanesulphonyl) -4-methylvalerohydra &lt; / RTI &gt; Prepared by reaction with bromoacetonitrile starting from zid.
Example 24
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - phenylethyl) valerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.093 g of (E) -2 ((4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Methyl-2 '- (2-phenylethyl) valero (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Hydrazide was obtained in the form of a white solid.
MS: 502 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.90 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -4-methyl-2 '- (2-phenylethyl) valerohydrazide was prepared in analogy to the method described in example 15, part (iii) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Starting from Drazide by reaction with 2-bromoethyl-benzene.
Example 25
(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Imidomethyl) valerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.127 g of (E) -2 (R) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( phthalimidomethyl) valerohydrazide. ) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( phthalimidomethyl) valerohydra The zide was obtained in the form of a white solid.
MS: 557 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO, 353K)} : 10.18 (1H, br s); 10.13 (1H, s); 8.40 (1H, broad singlet); 7.92-7.82 (4 H, m); 7.32-7.25 (4 H, m); 7.22-7.15 (1 H, m); 6.30 (1H, doublet, J = 15.5 Hz); 6.06-5.96 (1 H, m); 5.30 (2 H, s); 3.16 (3 H, s); 2.56-2.43 (1 H, m); 2.40-2.21 (3 H, m); 1.60-1.40 (2H, m); 1.10-0.99 (1H, m); 0.80 (3H, doublet, J = 6.5 Hz); 0.77 (3H, d, J = 7.0 Hz).
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.03 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] (R) - (methanesulfonyl) -4-methyl-2 '-( phthalimidomethyl) valerohydrazide was prepared in a manner similar to that described in Example 15, Part (iii) Phenyl] -3-butenyl] -2 '-( methanesulphonyl) -4-methylvalerohydra &lt; / RTI &gt; Starting from zid and by reaction with N-bromomethyl phthalimide.
Example 26
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- -Phthalimidoethyl) valerohydrazide &lt; / RTI &gt;
(RS) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.108 g of (E) -2 (R) - (4-methyl-4-phenyl-3-butenyl] -2 '-( methanesulfonyl) ) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( phthalimidoethyl) valerohydra The zide was obtained in the form of a white solid.
MS: 571 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.56 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -4-methyl-2 '- (phthalimidoethyl) valerohydrazide was prepared from (E) -2 (R) - Phenyl] -3-butenyl] -2 '-( methanesulphonyl) -4-methylvalerohydra &lt; / RTI &gt; Prepared by reaction with 2-bromoethyl phthalimide starting from zid.
Example 27
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 ' -phenyl Propiono hydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.159 g of (E) -3-cyclobutyl-2 (R) - [1 (S) - [(tetrahydro- (E) -3-cyclobutyl-2 &lt; RTI ID = 0.0 &gt; (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 ' -phenylpropionohydrazide as a gray solid .
MS: 486 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.12 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- -Thienyl] -2 '-( methanesulfonyl) -2 ' -phenylpropionohydrazide was prepared as follows:
Starting from 4-tert-butyl hydrogen 2 (R) - (cyclobutylmethyl) succinate in an analogous manner as described in example 2, parts (i) -2 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Apos; -phenylpropionohydrazide &lt; / RTI &gt; in the form of a white solid.
MS: 570 (M + H) &lt; ⁺ & gt ^; .
Example 28
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 ' -phenyl Propiono hydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.2 g of (E) -3-cyclopentyl-2 (R) - [1 (S) - [(tetrahydro- (E) -3-cyclopentyl-2 &lt; RTI ID = 0.0 &gt; (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 ' -phenylpropionohydrazide as a white solid .
MS: 500 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.39 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- -Thienyl] -2 '-( methanesulfonyl) -2 ' -phenylpropionohydrazide was prepared as follows:
Starting from 4-tert-butyl-hydrogen 2 (R) - (cyclopentylmethyl) succinate in a manner similar to that described in Example 2, Parts (i) -2 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Apos; -phenylpropionohydrazide &lt; / RTI &gt; in the form of a white solid.
MS: 584 (M + H) &lt; ⁺ & gt ^; .
Example 29
(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulphonyl) -2 '-( 4- ) -4-methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.35 g of (E) -2 '-( 4-bromophenyl) -2 (R) - [1 (S) - [(tetrahydro- (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide, 0.272 g of (E) Methyl-2 '- (methanesulfonyl) -4-methyl-2-oxo- The valero hydrazide was obtained in the form of a gray solid.
MS: 552 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO): 10.85} (1H, s); 10.31 (1H, broad singlet); 8.48 (1H, broad singlet); 7.58 (2 H, m); 7.32 (2 H, m); 7.29 (4 H, m); 7.23-7.16 (1 H, m); 6.23 (1H, doublet, J = 15.5 Hz); 6.07-5.97 (1 H, m); 3.23 (3 H, s); 2.60-2.50 (1 H, m); 2.41-2.12 (3 H, m); 1.57-1.48 (1 H, m); 1.47-1.35 (1 H, m); 1.16-1.06 (1H, m); 0.85 (3H, d, J = 6.5 Hz); 0.78 (3H, d, J = 7.0 Hz).
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.41 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(RS) -pyranyloxy) carbamoyl] -4 &lt; RTI ID = 0.0 &gt; -Phenyl-3-butenyl] -2 &apos;-( methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3 -2 (R) - [1 (S) - [(tetrahydro-naphthalen-2-ylmethoxy) -2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 636/638 (M + H) &lt; ⁺ & gt ^; .
Example 30
(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulphonyl) -4-methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 ((R) -2,2 '- (methanesulfonyl) -4-methylvalerohydrazide, 0.272 g of (E) -2' - (tert-butyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Hydrazide was obtained in the form of a gray solid.
MS: 454 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution increasing from 5 min to 20 min with 90% solvent B using solvent A containing 10% solvent B for 5 min; Flow rate of 1 ml / min. Retention time: 16.56 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3 (R) - [1 (S) - [(tetrahydro-2 (R) -2-tert-butyl- (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 537 (M + H) &lt; ⁺ & gt ^; .
Example 31
(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulphonyl) - 4-methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, starting from 0.149 g of (E) -2 '-( cyclohexylmethyl) -2 (R) - [1 (S) - [(tetrahydro- ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide, 0.116 g of (E) (Cyclohexylmethyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydra The zide was obtained in the form of a white solid.
MS: 494 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution increasing from solvent A containing 5% solvent B to 95% solvent B for 15 minutes; Flow rate of 1 ml / min. Retention time: 13.67 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl -2 (R) - (3-methylbutanoyl) -2 '-( methanesulphonyl) -4-methylvalerohydrazide was prepared in a similar manner as described in example 15, part (iii) Phenyl] -3-butenyl] -2 '-( methanesulphonyl) -4-methylvalerohydra &lt; / RTI &gt;Lt; RTI ID = 0.0 &gt; cyclohexylmethyl &lt; / RTI &gt; bromide.
Example 32
2 (R) - [1 (R) - (hydroxycarbamoyl) -2-phthalimidoethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, starting from 0.14 g of 2 (R) - [1 (R) - [(tetrahydro-2 (RS) -pyranyloxy) Starting from 0.092 g of 2 (R) - [1 (R) - (hydroxycarbamoyl) - (methylsulfonyl) -4-methyl-2'-phenylvalerohydrazide, 2-phthalimidoethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a white solid.
MS: 517 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution using Solvent A containing 10% Solvent B for 5 minutes and increasing to 90% Solvent B from 5 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 15.52 min. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.
(R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2-phthalimidoethyl] -2 '-( methanesulfonyl) - 4-methyl-2 ' -phenylvalerohydrazide was prepared as follows:
(R) - (tert-Butoxycarbonyl) -2-phthalimidoethyl] -4- (4-methoxyphenyl) propanoate in a similar manner to that described in Example 2, Parts (iii) Yl) -2 '-( methanesulphonyl) -2 '-( methanesulphonyl) carbamic acid starting from 2- (R) - [ Sulfonyl) -4-methyl-2 &apos; -phenylvalerohydrazide in the form of a white solid.
MS: 601 (M + H) &lt; ⁺ & gt ^; .
Example 33
2 (R) - [2-benzamido-1 (R) - (hydroxycarbamoyl) ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide
(R) - [(R) - [(tetrahydro-2 (RS) -pyranyloxy)] carba (R) - [2-benzamido-1 (R) - (methylsulfonyl) -4-methyl-2 ' -phenylvalerohydrazide, (Hydroxycarbamoyl) ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a white solid.
MS: 491 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution using Solvent A containing 5% Solvent B for 5 minutes and increasing to 95% Solvent B from 5 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 15.54 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide was prepared as follows:
(i) A solution of 2 (R) - [1 (R) - (tert-butoxycarbonyl) -2-phthalimidoethyl] -2 '-( methanesulfonyl) -Phenylvalerohydrazide in 50 ml of tetrahydrofuran was treated with 0.51 ml of hydrazine hydrate. The mixture was stirred under nitrogen overnight and then evaporated. The residue was stirred with 25 mL of dichloromethane / methanol / acetic acid / water (120: 15: 3: 2). After 2 hours, the precipitated solid was removed by filtration and the filtrate was evaporated. The residue was purified by chromatography on Kieselgel 60 using elution with dichloromethane / methanol / acetic acid / water (240: 24: 3: 2). Fractions containing the amine product were combined and evaporated, and the residue was dissolved in 30 mL of dichloromethane and washed with three portions of 10 mL of saturated sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the solution was evaporated to give 0.42 g of 2 (R) - [2-amino-1 (R) - (tert- butoxycarbonyl) ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a light yellow foam.
MS: 428 (M + H) &lt; ⁺ & gt ^; .
(ii) A mixture of 0.42 g of the amine prepared in part (i) and 0.138 g of benzoic acid in 7 ml dimethylformamide was cooled to 0 C with stirring and 0.335 g of 1-ethyl-3- (3-dimethylaminopropyl ) Carbodiimide was added. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate layer was washed successively with saturated sodium bicarbonate solution, 5% citric acid solution, water and saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. Ethyl acetate was evaporated and the residue triturated with a mixture of ether and hexane to give 0.331 g of 2 (R) - [2-benzamido-1 (R) - (tert- butoxycarbonyl) - (methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide as an off-white solid.
MS: 532 (M + H) &lt; ⁺ & gt ^; .
(R) - (2-benzamido-1 (R) - (tert-butoxycarbonyl) ethyl) -methanone in a similar manner to that described in Example 2, Parts (iii) ] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide there was obtained 2 (R) - [2-benzamido- (RS) -pyranyloxy) carbamoyl] ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a white solid.
MS: 575 (M + H) &lt; ⁺ & gt ^; .
Example 34
(R) - (hydroxycarbamoyl) ethyl] -2 '-( methanesulfonyl) -4- Methyl-2 ' -phenylvalerohydrazide
In analogy to the procedure described in the first paragraph of Example 2, starting from 0.195 g of 2 (R) - [2 - [(5-bromo-2-furyl) carboxamido] Starting from 0.127 g of 2 (R) -tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ethyl] -2 '-( methanesulfonyl) (R) - (hydroxycarbamoyl) ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -Phenylvalerohydrazide in the form of a cream solid.
MS: 560 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.69 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(tetrahydro-2 (RS) -pyranyloxy) carbazole &lt; / RTI &gt; Yl] ethyl] -2 &apos;-( methanesulfonyl) -4-methyl-2 &apos; -phenylvalerohydrazide was prepared as follows:
(R) - (tert-butoxycarbonyl) ethyl] -2 ' - (2-amino-1 H) -quinolinone in analogy to the method described in example 33, part (ii) (R) - [2 - [(5-bromo-2- (trifluoromethyl) -2-methoxy-benzenesulfonyl] (R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenyl The valero hydrazide was obtained in the form of a gray solid.
MS: 644 (M + H) &lt; ⁺ & gt ^; .
Example 35
Ethyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 2-thiazolyl) - phenylvalerohydrazide
(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- [ (2-thiazolyl) carboxamido] ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide there was obtained 0.041 g of 2 (R) - [ 2 '- (hydroxycarbamoyl) -2 - [(2-thiazolyl) carboxamido] ethyl] -2 '-( methanesulfonyl) -4-methyl-2 &apos; -phenylvalerohydrazide was reacted with Obtained as a gray solid.
MS: 498 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.14 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2 - [(2- thiazolyl) carboxamido] ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide was prepared as follows:
(R) - (tert-butoxycarbonyl) ethyl] -2 ' - (2-amino-1 H) -quinolinone in analogy to the method described in example 33, part (ii) (R) - [(R) - [(tetrahydro-2 (RS) - Carbamoyl] -2 - [(2-thiazolyl) carboxamido] ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide as a white solid Lt; / RTI &gt;
MS: 582 (M + H) &lt; ⁺ & gt ^; .
Example 36
Ethyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 2-thienylcarbamoyl) - phenylvalerohydrazide
(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- [ (2-thienyl) carboxamido] ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide, 0.115 g of 2 (R) - (hydroxycarbamoyl) -2 - [(2-thienyl) carboxamido] ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide was reacted with Obtained as a white solid.
MS: 497 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.39 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
2 - [(2-thienyl) carboxamido] ethyl] -1,2,3,4-tetrahydronaphthalene- -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide was prepared as follows:
(R) - (tert-butoxycarbonyl) ethyl] -2 ' - (2-amino-1 H) -quinolinone in analogy to the method described in example 33, part (ii) (RS) - [(tetrahydro-2 (RS) - [(R) (Methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide was obtained as white Obtained as a solid.
MS: 581 (M + H) &lt; ⁺ & gt ^; .
Example 37
2 '- (methanesulfonyl) -4-methyl-2'-phenylvalerohyde (2R) - [1 (R) - (hydroxycarbamoyl) -2- Dragged
(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- ( Starting from 0.072 g of 2 (R) - [1 (R) - (hydroxymethyl) -2 '-( methanesulphonyl) 2- (3-phenylureido) ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a white solid.
MS: 507 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.91 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
2- (3-Phenylureido) ethyl] -2 '-( 2-methoxy-benzoyl) Methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide was prepared as follows:
(i) A solution of 2 (R) - [2-amino-1 (R) - (tert- butoxycarbonyl) ethyl ] -2 '- (methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide, 0.325 ml of N, N-diisopropylethylamine and 0.21 ml of phenyl isocyanate was stirred under nitrogen for 2.5 hours Gt; 60 C &lt; / RTI &gt; The solvent was evaporated and the residue was partitioned between ethyl acetate and 1 M hydrochloric acid. The ethyl acetate solution was separated and washed with sodium bicarbonate solution and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give 0.705 g of 2 (R) - [1 (R) - (tert-butoxycarbonyl) -2- (3- phenylureido) ethyl] -2 ' Trifluoromethyl-phenyl) -4-methyl-2 &apos; -phenylvalerohydrazide in the form of a white solid.
MS: 547 (M + H) &lt; ⁺ & gt ^; .
(R) - [(R) - (tetrahydro-furan-2-yl) -methanone &lt; / RTI &gt; starting from the hydrazide prepared in the preceding paragraph, in a manner similar to that described in Example 2, Parts (iii) 2 '- (methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was obtained as a white solid Lt; / RTI &gt;
MS: 590 (M + H) &lt; ⁺ & gt ^; .
Example 38
Ethyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 2-pyrrolidin- Phenylvalerohydrazide
(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- [ (2-thienyl) sulfonamido] ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide there was obtained 0.066 g of 2 (R) - [1 ) - (hydroxycarbamoyl) -2 - [(2-thienyl) sulfonamido] ethyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide as a white solid Lt; / RTI &gt;
MS: 533 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.65 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
2 - [(2-thienyl) sulfonamido] ethyl] - &lt; / RTI &gt; 2 &apos;-( methanesulfonyl) -4-methyl-2 &apos; -phenylvalerohydrazide was prepared as follows:
(i) To a solution of 2 (R) - [2-amino-1 (R) - (tert- butoxycarbonyl) ethyl] -2 '-( methanesulfonyl) '-Phenylvalerohydrazide in 10 ml of dichloromethane was cooled to 0 ° C with stirring and 0.242 g of 2-thiophenesulfonyl chloride was added. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous citric acid. The ethyl acetate layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with ether to give 0.487 g of 2 (R) - [1 (R) - (tert-Butoxycarbonyl) -2 - [(2-thienyl) sulfonamido] ethyl] Methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a white solid.
MS: 574 (M + H) &lt; ⁺ & gt ^; .
(R) - [(R) - (tetrahydro-furan-2-yl) -methanone &lt; / RTI &gt; starting from the hydrazide prepared in the preceding paragraph, in a manner similar to that described in Example 2, Parts (iii) 2 (RS) -pyranyloxy) carbamoyl] -2 - [(2-thienyl) sulfonamido] ethyl] -2 &apos;-( methanesulfonyl) -4-methyl-2 &apos; -phenylvalerohydra The zide was obtained in the form of a white solid.
MS: 581 (M + H) &lt; ⁺ & gt ^; .
Example 39
(E) -2 '-( benzylsulfonyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] Lohia Dragaj
(RS) - [1 (S) - [(tetrahydro-2 (RS) -2- ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide there was obtained 0.051 g of (E) -2 '-( benzylsulfonyl ) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide as a white solid .
MS: 550 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.62 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl -3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide was prepared as follows:
(i) In a similar manner to that described in Example 1, Part (ii), 0.3 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) (E) -2 '-( benzylsulfonyl) -2 &lt; RTI ID = 0.0 &gt; (R) -phenyl- &lt; / RTI &gt; hydrazide and 0.543 g benzylsulfonyl chloride, [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylhydrazide in the form of a white solid.
MS: 591 (M + H) &lt; ⁺ & gt ^; .
(E) -2- (benzylsulfonyl) - 2 (2) from the hydrazide prepared in the preceding paragraph in a manner similar to that described in Example 1, Part (iii) and Example 2, Carbonyl] -4-phenyl-3-butenyl] -4-methyl-2 ' -phenylvalerohydra &lt; / RTI &gt; (R) - [1 (S) - [(tetrahydro- The zide was obtained in the form of a white solid.
MS: 634 (M + H) &lt; ⁺ & gt ^; .
Example 40
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Hydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.098 g of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) Phenyl) -3-butenyl] -2 '-( methanesulfonyl) -3-methyl-2 ' -phenylbutyl hydrazide there was obtained 0.054 g of (E) S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -3-methyl-2 ' -phenylbutyl hydrazide as a gray solid.
MS: 460 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.72 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (methanesulfonyl) -3-methyl-2 ' -phenylbutyl hydrazide was prepared as follows:
Starting from 4-tert-butyl-hydrogen 2 (R) -isopropyl succinate, (E) -2 (R) - [ Phenyl) -3-butenyl] -2 '-( methanesulphonyl) -3-methyl-2 ' -phenyl- Butyl hydrazide in the form of a white solid.
MS: 544 (M + H) &lt; ⁺ & gt ^; .
Example 41
(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyl (E) -2 ' -acetyl-2 '-( R) - [ 1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide in the form of a white solid.
MS: 438 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.29 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3- 2-phenylvalerohydrazide is prepared in a manner similar to that described in Example 4, Part (i) and (ii), as described in Example 2, Part (i) Starting from (E) -2 (R) - [1 (R) - (tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methyl valeric acid.
Example 42
(E) -2 '-( ethylcarbamoyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] Lohia Dragaj
To a solution of (E) -2 '-( ethylcarbamoyl) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) Yl] -4-phenyl-3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide in 10 ml of tetrahydrofuran was treated with 9 ml of methanesulfonic acid. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated. The residue was triturated with 5% sodium bicarbonate solution and dissolved in diethyl ether. The solution was dried over magnesium sulfate and evaporated to give a rubber. Chromatography on silica gel using elution with dichloromethane / methanol (19: 1) gave 0.02 g of (E) -2 '- (ethylcarbamoyl) -2 (R) - [1 (S) - Methyl-2-phenylvalerohydrazide as a white solid.
MS: 467 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution gradient from solvent A containing 40% solvent B to 60% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.80 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl -3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide was prepared as follows:
(i) A mixture of (E) -2 (R) - [1 (S) -3-butoxycarbonyl- Phenyl-3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide was heated with 0.88 ml of ethyl isocyanate under nitrogen at 0 &lt; To obtain a rubber. Chromatography on silica gel using hexane / ethyl acetate (2: 1) to elute gave 0.65 g of (E) -2 '-( ethylcarbamoyl) -2 (R) - [1 (S) -4-methyl-2 &apos; -phenylvalerohydrazide as a white foam.
(ii) 0.64 g of tert-butyl ester prepared according to part (i) was treated with a solution of 50% trifluoroacetic acid in dichloromethane at room temperature for 3 hours and evaporated. Toluene was added twice and evaporated each time. Purification of the residue by chromatography on silica gel using dichloromethane / methanol (19: 1) to elute gave 0.36 g of (E) -2 '-( ethylcarbamoyl) -2 (R) Carboxy-4-phenyl-3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide as a glass.
(iii) 0.35 g of the carboxylic acid prepared according to part (ii) was dissolved in 3 ml of dimethylformamide and cooled to 0 <0> C to give 0.26 g of O- (tetrahydro-2H-pyran- ) Hydroxylamine and 0.215 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was stirred at room temperature overnight and then poured into water. The solid was removed by filtration and washed sequentially with 2M hydrochloric acid solution, water, 5% sodium hydrogencarbonate solution and water, and then dried under vacuum. Chromatography on silica gel using hexane / ethyl acetate (1: 1) to elute gave 0.2 g of (E) -2 &apos;-( ethylcarbamoyl) -2 (R) - [l (S) - [(tetrahydro -2 (RS) -pyranyloxy) -carbamoyl] -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide as a white foam.
MS: 551 (M + H) &lt; ⁺ & gt ^; .
Example 43
(E) -2 '-( benzylcarbamoyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] Lohia Dragaj
To a solution of 0.17 g of (E) -2 '-( benzylcarbamoyl) -2 (R) - [1 (S) - {(O- tert- butyldimethylsilyl) hydroxycarbamoyl} Butenyl] -4-methyl-2'-phenylvalerohydrazide was stirred at room temperature in 5 ml of acetic acid / water / tetrahydrofuran (3: 1: 1) for 1.5 hours. The solvent was evaporated and the residue triturated with diethyl ether to give 0.03 g of (E) -2 '-( benzylcarbamoyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide as a white solid.
TLC: dichloromethane / methanol (3: 1) Rf = 0.43.
MS: 529 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.14 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - {(O-tert-butyldimethylsilyl) hydroxycarbamoyl} -4-phenyl- 3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide was prepared as follows:
-2 (R) - [1 (S) -carboxy-4-phenyl-3 (benzylcarbamoyl) -Butenyl] -4-methyl-2 ' -phenylvalerohydrazide.
0.72 g of the carboxylic acid prepared in the preceding paragraph was dissolved in 2 ml of dimethylformamide cooled to 0 ° C and 1.0 g of O- (tert-butyldimethylsilyl) hydroxylamine, 0.2 ml of N-ethylmorpholine and 0.3 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was stirred at room temperature overnight and evaporated. The residue was dissolved in dichloromethane and washed sequentially with 5% sodium bicarbonate solution, water, 2M hydrochloric acid, water, 5% sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give a brown semi- &Lt; / RTI &gt; Chromatography on silica gel eluting with dichloromethane / methanol (33: 1) followed by trituration with ethyl / hexane afforded 0.19 g of (E) -2 &apos;-( benzylcarbamoyl) -2 (R) (S) - {(O-tert-butyldimethylsilyl) hydroxycarbamoyl} -4-phenyl-3-butenyl] -4-methyl-2'-phenylvalerohydrazide as a solid.
TLC: dichloromethane / methanol (9:10): Rf = 0.65.
Example 44
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl Valero Hydrazide
(R) - [1 (S) - ({O-4-methoxybenzyl} hydroxycarbamoyl} -4-phenyl-3-butenyl] - 2 '- (methanesulfonyl) -4-methylvalerohydrazide was dissolved in a mixture of 2.5 ml of dichloromethane, 0.35 ml of trifluoroacetic acid and 0.1 ml of anisole at 0 DEG C. The mixture was stirred at room temperature for 6 hours The residue was triturated with diethyl ether to give 0.06 g of (E) -2 ' -cyclohexyl-benzoic acid as a colorless solid, mp &lt; RTI ID = 0.0 &gt; 2 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 &apos;-( methanesulfonyl) -4-methylvalerohydrazide as a white solid Respectively.
MS: 480 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.39 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(E) -2 ' -cyclohexyl-2 (R) - [1 (S) - {{O- 4- methoxybenzyl} hydroxycarbamoyl) ] -2 '-( methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(i) A solution of 10 g of (E) -2 (R) - [(1S) - (tert- butoxycarbonyl) -4-phenyl- 3-butenyl] -4-methylvaleric acid in 100 ml dichloromethane The solution was treated with 0.61 g of 4-dimethylaminopyridine, 6.1 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and 2.4 ml of methanol at 0 占 폚. The mixture was stirred at 0 &lt; 0 &gt; C for 1 hour, warmed to room temperature, then stirred for further 3 hours and evaporated. The residue in diethyl ether was washed sequentially with 2M hydrochloric acid, water and 5% sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give a brown oil. Elution was followed by chromatography on silica gel with hexane / diethyl ether (9: 1) followed by evaporation to give 6.9 g of diester. This was dissolved in a mixture of 45 ml of dichloromethane and 45 ml of trifluoroacetic acid, the solution was stirred for 2 hours and then evaporated. Toluene (2 x 30 mL) was added and evaporated to remove traces of trifluoroacetic acid and the product was dried under vacuum to give the succinate monomethyl ester as a light tan solid.
(ii) 2.0 g of the above succinate monomethyl ester was dissolved in 20 ml of dimethylformamide and the solution was cooled to 0 &lt; 0 &gt; C. 1.0 g of hydroxybenzotriazole hydrate, 1.5 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1.7 mL of N-ethylmorpholine and 1.5 g of O- Hydroxybenzyl) hydroxylamine were added. The mixture was stirred for 0.5 h at 5 &lt; 0 &gt; C and 2.5 h at room temperature and then evaporated under high vacuum. The residue in ethyl acetate was washed sequentially with 5% sodium bicarbonate solution, 2M hydrochloric acid, water, 5% sodium bicarbonate and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give a solid. Chromatography on silica gel using ethyl acetate / hexane (1: 4) to elute gave 1.83 g of methyl (E) -2 (R) - [(1S- ({O- (4-methoxybenzyl) Yl) -4-phenyl-3-butenyl] -4-methylvalerate as an oil which solidified upon standing to give a white solid.
MS: 440 (M + H) &lt; ⁺ & gt ^; .
(iii) 3.45 mL of a solution of trimethylaluminum (2M in hexane) was added dropwise to a suspension of 1.03 g of cyclohexylhydrazine in 5 mL dichloromethane under nitrogen. A vigorous release of gas was observed, and the solids dissolved slowly over a period of one hour, resulting in Solution A.
(iv) 0.44 g of the methyl ester prepared according to (ii) was dissolved in 4 ml of dichloromethane, solution A was added and the mixture was allowed to warm up in a water bath for 6 hours (bath temperature 45 ° C). The solution was cooled and treated very carefully with excess 2M hydrochloric acid (vigorous gas evaporation) and then extracted twice with 20 ml each time of ethyl acetate. The organic phase was washed sequentially with 5% sodium bicarbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to give a yellow rubber. Chromatography on silica gel using dichloromethane / methanol (24: 1) to elute yielded 0.19 g of hydrazide.
MS: 522 (M + H) &lt; ⁺ & gt ^; .
(v) 0.11 g of the hydrazide prepared according to (iv) was suspended in a mixture of 5 ml of dichloromethane and 0.026 ml of pyridine under nitrogen. 0.046 g of methanesulfonic anhydride was added and the mixture was stirred at room temperature for 3 hours and then diluted with 15 ml of dichloromethane. The solution was washed sequentially with 2 M hydrochloric acid, water and 5% sodium bicarbonate solution, dried over magnesium sulfate and then evaporated to give a white foam. Trituration with diethyl ether afforded 0.095 g of (E) -2 ' -cyclohexyl-2 (R) - [1 (S) - ({O- 4- methoxybenzyl} hydroxycarbamoyl) 3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide as a white solid.
MS: 600 (M + H) &lt; ⁺ & gt ^; .
Example 45
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-( methanesulfonyl) Valero Hydrazide
To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Butenyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in 50 ml of tetrahydrofuran was treated with 0.006 ml of methanesulfonic acid. The mixture was stirred at room temperature for 3 hours and then the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was triturated with hexane to give 0.119 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- (Methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 454 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.17 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(i) To a solution of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid in 10 ml of dichloromethane A solution of 0.60 g of hydrazide, 0.166 ml of isobutyraldehyde and a solution of crystals of 4-toluenesulfonic acid was stirred for 1 hour on 4 A molecular sieves. The mixture was filtered, the solvent was evaporated and replaced with 10 mL of methanol. A small amount of crystals of bromocresol green was added to obtain a yellow solution. To this was added 0.116 g of sodium cyanoborohydride in small batches. The yellow color of the solution was maintained by cyclic addition of a 4M solution of hydrogen chloride in dioxane. The methanol was evaporated and the residue was partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The aqueous layer was washed twice with dichloromethane and then the combined organic layers were washed twice with 5% aqueous sodium hydrogen carbonate solution. The dichloromethane layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using hexane / ethyl acetate (7: 3) to elute. (E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl- Lt; / RTI &gt; as a white solid.
MS: 417 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 2, Part (iv) and (v), 0.435 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) Starting from 0.249 g of (E) -2 (R) - [1 (S) - [(tetra Phenyl) -3-butenyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide as a white Obtained as a solid.
MS: 538 (M + H) &lt; ⁺ & gt ^; .
Example 46
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isopropyl-2 '- (methanesulfonyl) Valero Hydrazide
-2 (R) - [1 (S) - (hydroxycarbamoyl) - (R) - [ Phenyl-3-butenyl] -2 ' -isopropyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 440 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.16 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 47
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-cyclopentyl- Valero Hydrazide
-2 (R) - [1 (S) - (hydroxycarbamoyl) -2H-pyrrolo [2,3-d] pyrimidine was prepared in a manner similar to that described in Example 45 but using cyclopentanone instead of isobutyraldehyde in step (i) ) -4-phenyl-3-butenyl] -2'-cyclopentyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 466 (M + H) &lt; ⁺ & gt ^; .
HPLC: Accelerated gradient elution with solvent A containing 20% Solvent B for 2 min followed by increasing to 80% Solvent B over 18 min; Flow rate of 1 ml / min. Retention time: 17.57 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 48
(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4- tetrahydropyranyl) Trifluoromethyl-phenyl) -4-methylvalerohydrazide
(E) -2 (R) - [1 (S (R) -2, 3-dihydroxy-4-methylpiperazin-1-yl) -ethanone in a similar manner to that described in Example 45, but using tetrahydro- ) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4- tetrahydropyranyl) -2 '-( methanesulfonyl) -4-methylvalerohydrazide as white Obtained as a solid.
MS: 482 (M + H) &lt; ⁺ & gt ^; .
HPLC: Accelerated gradient elution with solvent A containing 20% Solvent B for 2 min followed by increasing to 80% Solvent B over 18 min; Flow rate of 1 ml / min. Retention time: 13.72 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 49
(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4- tetrahydrothiopyranyl) Sulfonyl) -4-methylvalerohydrazide
-2 (R) - [1 (S) - (R) - (2R) -2- (Hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4-tetrahydrothiopyranyl) -2 '-( methanesulfonyl) -4-methylvalerohydrazide as a white solid Lt; / RTI &gt;
MS: 498 (M + H) &lt; ⁺ & gt ^; .
HPLC: Accelerated gradient elution using Solvent A containing 20% Solvent B for 2 minutes followed by increasing to 80% Solvent B over 18 minutes; Flow rate of 1 ml / min. Retention time: 17.35 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 50
(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4-piperidinyl) -2 '-( methanesulfonyl ) -4-methylvalerohydrazide
(E) -2 (R) -methanone in a manner analogous to that described in Example 45, but using 1-3-butoxycarbonyl-4-piperidinone instead of isobutyraldehyde in step (i) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4-piperidinyl) -2 '-( methanesulfonyl) Lt; / RTI &gt; as a white solid.
MS: 481 (M + H) &lt; ⁺ & gt ^; .
HPLC: Accelerated gradient elution using Solvent A containing 20% Solvent B for 2 minutes followed by increasing to 80% Solvent B over 18 minutes; Flow rate of 1 ml / min. Retention time: 11.39 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 51
(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( isobutyl) -2 '-( isopentanoyl) -4 - methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.047 g of (E) -2 (R) -4-methyl-3-butenyl] -2 '-( isobutyl) - (1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( isobutyl) -2 '-( isopentanoyl) -4-methylvalerohydrazide Obtained as a white solid.
MS: 460 (M + H) &lt; ⁺ & gt ^; , 482 (M + Na) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.79 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] - (isobutyl) -2 '-( isopentanoyl) -4-methylvalerohydrazide was prepared as follows:
(i) To a solution of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- A solution of 0.25 g of 4-methylvalerohydrazide, 0.061 ml of pyridine and crystals of 4-dimethylaminopyridine was cooled to 0 &lt; 0 &gt; C under a nitrogen atmosphere. 0.091 ml of isopentanoyl chloride was added and the reaction mixture was allowed to warm to room temperature. After stirring for 2 hours at room temperature, the reaction mixture was diluted with dichloromethane and washed with 2M aqueous hydrochloric acid and then brine. The dichloromethane phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was then dissolved in 10 ml of a 20% solution of trifluoroacetic acid in dichloromethane and stirred for 2 hours at room temperature. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel using 1% methanol in dichloromethane to elute. (E) -2 (R) - [1 (S) - (carboxy) -4-phenyl-3-butenyl] -2 &apos;-( isobutyl) -2 &apos;-( isopentanoyl) -4 -Methylvalerohydrazide in the form of a white foam.
MS: 445 (M + H) &lt; ⁺ & gt ^; .
(E) -2 (R) - [1 (S) - (carboxy) -4-phenyl-3-butenyl] Starting from 0.097 g of (E) -2 (R) - [1 (S) - [(2-isopropylpiperidin- (Isobutanoyl) -4-methylvalerohydra (2-methoxyphenyl) -3-butenyl] -2 '-( isobutyl) -2 '-( isopentanoyl) The zide was obtained in the form of a white solid.
MS: 544 (M + H) &lt; ⁺ & gt ^; .
Example 52
(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( isobutyl) -2 '-( cyclohexanecarbonyl) 4-methylvalerohydrazide
-2 (R) - [1 (S) - (hydroxymethyl) -2, 3-dihydroxybenzoyl chloride in a similar manner to that described in Example 51, but using cyclohexanecarbonyl chloride instead of isopentanoyl chloride in step Phenyl-3-butenyl] -2 '-( isobutyl) -2 '-( cyclohexanecarbonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 486 (M + H) &lt; ⁺ & gt ^; .
HPLC: Accelerated gradient elution using Solvent A containing 35% Solvent B for 5 minutes and increasing to 70% Solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 15.44 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 53
(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-N- (2,6-dioxopiperidino) valeramide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] (E) -2 (R) - [1 (S) -tetrahydroisoquinolin-2- - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-N- (2,6-dioxopiperidino) valeramide as a white solid.
MS: 416 (M + H) &lt; ⁺ & gt ^; .
HPLC: Accelerated gradient elution using Solvent A containing 20% Solvent B for 5 minutes and increasing to 70% Solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.79 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4- Methyl-N- (2,6-dioxopiperidino) valeramide was prepared as follows:
(i) To a solution of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohyyridine in 30 ml anhydrous toluene A solution of 1.0 g of Drazide, 0.35 g of glutaric anhydride and 0.85 ml of triethylamine was heated to reflux under a nitrogen atmosphere for 7 hours. The mixture was cooled to room temperature and washed with 2M aqueous hydrochloric acid, 5% aqueous sodium bicarbonate and brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was triturated with diethyl ether to give 0.623 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl- N- (2,6-dioxopiperidino) valeramide as a white solid.
MS: 457 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 2, Part (iv) and (v), 0.62 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) Starting from 0.095 g of (E) -2 (R) - [1 (S) -Phenyl-3-butenyl] -4-methyl-N- (2,6-dioxopiperidino) valeramide, Phenyl) -3-butenyl] -4-methyl-N- (2,6-dioxopiperidino) valeramide as a white solid in the form of a white solid .
MS: 500 (M + H) &lt; ⁺ & gt ^; .
Example 54
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] - 4-methylvaleramide
(E) -N- (tetrahydro-1,2-thiazin-2-yl) -2 (R) - [1 (S) Starting from 0.01 g of (E) -N- (tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleramide. (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleramide as a white solid .
MS: 438 (M + H) &lt; ⁺ & gt ^; .
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyl Oxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleramide was prepared as follows:
(i) A solution of 5.64 g of tert-butyl ester of leucic acid and 3.6 ml of pyridine in 40 ml of dichloromethane is added dropwise to a solution of 6.0 ml of trifluoromethane sulfonic anhydride in 60 ml of dichloromethane at 0 & . After 10 minutes the mixture was washed twice with water and then dried over anhydrous magnesium sulfate. The mixture was concentrated to approximately 1/3 of its original volume and then treated with 1.32 g of a 60% suspension of sodium hydride in mineral oil in mineral oil under a nitrogen atmosphere for 2 hours under a nitrogen atmosphere with 5.22 g of tert-butylmethylmalonate in 50 ml of dimethylformamide (0 &lt; 0 &gt; C) solution of the resulting anion. The mixture was allowed to warm to room temperature overnight and then the solvent was evaporated. The residue was dissolved in ethyl acetate and the solution was washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to give 10.0 g of 1,2,3-butyl-1,4-dimethyl-1,1,2 (R) -pentane-tricarboxylate in the form of a red oil .
(ii) 1.53 g of a 60% suspension of sodium hydride in mineral oil was added dropwise to a solution of 1,2,3-butyl-1,4-dimethyl-1,1,2 (R) -pentanetricarboxylic acid in 120 ml of dimethylformamide Lt; RTI ID = 0.0 &gt; ml &lt; / RTI &gt; The mixture was stirred until the gas evolution ceased (about 1 hour), a solution of 7.54 g of cinnamylbromide in 70 ml of dimethylformamide was added dropwise and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate and washed twice with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel using hexane / ethyl acetate (9: 1) to elute. (E) -1,2,3-Butyl-1,4-dimethyl-1- (3-phenyl- Pentanetricarboxylate in the form of a pale yellow oil.
(iii) To a solution of (E) -1,2-tert-butyl-1,4-dimethyl-1- (3-phenylprop- -Yl) -1,1,2 (R) -pentanetricarboxylate in 10 ml of tetrahydrofuran was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was dissolved in 20 mL of toluene. 1.6 ml of triethylamine was added and the mixture was stirred at reflux temperature for 2 hours. After cooling, the mixture was washed with 2M aqueous hydrochloric acid and water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to give a pale yellow oil. The oil was dissolved in 10 mL of hexane and 0.6 g of cyclohexylamine was added. The resulting salt was collected by filtration, then suspended in 20 mL of ether and washed with 1 M sulfuric acid. The ether phase was dried over anhydrous magnesium sulphate and evaporated to give 1.5 g of (E) -2 (R) -isobutyl-4-methyl-3 - [(RS) ) -Succinate as a white solid.
(iv) A solution of 40 g of 4-chloro-1-butanesulfonyl chloride in 400 ml of diethyl ether was added dropwise at room temperature to a solution of 30.4 g of tert-butyl carbazate and 17 ml of pyridine in 400 ml of diethyl ether . The mixture was stirred at room temperature for 72 hours and then washed with water. The organic phase was separated and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting oily residue was purified by flash column chromatography on silica gel using hexane / ethyl acetate (increasing to 8: 2, 6: 4) to elute. 10.25 g of tert-butyl 2 - [(4-chlorobutyl) sulfonyl] carbazate were obtained in the form of a white solid.
(v) 1.7 g of a 60% suspension of sodium hydride in mineral oil was added to a solution of 10.25 g of tert-butyl-2 - [(4-chlorobutyl) sulfonyl] carbazate in 300 ml of anhydrous tetrahydrofuran under nitrogen atmosphere at room temperature . After stirring at room temperature for 48 hours, the solvent was evaporated and the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from ethyl acetate / hexane to give 1.86 g of tert-butyl (tetrahydro-1,2-thiazin-2-yl) carbamate S, S-dioxide in the form of a light yellow solid.
(vi) A solution of 1.86 g of tert-butyl (tetrahydro-1,2-thiazin-2-yl) carbamate S, S-dioxide in 20 ml of 4 M hydrogen chloride in ethyl acetate was stirred at room temperature for 1 hour . The solvent was evaporated and the residue was stirred in ether for 5 min and then filtered to give 1.24 g of tetrahydro-l, 2-thiazin-2-amine S, S-dioxide in the form of a white solid.
(vii) To a solution of 1.39 g of (E) -2 (R) -isobutyl-4-methyl-3 [(RS) -3-phenylprop-2-en- 1 -yl)] succinate in 15 ml of dichloromethane Was cooled to -10 &lt; 0 &gt; C under a nitrogen atmosphere. 4 drops of dimethylformamide and 0.418 ml of oxalyl chloride were added and the mixture was warmed to 0 &lt; 0 &gt; C over 1 hour. The solvent was evaporated and replaced with 2 mL of dichloromethane. The resulting solution was then added dropwise to a solution of 1.24 g of tetrahydro-1,2-thiazin-2-amine S, S-dioxide and 1.4 ml of triethylamine in 20 ml of dichloromethane at 0 ° C under a nitrogen atmosphere. The mixture was maintained at 0 &lt; 0 &gt; C overnight and then washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate / hexanes (2: 8, increasing to 10: 0). A solution of 0.44 g of (E) -N- (tetrahydro-1,2-thiazin-2-yl) -2 (R) - [1 (S) - (methoxycarbonyl) &Lt; / RTI &gt; thienyl] -4-methylvaleramide as a white solid.
(viii) 0.573 ml of a 2M solution of trimethylaluminum in toluene is added to a solution of 0.134 g of O- (tetrahydro-2H-pyran-2 (RS) -yl) hydroxylamine in 5 ml anhydrous toluene at 0 & Respectively. The mixture was stirred at room temperature for 1 hour and then 0.10 g of (E) -N- (tetrahydro-1,2-thiazin-2-yl) -2 (R) - [1 (S) Carbonyl) -4-phenyl-3-butenyl] -4-methylvaleramide was added in one portion. The mixture was heated at 55 &lt; 0 &gt; C for 3 h and then cooled to room temperature overnight. The mixture was diluted with ethyl acetate and washed successively with 2M aqueous hydrochloric acid and 5% aqueous sodium bicarbonate, then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was triturated with diethyl ether to give 0.048 g of (E) -N- (tetrahydro-1,2-thiazin-2-yl) -2 (R) - [1 (S) - [ (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleramide in the form of a white solid.
MS: 522 (M + H) &lt; ⁺ & gt ^; .
Example 55
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 ' -phenyl hexanoylhydrazide
(R) - [1 (S) - [(carboxy) -4-phenyl-3-butenyl] -2 ' - (methanesulfonyl) -2'-phenylhexanohydrazide, 0.10 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) Butenyl] -2 '-( methanesulfonyl) -2 ' -phenylhexanoahydrazide as a white solid.
MS: 474 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.97 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(E) -2 (R) - [1 (S) - (carboxy-4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 ' -phenyl hexanohydrazide Was prepared as follows:
(i) By analogy with the method described in example 54, parts (i) and (ii), but using benzyl 2-hydroxy-hexanoate and benzyl t-butyl- Yl) -1,1,2 (R) -hexanetricarboxylate as a yellow oil &lt; RTI ID = 0.0 &gt;Lt; / RTI &gt;
(ii) A solution of 2.27 g of sodium hydroxide in 20 ml of water was added dropwise to a solution of (E) -1,2-dibenzyl-l-tert-butyl- l- (3-phenylprop- -Yl) -1, 1, 2 (R) -hexanetricarboxylate in 10 ml of tetrahydrofuran. The mixture was heated to reflux overnight, then cooled and evaporated. The residue was diluted with water and acidified to pH 1 with concentrated hydrochloric acid. The aqueous phase was washed twice with ethyl acetate and the combined organic phases were washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in 50 mL of toluene. 1.53 ml of triethylamine was added to the mixture, followed by heating to reflux for 3.5 hours and cooling overnight. The mixture was washed with 2M aqueous hydrochloric acid and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the yellow oil obtained was dissolved in hexane and treated with 1.09 g of cyclohexylamine to give the salt which was collected by filtration. The salt was then partitioned between ethyl acetate and 1N sulfuric acid and the organic phase was washed successively with water, dried over anhydrous magnesium sulfate and evaporated to give 1.3 g of (E) -2 (R) -butyl- 3 - [(RS) - (3-phenylprop-2-en-1-yl)] succinate as a light yellow solid.
(R) -butyl-4-tert-butyl-3 - [(RS) - (3) (R) - [1 (S) - (carboxy)] - 4-phenyl-3-butenyl] -piperidin- -2 '-( methanesulfonyl) -2 ' -phenylhexanoahydrazide as a white solid.
MS: 459 (M + H) &lt; ⁺ & gt ^; .
Example 56
(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 ' Hydrazide
(E) -2 (R) - [1 (S) - ({O-4-methoxybenzyl} hydroxycarbamoyl) -4 (E) -2 (R) - [1 (S) -phenyl-3-butenyl] -2 '-( methanesulfonyl) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '- (methanesulfonyl) -2', 3-diphenylpropionohydrazide as a white solid.
MS: 508 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.25 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(E) -2 (R) - [1 (S) - ({O-4- methoxybenzyl} hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- Methanesulfonyl) -2 ', 3-diphenylpropionohydrazide was prepared as follows:
(E) - (R) - [l- (3-Methoxy-benzenesulfonyl) -propyl] -methanone in a similar manner to that described in Example 55, 2 '- (methanesulfonyl) -2', 3-diphenylpropionohydrazide as a white solid.
(ii) To a solution of (E) -2 (R) - [1 (S) - (carboxy) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) 0.29 g of diphenylpropionohydrazide was cooled to 0 C under a nitrogen atmosphere and 0.18 g of (O-4-methoxybenzyl) hydroxylamine and 0.124 g of 1-ethyl-3- (3-dimethyl Aminopropyl) -carbodiimide hydrochloride were added. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give 0.17 g of (E) -2 (R) - [1 (S) - ({O- 4- (methoxybenzyl} hydroxycarbamoyl) 2 '- (methanesulfonyl) -2', 3-diphenylpropionohydrazide as a white solid.
Example 57
(RS) - [(RS) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2,2 ' Dragged
(RS) - (1 (RS) - (tetrahydro-2 (RS) -pyranyloxy} carbamoyl] - Starting from 0.598 g of (E) -2 (RS) - [1 (RS) -2-oxo- - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '- (methanesulfonyl) -2,2'-diphenylacetohydrazide in the form of a white solid.
MS: 494 (M + H) &lt; ⁺ & gt ^; .
HPLC: Accelerated gradient elution using Solvent A containing 35% Solvent B for 5 minutes and increasing to 80% Solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 8.54 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(RS) - [(RS) - (tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 & (Methanesulfonyl) -2, 2 ' -diphenylacetic &lt; / RTI &gt; hydrazide was prepared as follows:
(RS) - [1 (RS) - (carboxy (R) - (RS) - ) -4-phenyl-3-butenyl] -2 '- (methanesulfonyl) -2,2'-diphenylacetohydrazide in the form of a white solid.
MS: 479 (M + H) &lt; ⁺ & gt ^; .
(RS) - [1 (RS) - (carboxy) -4-phenyl-3-butenyl] -methanone in a manner analogous to that described in Example 2, Part (v) (RS) - [1 (RS) - [(tetrahydro-2 (S) -2 '-( methanesulphonyl) -2,2 ' - diphenylacetohydrazide, RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '- (methanesulfonyl) -2,2'-diphenylacetohydrazide in the form of a white solid.
MS: 578 (M + H) &lt; ⁺ & gt ^; .
Example 58
(R) - [1 (S) - (hydroxycarbamoyl) -4- (2-thiazolyl) -3-butenyl] -2 '-( methanesulfonyl) 2'-phenylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.17 g of (E) -2 ((2-thiazolyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide, R ') - [1 (S) - (hydroxycarbamoyl) -4- (2-thiazolyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 &apos; -phenylvalero Hydrazide was obtained in the form of a white solid.
MS: 481 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.97 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (2-thiazolyl) -3- Phenyl] -2 '- (methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was prepared as follows:
(i) A solution of 4.0 g (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid in 200 ml dichloromethane Was cooled to -78 &lt; 0 &gt; C and the ozone was bubbled through the solution until the solution turned blue. The mixture was allowed to warm to room temperature and 20 mL of dimethyl sulfide was added. The mixture was stirred at room temperature for 3 hours and then the solvent was evaporated. The residue was purified by flash column chromatography on silica gel using hexane / ethyl acetate (1: 1) to elute. 1.8 g of 2 (R) - [1 (S) - (tert-butoxycarbonyl) -propan-3-ol] -4-methyl valeric acid as a light yellow solid.
(ii) 0.25 g of potassium tert-butoxide was added to a solution of 0.79 g of triphenyl (2-thiazolylmethyl) phosphonium chloride in 10 ml anhydrous toluene. After stirring at room temperature for 3 hours, a solution of 0.83 g of 2 (R) - [1 (S) - (tert-butoxycarbonyl) -propan-3-al] -4-methylvaleric acid in 5 ml of toluene Was added and the mixture was further stirred at room temperature for 48 hours. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel using dichloromethane / methanol (95: 5) to elute. (S) - (tert-Butoxycarbonyl) -4- (2-thiazolyl) -3-butenyl] -methylvaleric acid was dissolved in 0.43 g of pale yellow oil &Lt; / RTI &gt;
MS: 354 (M + H) &lt; ⁺ & gt ^; .
(R) - [1 (S) - (3) (3) (3) (R) - [1 (S) - [(tetrahydro-isoquinolin-4- 2 (RS) -pyranyloxy) carbamoyl] -4- (2-thiazolyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide &Lt; / RTI &gt; as a white solid.
MS: 565 (M + H) &lt; ⁺ & gt ^; .
The following examples illustrate typical pharmaceutical formulations containing the hydrazine derivatives provided by the present invention:
Example 59
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyryl-2'- Hydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'- A solution of 0.32 g of isobutyryl-2 ' -isobutyl-4-methylvalerohydrazide was treated with 0.03 g of 4-toluenesulfonic acid. After the mixture was stirred at room temperature for 2 hours, the solvent was evaporated to obtain a glassy substance. The residue was triturated with diethyl ether to give 0.15 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyryl -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.
MS: 446 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution using solvent A containing 20% solvent B for 5 minutes and increasing to 65% solvent B from 5 minutes to 20 minutes; Flow rate of 1 ml / min. Retention time: 17.48 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Isobutyryl-2 ' -isobutyl-4-methylvalerohydrazide was prepared as follows:
(i) To a solution of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] -2 ' -isobutyl- A solution of 0.70 g of 4-methylvalerohydrazide, 0.38 ml of pyridine and crystals of 4-dimethylaminopyridine was cooled to 0 C under a nitrogen atmosphere. 0.67 ml of isobutyric anhydride was added and the reaction mixture was allowed to warm to room temperature. After stirring for 16 hours at room temperature, the reaction mixture was diluted with dichloromethane and washed with 2M aqueous hydrochloric acid and then brine. The dichloromethane phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. Chromatography on silica gel using ethyl acetate / hexane (1: 5) followed by evaporation gave 0.56 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) - Phenyl-3-butenyl] -2 ' -isobutyryl-2 ' -isobutyl-4-methylvalerohydrazide in the form of a white foam.
MS: 487 (M + H) &lt; ⁺ & gt ^; .
(ii) 0.56 g of tert-butyl ester was dissolved in 20 ml of a 50% solution of trifluoroacetic acid in dichloromethane and stirred at room temperature for 1.5 hours. The solvent was evaporated, toluene (2 x 10 mL) was added and evaporated to remove traces of trifluoroacetic acid. The residue was triturated with diethyl ether / hexane (1: 1) to give 0.39 g of (E) -2 (R) - [1 (S) - (carboxy) Isobutyryl-2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.
MS: 431 (M + H) &lt; ⁺ & gt ^; .
(E) -2 (R) - [1 (S) - (carboxy) -4-phenyl-3-butenyl] -methanone in a manner similar to that described in Example 2, Part (v) 2-isobutyryl-2'-isobutyl-4-methylvalerohydrazide there was obtained 0.32 g of (E) -2 (R) - [1 (S) - [(tetrahydro- (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyryl-2'-isobutyl-4-methylvalerohydrazide in the form of a white solid Respectively.
MS: 530 (M + H) &lt; ⁺ & gt ^; .
Example 60
(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydra Jed
Acetyl-2 (R) - [1 (S) - ((R) -2 ' Hydroxy-carbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-4-methylvalerohydrazide in the form of a white solid.
MS: 418 (M + H) &lt; ⁺ & gt ^; .
HPLC: elution with solvent A; Flow rate of 1 ml / min. Retention time: 4.86 min. Solvent A: H ₂ O / 0.1% TFA. Column type: HYPERPEP 300A.
Example 61
(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerohydra Jed
Benzoyl-2 ' -isobutyl-2 (R) - [(R) 1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide in the form of a white solid.
MS: 480 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution increasing from solvent A containing 5% solvent B to 95% solvent B for 15 minutes; Flow rate of 1 ml / min. Retention time: 12.37 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 62
Methyl (E) - [2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -1-isobutyl hydrazino] gly Oxylate
To a solution of methyl (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Methyl valeryl] -1-isobutyl hydrazino] glyoxylate in 20 ml of tetrahydrofuran was treated with 0.04 g of 4-toluenesulfonic acid. The mixture was stirred at room temperature for 2.5 hours and then the solvent was evaporated to give a white semi-solid mass. The residue in ethyl acetate was washed with 5% sodium bicarbonate solution, dried over magnesium sulphate and evaporated to give a solid. This was triturated with diethyl ether to give 0.19 g of methyl (E) - [2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- -1-isobutylhydrazino] glyoxylate as a white solid.
MS: 462 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.26 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(E) - [2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl- Methylvaleryl] -1-isobutylhydrazino] glyoxylate was prepared as follows:
(i) To a solution of (E) -2 (R) - [(1S) - (tert-butoxycarbonyl) -4-phenyl-3-butenyl] -2'- A solution of 1.0 g of methyl valerohydrazide, 0.40 ml of pyridine and crystals of 4-dimethylaminopyridine was cooled to 0 &lt; 0 &gt; C under a nitrogen atmosphere. 0.27 ml of methyl oxalyl chloride was added and the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 16 h, the reaction mixture was evaporated to dryness. The residue in ethyl acetate was washed with 2M aqueous hydrochloric acid, 5% sodium bicarbonate solution and water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was triturated with hexane to give 0.91 g of methyl (E) - [2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] Yl] -1-isobutyl hydrazino] glyoxylate as a white solid.
MS: 503 (M + H) &lt; ⁺ & gt ^; .
(ii) 0.90 g of tert-butyl ester prepared in paragraph (i) was dissolved in 20 ml of a 50% solution of trifluoroacetic acid in dichloromethane and stirred at room temperature for 3 hours. The solvent was evaporated, toluene (2 x 20 mL) was added and evaporated to remove traces of trifluoroacetic acid. The residue was dried under vacuum to give 0.95 g of (E) - [2 (R) - [1 (S) - (carboxy) -4-phenyl-3-butenyl] -4-methylvaleryl] Hydrazino] glyoxylate in the form of a gum.
MS: 446 (M + H) &lt; ⁺ & gt ^; .
(iii) The carboxylic acid prepared in paragraph (ii) is dissolved in 5 ml of dimethylformamide and cooled to 0 <0> C and 0.75 g of O- (tetrahydro-2H-pyran-2 (RS) Amine and 0.48 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, 2M hydrochloric acid, 5% sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give a foam. Chromatography on silica gel using ethyl acetate / hexane (2: 3) followed by evaporation gave 0.350 g of methyl (E) - [2 (R) - [1 (S) - [(tetrahydro- ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvaleryl] -1-isobutyl hydrazino] glyoxylate in the form of a white solid.
MS: 546 (M + H) &lt; ⁺ & gt ^; .
Example 63
(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- Sun) Valero Hydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl} -2 (R) - [1 (S) - (hydroxymethyl) -2 ' -isobutyl-4-methyl-2 '-( methylglyoxyloyl) valerohydrazide 3-butenyl] -2 ' -isobutyl-4-methyl-2 '-( methylglyoxyloyl) valerohydrazide in the form of a white solid.
MS: 462 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.19 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
-2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl) -Isobutyl-4-methyl-2 '-( methylglyoxyloyl) valerohydrazide was prepared in analogy to the procedure described in example 62 (i) - (iii) using pyloyl chloride instead of methyl oxalyl chloride. &Lt; / RTI &gt;
MS: 530 (M + H) &lt; ⁺ & gt ^; .
Example 64
(R) - [(RS) - (hydroxycarbamoyl) -4- (3-pyridyl) -3-butenyl] -2 '-( methanesulfonyl) 2'-phenylvalerohydrazide
To a solution of (E) -2 (R) - [1 (RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (3-pyridyl) ] -2 '-( methanesulphonyl) -4-methyl-2 ' -phenylvalerohydrazide in 20 ml of tetrahydrofuran was treated with 0.097 g of 4-toluenesulfonic acid. The mixture was stirred at room temperature for 2.5 hours and then diluted with water. The solid was filtered, washed with water and diethyl ether and dried under vacuum to give 0.138 g of (E) -2 (R) - [1 (RS) - (hydroxycarbamoyl) -4- ) -3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylhydrazide in the form of a white solid.
MS: 475 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention times: 9.53 and 9.92 min (ratio of diastereomers (3: 1)). Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (3-pyridyl) -3- Phenyl] -2 '- (methanesulfonyl) -4-methyl-2'-phenylvalerohydrazide was prepared as follows:
(i) A solution of 6.81 g of 1,2-dibenzyll-tert-butyl-4-methyl-1 (RS), 1,2 (R) -pentanetricarboxylate in 50 ml anhydrous tetrahydrofuran was stirred at room temperature Lt; / RTI &gt; under nitrogen. 0.66 g of 60% sodium hydride was added and the mixture was stirred for 10 minutes. A solution of 2.66 g of 4- (3-pyridyl) allyl acetate in 40 ml anhydrous tetrahydrofuran and 0.87 g of tetrakis (triphenylphosphine) -palladium (0) was added and the mixture was stirred at room temperature for 4 hours. The tetrahydrofuran was evaporated and the residue was partitioned between dichloromethane and saturated sodium chloride solution. The organic solution was dried over anhydrous magnesium sulfate and evaporated to give a pale brown oil. Chromatography on silica gel eluting with ethyl acetate / hexane (2: 3) and evaporation of the solvent gave 7.50 g of (E) -1,2-dibenzyll-tert-butyl- En-1-yl] -1 (RS), 1,2 (R) -pentanetricarboxylate.
MS: 572 (M + H) &lt; ⁺ & gt ^; .
(ii) A solution of 2.80 g of sodium hydroxide in 40 ml of water was added dropwise to a solution of (E) -1,2-dibenzyll-butyl-4-methyl- 1- [3- (3- 1-yl) -1 (RS), 1,2 (R) -pentanetricarboxylate in 10 ml of tetrahydrofuran. The mixture was heated to reflux for 20 hours, then cooled and evaporated. The residue was diluted with water and acidified to pH 6.5 with concentrated hydrochloric acid. The aqueous phase was extracted twice with diethyl ether, and the organic phases were combined and extracted with 50 ml of 0.25 M sodium hydroxide solution. The solution was acidified to pH 6.5 with concentrated hydrochloric acid and re-extracted with diethyl ether (2 x 50 mL). The combined organic phases were washed with brine, dried over magnesium sulphate and evaporated to give 1.73 g of (E) -2 (R) -butyl-4-tert- butyl- 3 - [(RS) Pyridyl) prop-2-en-1-yl)] succinate as a red gum.
MS: 348 (M + H) &lt; ⁺ & gt ^; .
Starting from 0.52 g of the carboxylic acid prepared in part (ii) of this example, (iii) 0.447 g of (E) -2 (R) - [ (RS) - (tert-butoxycarbonyl) -4- (3-pyridyl) -3-butenyl] -4-methyl-2 ' -phenylvalo hydrazide in the form of a white solid Respectively.
MS: 438 (M + H) &lt; ⁺ & gt ^; .
(iv) In a similar manner to that described in Example 1, Part (ii), 0.44 g of (E) -2 (R) - [1 (RS) - (tert- butoxycarbonyl) -4- Starting from 0.51 g of (E) -2 (R) - [1 (RS) - (tert-Butyl) -3-butenyl] -4-methyl- (3-pyridyl) -3-butenyl] -4-methyl-2 '-( methanesulfonyl) -2 ' -phenylvalerohydrazide in the form of a white solid .
MS: 516 (M + H) &lt; ⁺ & gt ^; .
(v) In a similar manner to that described in Example 1, part (iii), 0.50 g of (E) -2 (R) - [1 (RS) - (tert- butoxycarbonyl) -4- Starting from 0.36 g of (E) -2 (R) - [1 '-( 2-methanesulfonyl- (RS) - (carboxy) -4- (3-pyridyl) -3-butenyl] -4-methyl-2 '- (methanesulfonyl) -2'-phenylvalerohydrazide.
MS: 460 (M + H) &lt; ⁺ & gt ^; .
(vi) The carboxylic acid prepared in paragraph (v) is dissolved in 2 ml of dimethylformamide, cooled to 0 C and treated with 0.27 g of O- (tetrahydro-2H-pyran-2 (RS) Amine and 0.16 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water and 5% sodium bicarbonate solution, then dried over anhydrous magnesium sulfate and evaporated. The resulting pale yellow rubber was triturated with diethyl ether to provide 0.22 g of (E) -2 (R) - [1 (RS) - [(tetrahydro-2 (RS) -pyranyloxy) (3-pyridyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a white solid.
MS: 559 (M + H) &lt; ⁺ & gt ^; .
Example 65
2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohy- &lt; / RTI &gt; Dragged
To a solution of 2 (R) - [1 (S) - [(benzyloxy) carbamoyl] -4- (3- pyridyl) butyl] -2'-isobutyl-2 '-( methanesulfonyl) A solution of 0.33 g of 4-methylvalerohydrazide was hydrogenated for 1.5 hours in the presence of 80 mg of 10% palladium on carbon. The catalyst was removed by filtration and the solvent was evaporated. The residue was triturated with diethyl ether to give 0.26 g of 2 (R) - [1 (S) - (hydroxycarbamoyl) -4- (3- pyridyl) butyl] -2'- Methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 457 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.59 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(3-pyridyl) butyl] -2 ' -isobutyl-2 '-( methanesulphonyl) -4-methylvalerohydrazide was prepared as follows:
(i) To a solution of (E) -1,2-dibenzyll-butyl-4-methyl-l- [3- (3-pyridyl) -1,1 (RS), 1,2 (R) -pentanetricarboxylate in 10 ml of methanol was hydrogenated over 400 mg of 10% palladium on carbon for 5 hours. The catalyst was removed by filtration and the solvent was evaporated. Toluene (2 x 10 mL) was added and evaporated to remove the final traces of isopropanol. The residue was refluxed in a mixture of 40 ml of toluene and 0.42 ml of triethylamine for 2 hours and the solvent was removed by evaporation to give a red oil. The oil in 10 mL dichloromethane was cooled to 0 C with stirring under nitrogen and then 0.95 mL of N-ethylmorpholine was added followed by 0.49 g of 1-hydroxybenzotriazole and 0.72 g of 1-ethyl-3- ( 3-dimethylaminopropyl) carbodiimide hydrochloride were added. After stirring at 0 &lt; 0 &gt; C for 15 min, the solution was treated with 0.98 g of isobutylhydrazine tosylate salt and the mixture was allowed to warm to room temperature and then stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, 5% sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated. Chromatography on silica gel using elution with dichloromethane / methanol (19: 1) gave 0.63 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4- (3- ) Butyl] -2 &apos; -isobutyl-4-methylvalerohydrazide as a white solid.
MS: 420 (M + H) &lt; ⁺ & gt ^; .
(ii) In a manner similar to that described in Example 1, Part (ii), 0.62 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4- ) Butyl] -2'-isobutyl-4-methylvalerohydrazide there was obtained 0.68 g of 2 (R) - [1 (S) - (tert-butoxycarbonyl) -4- Pyridyl) butyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a solid.
MS: 498 (M + H) &lt; ⁺ & gt ^; .
(iii) In a similar manner to that described in Example 1, part (iii), 0.68 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4- Starting from 0.55 g of 2 (R) - [1 (S) - (carboxy) -4- ( 3-pyridyl) butyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide.
MS: 442 (M + H) &lt; ⁺ & gt ^; .
(iv) The carboxylic acid prepared in paragraph (iii) was dissolved in 3 ml of dimethylformamide, cooled to 0 ° C and 0.45 g of O-benzyl-hydroxylamine and 0.26 g of 1-ethyl-3- (3 -Dimethylaminopropyl) &lt; / RTI &gt; carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water and 5% sodium bicarbonate solution, then dried over anhydrous magnesium sulfate and evaporated. The resulting rubber was triturated with diethyl ether to give 0.34 g of 2 (R) - [1 (S) - [(benzyloxy) carbamoyl] -4- (3- pyridyl) butyl] 2 &apos;-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 547 (M + H) &lt; ⁺ & gt ^; .
Example 66
(R) - [1 (S) - (hydroxycarbamoyl) -4- (4-methoxyphenyl) -3-butenyl] -2 '-( methanesulfonyl) -2'-phenylvalerohydrazide
0.079 g of (E) -2 (R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (4- Starting from 0.041 g of (E) -2 (R) - [(2-methoxyphenyl) -3-butenyl] -2 '-( methanesulfonyl) (S) - (hydroxycarbamoyl) -4- (4-methoxyphenyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide &Lt; / RTI &gt; as a white solid.
MS: 504 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.22 minutes. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.
(R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (4- methoxyphenyl) -3-butenyl] -2 ' - (methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide was prepared as follows:
Methyl-1 (RS), 1,2 (R) -Pentane (RS), and the like were prepared in a manner similar to that described in Example 64, Part (i) (R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- ( Methoxyphenyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide as an off-white solid.
MS: 588 (M + H) &lt; ⁺ & gt ^; .
Example 67
2 (R) - [4-cyclohexyl-1 (S) - (hydroxycarbamoyl) -butyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydrazide
(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl- (RS) - ] - butyl] -2'-isobutyl-2'- (methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.11 g of 2 (R) - [4-cyclohexyl- - (hydroxycarbamoyl) -butyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 462 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.82 minutes. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.
(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -butyl] -2 ' -isobutyl-2 ' - (methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(i) A solution of 1.0 g of 2 (R) - [1 (S) - (tert-butoxycarbonyl) -4-phenyl-butyl] -4-methylvaleric acid in 30 ml acetic acid was treated with 300 mg platinum oxide Lt; / RTI &gt; for 1.5 hours. The catalyst was removed by filtration and the solvent was evaporated. Toluene (3 x 10 mL) was added and evaporated to remove the final traces of acetic acid. Chromatography on silica gel eluting with diethyl ether / hexane (1: 7) gave 0.67 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-cyclohexyl- butyl ] -4-methylvaleric acid as a white solid.
TLC: methanol / dichloromethane (1:19): Rf 0.51.
(ii) In a similar manner to that described in Example 1, part (i), 0.66 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-cyclohexyl- butyl] -4-methylvaleric acid, 0.27 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4- (4- cyclohexyl) butyl] -2'- -4-methylvalerohydrazide (from hexane) in the form of a white solid.
MS: 425 (M + H) &lt; ⁺ & gt ^; .
(iii) In a similar manner to that described in Example 1, Part (ii), 0.26 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4- (4- ) Butyl] -2'-isobutyl-4-methylvalerohydrazide there was obtained 0.31 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4- Hexyl) butyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide.
MS: 503 (M + H) &lt; ⁺ & gt ^; .
(iii) In a similar manner to that described in Example 1, part (iii), 0.30 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4- (4-cyclohexyl Starting from 0.24 g of 2 (R) - [1 (S) - (carboxy) -4-methylvalerohydrazide starting from 2- (4-cyclohexyl) butyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide.
MS: 447 (M + H) &lt; ⁺ & gt ^; .
(vi) The carboxylic acid prepared in paragraph (v) was dissolved in 3 ml of dimethylformamide, cooled to 0 C and treated with 0.19 g of O- (tetrahydro-2H-pyran-2 (RS) Amine and 0.113 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water, 5% sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated. The resulting solid was triturated with diethyl ether to give 0.18 g of 2 (R) - [4-cyclohexyl-1 (S) - [(tetrahydro- 2 (RS) -pyranyloxy) carbamoyl] 2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 546 (M + H) &lt; ⁺ & gt ^; .
Example 68
(R) - [1 (S) - (hydroxycarbamoyl) -4- (4- (methoxycarbonyl) phenyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -Phenylvalerohydrazide, starting from 0.059 g of &lt; RTI ID = 0.0 &gt; (methoxycarbonyl) (R) - [1 (S) - (hydroxycarbamoyl) -4- (4- (methoxycarbonyl) phenyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a white solid.
MS: 532 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.09 min. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (4- (methoxycarbonyl) phenyl ) -3-butenyl] -2 '-( methanesulphonyl) -4-methyl-2 ' -phenylvalerohydrazide is prepared by reacting cinnamylbromide with 4-methoxycarbonyl-cinnamylbromide Was prepared as a white solid in a similar manner to that described in Example 2 (i) - (v) except substituting.
MS: 616 (M + H) &lt; ⁺ & gt ^; .
Example 69
(R) - [1 (S) - (hydroxycarbamoyl) -4- (4-nitrophenyl) -3-butenyl] -2 '-( methanesulfonyl) 2'-phenylvalerohydrazide
To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (4-nitro Phenyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in 10 ml of DMF was treated with 0.020 g of 4-toluenesulfonic acid. The mixture was stirred at room temperature for 5 hours and then the solution was evaporated. The resulting rubber was triturated with diethyl ether to give 0.063 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4- (4- nitrophenyl) 2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a light brown solid.
MS: 519 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.07 minutes. Solvent A: H ₂ O; Solvent B: CH ₃ CN. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (4-nitrophenyl) -3- (3-pyridyl) allyl acetate and tetrakis (triphenylphosphine) palladium (II) in step (i) -Methanone was prepared as a white solid by a procedure similar to that of Example 64 (i) - (vi) except that palladium (0) was replaced by 4-nitro-cinnamylbromide.
MS: 603 (M + H) &lt; ⁺ & gt ^; .
Example 70
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Morpholinocarbonyl) methyl] valerohydrazide &lt; / RTI &gt;
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Methyl] -2 ' - [(morpholinocarbonyl) methyl] valerohydrazide, 0.08 g of ( Methyl) -2 ' - [(morpholin-2-yl) -2 '-( methanesulfonyl) Polynocarbonyl) methyl] valerohydrazide in the form of a white solid.
MS: 525 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO): 10.52} (1H, s); 10.47 (1H, s); 8.82 (1H, s); 7.35-7.25 (4 H, m); 7.23-7.17 (1 H, m); 6.28 (1H, doublet, J = 15.5 Hz); 6.09-5.98 (1 H, m); 4.40-4.26 (2 H, m); 3.64-3.30 (8H, m); 3.15 (3 H, s); 2.63-2.54 (1 H, m); 2.37-2.08 (3 H, m); 1.50-1.28 (2 H, m); 0.98-0.89 (1H, m); 0.78 (6 H, m).
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.19 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and N-bromoacetylmorpholine in an analogous manner as described in example 15, part (iii).
MS: 609 (M + H) &lt; ⁺ & gt ^; .
Example 71
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- -Morpholinoethyl) valerohydrazide &lt; / RTI &gt;
In a similar manner to that described in the first paragraph of Example 2, the ethyl acetate solution of the product was washed with sodium bicarbonate solution to obtain the free base, then 0.13 g of (E) -2 (R) - [ Methyl-2 '-( 2-methoxy-benzenesulfonyl) -2 '-( methanesulphonyl) (Morpholinoethyl) valerohydrazide was added 0.1 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- Methanesulfonyl) -4-methyl-2 '-( 2-morpholinoethyl) valerohydrazide in the form of a white solid.
MS: 511 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.71 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 4- (2-chloroethyl) morpholine in accordance with the general method of example 15, step (iii).
MS: 595 (M + H) &lt; ⁺ & gt ^; .
Example 72
Methyl (E) -2- [2- (2R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- Methanesulfonyl) hydrazino] acetate &lt; / RTI &gt;
In a manner similar to that described in the first paragraph of Example 2, 0.12 g of methyl (E) -2- [2- [2 (R) - [1 (S) - [(tetrahydro- Methyl) valeryl] -1- (methanesulfonyl) hydrazino] acetate, 0.09 g of methyl (E) -2 - [2- (2R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] Lt; / RTI &gt; acid in the form of a white solid.
MS: 470 (M + H) &lt; ⁺ & gt ^; .
_{nmr (d 6 DMSO): 10.77} (1H, s); 10.53 (1 H, m); 8.83 (1 H, m); 7.35-7.25 (4 H, m); 7.22-7.16 (1 H, m); 6.27 (1 H, d, J = 15.5 Hz); 6.08 - 5.99 (1 H, m); 4.41-4.17 (2 H, m); 3.66 (3 H, s); 3.14 (3 H, s); 2.62-2.53 (1 H, m); 2.35-2.07 (3 H, m); 1.50-1.40 (1H, m); 1.38-1.25 (1H, m); 1.00-0.92 (1H, m); 0.79 (6 H, m).
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.93 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and methyl bromoacetate in an analogous manner as described in example 15, part (iii).
MS: 554 (M + H) &lt; ⁺ & gt ^; .
Example 73
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) - phenylpropyl) valerohydrazide
(E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -methanone in a manner analogous to that described in the first paragraph of Example 2, 4-methyl-2 '- (3-phenylpropyl) valerohydrazide there was obtained 0.091 g of (E) -2 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 3-phenylpropyl) val Loehydrazide was obtained in the form of a gray solid.
MS: 516 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.01 and 13.19 min (double peak). Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 1-bromo-3-phenylpropane, in a manner similar to that described in Example 15, Part (iii).
MS: 600 (M + H) &lt; ⁺ & gt ^; .
Example 74
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) 2-naphthyl) methyl] valerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Methyl] valerohydrazide, starting from 0.109 g of (E (4-phenyl-3-butenyl] -2 '-( methanesulfonyl) ) -2 - ((methanesulfonyl) -4-methyl-2 '- [(2- Naphthyl) methyl] valerohydrazide in the form of a gray solid.
MS: 538 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Time of stay: 13.09 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Iii), starting with (methanesulfonyl) -4-methyl-2 '- [(2-naphthyl) methyl] valerohydrazide and 2-bromomethylnaphthalene Were prepared in a similar manner.
MS: 622 (M + H) &lt; ⁺ & gt ^; .
Example 75
-2 '-( methoxyethyl) - &lt; / RTI &gt; 2 &apos;-( methanesulfonyl) 4-methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-methyl-2-methoxy-4-methyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 2- methoxyethyl) -4- methylbutanoyl hydrazide, 0.073 g (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -2 '-( 2- methoxyethyl ) -4-methylvalerohydrazide in the form of a gray solid.
MS: 456 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.67 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 2-bromoethyl methyl ether in an analogous manner as described in example 15, part (iii).
MS: 540 (M + H) &lt; ⁺ & gt ^; .
Example 76
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 2-hydroxyethyl) -2 '-( methanesulfonyl ) -4-methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 4-methylvalerohydrazide there was obtained 0.041 g of (E) - (4-phenyl-3-butenyl] -2 '-( 2-hydroxyethyl) -2 '-( methanesulfonyl) -2 '-( 2-hydroxyethyl) -2 '-( methanesulfonyl) -4-phenyl- Methylvalerohydrazide in the form of a cream solid.
MS: 442 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.16 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 2-bromoethanol in analogy to that described in Example 15, part (iii).
MS: 526 (M + H) &lt; ⁺ & gt ^; .
Example 77
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) 4-pyridyl) methyl] valerohydrazide p-toluenesulfonate
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Methyl] valerohydrazide there was obtained 0.077 g of (E (4-phenyl-3-butenyl) -2 '-( methanesulfonyl) -2 - ((methanesulfonyl) -4-methyl-2 '- [(4-methyl- Pyridyl) methyl] valerohydrazide p-toluenesulfonate as an off-white solid.
MS: 489 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.59 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 4-bromomethylpyridine hydrobromide in an analogous manner as described in example 15, part (iii).
MS: 573 (M + H) &lt; ⁺ & gt ^; .
Example 78
(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulphonyl) - 4-methylvalerohydrazide
(RS) - [(S) - [(tetrahydro-2 (RS) - Starting from 0.092 g of (E) -2 '-( 2-methanesulfonyl-4-methylvalerohydrazide, -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide &Lt; / RTI &gt; as a white solid.
MS: 452 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.47 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and cyclopropylmethyl bromide, in a manner similar to that described in Example 15, Part (iii).
Example 79
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- (S) -methylbutyl] valerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.101 g of (E) -methyl-2 '- [2 (S) -methylbutyl] valerohydrazide ) -2 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- ) -Methylbutyl] valerohydrazide in the form of a white solid.
MS: 468 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.70 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Iii), starting from (S) - (+) - l-bromo-2-methylbutane, starting with (S) - .
Example 80
(R) -methylpropyl] - &lt; / RTI &gt; &lt; RTI ID = 0.0 & 2 &apos;-( methanesulfonyl) -4-methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 4-phenyl-3-butenyl] -2 ' - [3-hydroxy-2- (R) -methylpropyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide, (R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' - [ Propyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 470 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.20 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (S) - (+) - 3-bromo-2-methyl-l-propanol, starting from (S) - &Lt; / RTI &gt;
Example 81
(S) -methylpropyl] - &lt; / RTI &gt; &lt; RTI ID = 0.0 & 2 &apos;-( methanesulfonyl) -4-methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 4-phenyl-3-butenyl] -2 '- [3-hydroxy-2 (S) -methylpropyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide, -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' - [ Propyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 470 (MH) ^&lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.11 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Iii), starting from (R) - (-) - 3-bromo-2-methyl-1-propanol, &Lt; / RTI &gt;
Example 82
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isopentyl- Valero Hydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.08 g of (E) -2 (R) - (4-phenyl-3-butenyl] -2 ' -isopentyl-2 '-( methanesulphonyl) Phenyl] -3-butenyl] -2 ' -isopentyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide as a white solid &lt; RTI ID = .
MS: 468 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.63 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 1-bromo-3-methylbutane in analogy to that described in example 15, part (iii).
Example 83
(E) -2 '-( Cyclobutylmethyl) -2 (R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] - methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -2 '-( cyclohexylmethyl) ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide, 0.075 g of (E) - (cyclobutylmethyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Lt; / RTI &gt; as a white solid.
MS: 466 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.34 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and cyclobutylmethyl bromide, in a manner similar to that described in Example 15, Part (iii).
Example 84
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -Methyl-2-butenyl) valerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Butenyl] valerohydrazide, starting from 0.137 g of ((3-methyl-2-butenyl) -2 '- (methanesulfonyl) -4-methyl-2' - (3- (4-fluorophenyl) Methyl-2-butenyl) valerohydrazide in the form of a white solid.
MS: 466 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.95 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 3,3-dimethylallyl bromide, in a manner similar to that described in Example 15, Part (iii).
Example 85
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerate Lohia Dragaj
In a manner similar to that described in the first paragraph of Example 2, 0.17 g of (E) -2 ' -benzyl-2 '-( butanesulfonyl) -2 (R) - [1 (S) - [ (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide there was obtained 0.115 g of (E) -2 ' (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide as a white solid Respectively.
MS: 530 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.83 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was prepared as follows:
(i) In a similar manner to that described in Example 1, Part (ii), 0.54 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -3-butenyl] -4-methylvalerohydrazide and 1-butanesulfonyl chloride there was obtained 0.425 g of (E) -2 '-( butanesulfonyl) -2 (R) S) - (tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide in the form of a white foam.
MS: 481 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 15, Part (iii), 0.416 g of (E) -2 '- (butanesulfonyl) -2 (R) - [1 (S) 4-methylvalerohydrazide and benzyl bromide there was obtained 0.463 g of (E) -2 ' -benzyl-2 '-( butanesulfonyl) -4-phenyl- ) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide in the form of a light yellow gum .
MS: 571 (M + H) &lt; ⁺ & gt ^; .
(iii) In a manner similar to that described in Example 2, Part (v), following Example 1, Part (iii), 0.46 g of (E) -2'- benzyl-2 '-( butanesulfonyl) Starting from 0.174 g of (E) - [(S) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide, -2 ' - benzyl-2 '-( butane sulphonyl) -2 (R) - [1 (S) - [(tetrahydro- &Lt; / RTI &gt; thienyl] -4-methylvalerohydrazide in the form of a white solid.
MS: 614 (M + H) &lt; ⁺ & gt ^; .
Example 86
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - methylallyl) valerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 4-methyl-2 '- (2-methylallyl) valerohydrazide there was obtained 0.063 g of (E) -2 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 2- Loehydrazide was obtained in the form of a gray solid.
MS: 452 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.75 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and methyl allyl chloride in an analogous manner as described in example 15, part (iii).
Example 87
(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulphonyl) -2 '-( 2- ) -4-methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, starting from 0.183 g of (E) -2 '-( 2-cyclohexylethyl) -2 (R) - [1 (S) - [(tetrahydro- (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide, 0.12 g of (E) 2 '- (2-cyclohexylethyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) Methylvalerohydrazide in the form of a white solid.
MS: 508 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention times: 13.93 and 14.02 min (double peak). Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 2-cyclohexylethyl bromide, in a similar manner as described in example 15, part (iii).
Example 88
(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' (Methanesulfonyl) -4-methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 4-phenyl-3-butenyl] -2 '- [2- (3-indolyl) ethyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide, (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 ' (Methanesulfonyl) -4-methylvalerohydrazide in the form of a pale orange foam.
MS: 541 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.52 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 3- (2-bromoethyl) indole in an analogous manner as described in example 15, part (iii).
Example 89
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) - phenylallyl) valerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.123 g of (E) -2 (4-Phenyl-3-butenyl] -2 '-( methanesulfonyl) (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 3-phenylallyl) valerate The rohiodrazide was obtained in the form of a light yellow solid.
MS: 514 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.69 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and cinnamyl bromide, in a similar manner as described in example 15, part (iii).
Example 90
(E) -2 ' -benzyl-2 '-( ethanesulfonyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) Lohia Dragaj
In a manner similar to that described in the first paragraph of Example 2, 0.1 g of (E) -2 ' -benzyl-2 '-( ethanesulfonyl) -2 (R) - [1 (S) - [ (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methylvalerohydrazide there was obtained 0.054 g of (E) - (ethanesulfonyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvalerohydrazide as a gray solid Respectively.
MS: 502 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.70 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was prepared from (E) -2 (R) - [1 (S) - (tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide, Prepared by methods analogous to those described in Example 85, parts (i) - (iii), starting with the phosphoryl chloride.
Example 91
(E) -2 '-( 2,2,2-trifluoroethanesulfonyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) 4-methyl-2 ' -phenylvalerohydrazide
-2 (R) - [1 (S) -tetrahydrofuran-2-ylmethoxy) Phenyl] -3-butenyl] -4-methyl-2 ' -phenylvalerohydrazide there was obtained 0.093 g of ((R) E) -2 '-( 2,2,2-Trifluoroethanesulfonyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- -Methyl-2 ' -phenylvalerohydrazide as an off-white solid.
MS: 542 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.42 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - (tert-butoxycarbonyl) -4-phenyl- Prepared in a similar manner as described in example 17, parts (i) - (iii), starting with 2,2-trifluoroethanesulfonyl chloride.
Example 92
(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 3-hydroxypropyl) -2 '-( methanesulfonyl ) -4-methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 4-methylvalerohydrazide, 0.119 g of (E) - (3-hydroxy-propyl) 2 '- (3-hydroxypropyl) -2' - (methanesulfonyl) -4-phenyl- Methylvalerohydrazide was obtained in the form of a gray solid.
MS: 456 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.61 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 3-bromo-1-propanol, in a manner similar to that described in Example 15, Part (iii).
Example 93
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] valerohydrazide
(E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-methyl-2 '- [2- (3,4,4-trimethyl-2,5-dioxo-1-imidazole (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 (Methanesulfonyl) -4-methyl-2 '- [2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethyl] valerohydrazide as gray Obtained as a solid.
MS: 566 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.37 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylhydrazide and 3- (2-bromoethyl) -1,5,5-trimethylhydantoin in analogy to Example 15, part (iii) &Lt; / RTI &gt;
Example 94
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) - pentenyl) valero hydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.105 g of (E) -2 (4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 4-pentenyl) valerohydrazide (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 4-pentenyl) valerate Lohydrazide was obtained in the form of a white solid.
MS: 466 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.31 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 5-bromo-1-pentene, in a manner analogous to that described in Example 15, Part (iii).
Example 95
(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulphonyl) -4-valerohydrazide
(R) - [1 (S) - [(tetrahydro-2 ((R) Starting from 0.081 g of (E) -2 '-( methanesulphonyl) -4-valerohydrazide, - (3-butenyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Draizide was obtained in the form of a white solid.
MS: 452 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.80 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 4-bromo-1-butene in analogy to that described in Example 15, part (iii).
Example 96
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- Lohia Dragaj
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.129 g of (E) -2 (R) - [(2-methyl- 1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' propylvalerohydrazide as a white solid .
MS: 440 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.77 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 1-bromopropane in an analogous manner as described in example 15, part (iii).
Example 97
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Lohia Dragaj
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyl Oxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.129 g of (E) -2 ' (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid .
MS: 454 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.12 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 1-bromobutane in an analogous manner as described in example 15, part (iii).
Example 98
(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulphonyl) -4-methylvalerohydrazide p-toluenesulfonate
(R) - [1 (S) - [(tetrahydro-2 ((R) Phenyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide, 0.086 g of (E) -2 - (2-aminoethyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Lohydrazide p-toluenesulfonate was obtained in the form of a gray solid.
MS: 441 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.58 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was prepared as follows:
To a solution of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] (Methanesulfonyl) -4-methyl-2 '-( 2-phthalimidoethyl) valerohydrazide in 20 ml of tetrahydrofuran was treated with 0.25 ml of hydrazine hydrate. The mixture was stirred at room temperature overnight. The suspended white solid was filtered off and the filtrate was concentrated and the residue was chromatographed on silica gel using 5% methanol in dichloromethane to elute. The product was triturated with ether to give 0.23 g of (E) -2 '-( 2-aminoethyl) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) Yl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 525 (M + H) &lt; ⁺ & gt ^; .
Example 99
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - (1-pyrrolyl) ethyl] valerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] 4-methyl-2 '- [2- (1-pyrrolyl) ethyl] valerohydrazide, 0.041 g of (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - (1-pyrrolyl) ethyl] valerohydrazide in the form of a gray solid.
MS: 491 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.05 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Iii), starting from 1- (methanesulfonyl) -4-methylvalerohydrazide and 1- (2-bromomethyl) -pyrrole.
Example 100
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3- -Thienyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.145 g of (E) -2 '- [2- (1,3-dioxolan-2-yl) ethyl] -2 (R) (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide Starting from 0.067 g of (E) -2 '- [2- (1,3-dioxolan-2-yl) ethyl] -2 (R) - [1 (S) - (hydroxycarbamoyl) -Phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a pale orange solid.
MS: 498 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.63 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERSIL ODS.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 2- (2-bromoethyl) -1,3-dioxolane in an analogous manner as described in example 15, part (iii) .
Example 101
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4- methoxybenzenesulfonyl) Hydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.115 g of (E) -2 (R) - [1 '-( 2-methoxybenzenesulfonyl) (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( 4-methoxybenzenesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 490 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.53 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was prepared as follows:
(i) In a similar manner to that described in Example 1, Part (ii), 0.54 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -3-butenyl] -4-methylvalerohydrazide and 4-methoxybenzenesulfonyl chloride there was obtained 0.492 g of (E) -2 (R) - [1 (S) Butoxycarbonyl) -4-phenyl-3-butenyl] -2 '-( 4-methoxybenzenesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 531 (M + H) &lt; ⁺ & gt ^; .
(ii) Following a procedure similar to that described in Example 2, Part (v), Example 1, Part (iii), 0.482 g of (E) -2 (R) - [1 (S) - Starting from 0.194 g of (E) - (tert-butoxycarbonyl) -4-phenyl-3-butenyl] -2 '-( 4- methoxybenzenesulfonyl) -4- methylvalerohydrazide, 2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( 4-methoxybenzenesulfonyl ) -4-methylvalerohydrazide in the form of a white solid.
MS: 574 (M + H) &lt; ⁺ & gt ^; .
Example 102
Phenyl-2 ' - [(2-hydroxy-phenyl) Phenylvinyl) sulfonyl] valerohydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.245 g of (E, E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) Methyl-2'-phenyl-2 '- [(2-phenylvinyl) sulfonyl] valerohydrazide, 0.086 g of (E, Phenyl-2'-phenyl-2 '- [(2-phenylvinyl) -4-methyl- Sulfonyl] valerohydrazide in the form of a white solid.
MS: 562 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.94 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - (tert-butoxycarbonyl) -4-phenyl- (V), starting from Example 1, part (ii) and (iii), starting from trans-beta-styrene sulfonyl chloride.
Example 103
(R) - [1 (S) - (hydroxycarbonyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl Valero Hydrazide
(RS) - [(S) - [(tetrahydro-2 (RS) -pyran-2- Phenyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.042 g of (E) -2 ' - furfural -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide as a white solid Lt; / RTI &gt;
MS: 478 (M + H) &lt; ⁺ & gt ^; .
HPLC: same amount eluted with 50% CH ₃ CN / water; Flow rate of 1 ml / min. Retention time: 3.82 min. Column type: Waters symmetric 10 cm, C ₁₈ , 0.46 cm bore.
Starting material was prepared from (E) -2 (R) - [1 (S) - (tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide and 2- Prepared by methods analogous to those described in Example 45, parts (i) and (ii), starting from furandaldehyde.
Example 104
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Lohia Dragaj
In a manner similar to that described in the first paragraph of Example 2, 0.136 g of (E) -2'-ethyl-2 (R) - [1 (S) - [(tetrahydro- Oxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.087 g of (E) -2 & (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid .
MS: 426 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution increasing from solvent A containing 20% solvent B to 80% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 14.12 minutes. Solvent A: 100% 0.05 M triethylammonium phosphate buffer, pH 2.5 (TEAP); Solvent _{B: 80% CH 3 CN /} (TEAP). Column type: Waters symmetric 10 cm, 0.46 cm bore.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and ethyl iodide in an analogous manner as described in example 15, part (iii).
Example 105
(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulphonyl) -2 '-( 2,6- dichlorobenzyl) -2- Trifluoromethyl-phenyl) -4-methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.09 g of (E) -2 '-( 2,6-dichlorobenzyl) -2 (R) - [1 (S) - [(tetrahydro- Starting from 0.05 g of (E) -methanesulfonyl-4-methylvalerohydrazide, starting from 2- (RS) -pyranyloxy) carbamoyl] -2 '-( methanesulphonyl) - &lt; / RTI &gt; 2 &apos;-( 2,6- dichlorobenzyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) Methyl valerohydrazide in the form of a white solid.
MS: 556/558 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution from solvent A containing 30% solvent B to 95% solvent B over 7 minutes; Flow rate of 1 ml / min. Retention time: 7.30 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.1%} TFA. Column type: HYPERSIL ODS.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 2,6-dichlorobenzyl bromide, in a manner similar to that described in Example 15, Part (iii).
Example 106
(R) - [(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulphonyl) - 4-methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.04 g of (E) -2 '-( cyclopentylmethyl) -2 (R) - [1 (S) - [(tetrahydro- ) - pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4- methylvalerohydrazide, 0.041 g of (E) - (cyclopentylmethyl) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] Draizide was obtained in the form of a white solid.
MS: 480 (M + H) &lt; ⁺ & gt ^; .
HPLC: 60% CH ₃ equivalent amount eluted using a CN / TEAP; Flow rate of 1 ml / min. Retention time: 3.25 minutes. Column type: Waters symmetry 10 cm, C ₁₈ , 0.46 cm inside diameter.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and cyclopentylmethylmethane sulfonate in an analogous manner as described in example 15, part (iii).
Example 107
2 (S) - (hydroxycarbamoyl) ethyl-2'-isobutyl-2 '- (methanesulfonyl) -4-methylhydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.066 g of 2 (R) - [2- (2-benzofuranyl) -1 (S) - [(tetrahydro- Yl) carbamoyl] ethyl-2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.015 g of 2 (R) - [2- Furanyl) -1 (S) - (hydroxycarbamoyl) ethyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 468 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution increasing from solvent A containing 5% solvent B to 98% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.34 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was prepared as follows:
(i) 1.14 g of 60% sodium hydride were added to a solution of 1,2-dibenzyl-l-tert-butyl-4-methyl-1,1,2 (R) - Lt; / RTI &gt; was added to a stirred solution of 12.35 g pentane tricarboxylate. The mixture was stirred at freezing temperature for 30 minutes and further at room temperature for 1.5 hours. The mixture was again cooled to freezing temperature and then 5.78 g of 2-bromomethylbenzofuran was added. The mixture was slowly returned to room temperature and stirred overnight. The solution was then evaporated and the residue was partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate solution was washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using hexane / ether (9: 1) to elute. 14.64 g of 1,2-dibenzyl-l-tert-butyl-1- (2-benzofuranyl) methyl-4-methyl-1,1,2 (R) -pentanetricarboxylate was obtained in the form of a colorless oil Respectively.
(ii) A solution of 14.64 g of 1,2-dibenzyl-l-tert-butyl-l- (2-benzofuranyl) methyl-4-methyl- 1,1,2 (R) -pentanetricarboxylate in 150 ml Of ethanol and a solution of 9.8 g of sodium hydroxide in 55 ml of water was added. The mixture was heated to reflux for 24 hours, then cooled and the solvent was evaporated. The residue was dissolved in 400 ml of water and the pH was adjusted to 3 by addition of 4 M sulfuric acid solution. The aqueous solution was extracted with 400 mL of ethyl acetate and the extract was washed successively with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in 150 ml of toluene containing 3.8 ml of triethylamine. The mixture was heated to reflux for 2 hours, cooled, and washed successively with 5% citric acid solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was dissolved in 50 mL of hexane and treated with 2.43 g of cyclohexane. After maintaining the mixture in the refrigerator for 2 hours, the resulting white solid was filtered and washed with hexane. The solid was suspended in 150 mL of ethyl acetate and shaken with two 50 mL portions of 2 M sulfuric acid. The ethyl acetate solution was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. 3.701 g of 4-tert-butylhydrogen 3 (S) - (2-benzofuranyl) methyl-2 (R) -isobutyl succinate as a light yellow gum.
(iii) Starting from 4-tert-butyl hydrogen 3 (S) - (2-benzofuranyl) methyl-2 (R) -isobutyl succinate and starting from part (iii) - [2- (2-benzofuranyl) - 1 (S) - [(tetrahydro-furan-2-ylmethyl) 2 (RS) -pyranyloxy) carbamoyl] ethyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 552 (M + H) &lt; ⁺ & gt ^; .
Example 108
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) 3-pyridyl) methyl] valerohydrazide methanesulfonate
(E) -2 (R) - [1 (S) - [(1R) -2,5-Diethoxy- (Methanesulfonyl) -4-methyl-2 ' - [(3-pyridyl) Methyl] valerohydrazide, 0.177 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- Methanesulfonyl) -4-methyl-2 '- [(3-pyridyl) methyl] valerohydrazide methanesulfonate as an orange solid.
MS: 489 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 8.05 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 3-bromomethylpyridine hydrobromide in an analogous manner as described in example 15, part (iii).
Example 109
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - (2-pyridyl) ethyl] valerohydrazide methanesulfonate
(E) -2 (R) - [1 (S) - [(1R) -2,5-Dihydroxy- (Methanesulfonyl) -4-methyl-2 ' - [(2-pyridyl) Ethyl] valerohydrazide, 0.13 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- Methanesulfonyl) -4-methyl-2 '- [(2-pyridyl) ethyl] valerohydrazide methanesulfonate in the form of a pale orange solid.
MS: 503 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.97 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was a mixture of (E) -2 (R) - [1 (S) - [(tetrahydro-2 (R) -pyranyloxy) carbamoyl] (Iii), starting from 2- (methanesulfonyl) -4-methylvalerohydrazide and 2- (2-bromoethyl) pyridine hydrobromide.
Example 110
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- - (4-pyridyl) ethyl] valerohydrazide methanesulfonate
(E) -2 (R) - [1 (S) - [(1R) -2,5-Diethoxy- (Methanesulfonyl) -4-methyl-2 ' - [2- (4-pyrimidinylcarbamoyl) Yl) ethyl] valero hydrazide, 0.104 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) - (methanesulfonyl) -4-methyl-2 '- [2- (4-pyridyl) ethyl] valerohydrazide methanesulfonate in the form of a pale orange solid.
MS: 503 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.74 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 4- (2-bromoethyl) pyridine hydrobromide in an analogous manner as described in example 15, part (iii).
Example 111
2 (S) - (hydroxycarbamoyl) -propyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydra Jed
(R) - [3-Cyclohexylidene-1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) Carbamoyl] propyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.042 g of 2 (R) - [3-cyclohexylidene- (S) - (hydroxycarbamoyl) propyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 446 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.20 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was prepared as follows:
(i) Cyclohexylamine salt The title compound was prepared in analogy to example 107, parts (i) and (ii), except that instead of crystallization of the salt, the product was purified by flash chromatography on silica gel using hexane / ether (4: 1) Starting from 1,2-dibenzyl-l-tert-butyl 4-methyl-1,1,2 (R) -pentanetricarboxylate and (2-bromoethylidene) cyclohexane in a manner analogous to that described, , 4-tert-butyl hydrogen 3 (S) - [(2-cyclohexylidene) ethyl] -2 (R) -isobutyl succinate in the form of a pale yellow gum.
MS: 339 (M + H) &lt; ⁺ & gt ^; .
(ii) In a manner similar to that described in Example 2, Part (iii) - (v), tert-butyl hydrogen 3 (S) - [(2- cyclohexylidene) ethyl] -2 ) -Isobutylsuccinate and isobutylhydrazine and deprotecting the tertiary butyl ester using trimethylsilyl trifluoromethanesulfonate in 1,4-dioxane instead of trifluoroacetic acid to give 2 (R - (3-cyclohexylidene-1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] propyl] -2'-isobutyl- Methyl valerohydrazide in the form of a yellow solid.
MS: 530 (M + H) &lt; ⁺ & gt ^; .
Example 112
(S) - (hydroxycarbamoyl) propyl] -2 ' -isobutyl-2 '-( methanesulphonyl) -4-methylvalerohydrazide
In analogy to the procedure described in the first paragraph of Example 2, 0.09 g of 2 (R) - [3- (tetrahydro-2H-pyran-4-ylidene) - 1 (S) - [(tetrahydro- Starting from 2 (RS) -pyranyloxy) carbamoyl] propyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydrazide, 0.046 g of 2 (R) (S) - (hydroxycarbamoyl) propyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerate Lohydrazide was obtained in the form of a white solid.
MS: 448 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.22 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was prepared as follows:
(i) Cyclohexylamine salt The title compound was prepared in analogy to example 107, parts (i) and (ii), except that instead of crystallization of the salt, the product was purified by flash chromatography on silica gel using hexane / ether (4: 1) (R) -pentanetricarboxylate and 4- (2-bromoethylidene) tetra (2-bromoethylidene) tetra (S) - [(tetrahydro-2H-pyran-4-ylidene) ethyl] -2 (R) -isobutyl succinate as a pale yellow In the form of a rubber.
MS: 341 (M + H) &lt; ⁺ & gt ^; .
(ii) In a manner similar to that described in Example 2, Part (iii) - (v), tert-butyl hydrogen 3 (S) - [(tetrahydro-2H-pyran- ] -2 (R) -isobutylsuccinate and isobutylhydrazine and using tert-butyl ester in the presence of trimethylsilyl trifluoromethanesulfonate in 1,4-dioxane instead of trifluoroacetic acid (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] propyl] -2 '-( methanesulfonyl) -Isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a gray solid.
MS: 532 (M + H) &lt; ⁺ & gt ^; .
Example 113 Synthesis of
(S) - (hydroxycarbamoyl) -propyl] -2 ' -isobutyl-2 '-( methanesulphonyl) -4-methylvalerohydrazide
In analogy to the procedure described in the first paragraph of Example 2, starting from 0.14 g of 2 (R) - [3- (tetrahydro-2H-pyran-4-yl) -1 (S) - [(tetrahydro- (RS) -pyranyloxy) carbamoyl] propyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.083 g of 2 (R) - [ (S) - (hydroxycarbamoyl) propyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4- methylvalerohy Drazide was obtained in the form of a gray solid.
MS: 450 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.15 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was prepared as follows:
(i) A solution of 0.397 g of 4-tert-butylhydrogen 3 (S) - [(tetrahydro-2H-pyran-4-ylidene) ethyl] -2 (R) -isobutylsuccinate in 10 ml of methanol Under hydrogen atmosphere, 0.196 g of 10% palladium on charcoal catalyst was shaken until no further absorption of hydrogen was observed. The catalyst was filtered off and the filtrate was evaporated. 0.331 g of 4-tert-butyl hydrogen 3 (S) - [(tetrahydro-2H-pyran-4-yl) ethyl] -2 (R) -isobutyl succinate in the form of a colorless gum.
MS: 343 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 2, parts (iii) - (v), tert-butyl hydrogen 3 (R) - (tetrahydro-2H- (S) - [(tetrahydro-2 (RS) - isobutylsuccinate and isobutylhydrazine there was obtained 2 (R) - [3- (tetrahydro- ) -Pyranyloxy) carbamoyl] propyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 534 (M + H) &lt; ⁺ & gt ^; .
Example 114
2 (R) - [3-cyclohexyl-1 (S) - (hydroxycarbamoyl) -propyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydrazide
(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl- (RS) - ] Propyl] -2'-isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.093 g of 2 (R) - [3-cyclohexyl- (Hydroxycarbamoyl) propyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 448 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.82 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from 4-tert-butylhydrogen 3 (S) - (2-cyclohexylidene) ethyl-2 (R) - &lt; / RTI &gt; isobutylsuccinate.
Example 115
2 (S) - (hydroxycarbamoyl) -4-phenyl-3-butynyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydra Jed
(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-propionic acid ethyl ester was prepared in analogy to the manner described in the first paragraph of example 2 from 0.189 g of 2 (R) Starting from 0.098 g of 2 (R) - [1 (S) - (hydroxymethyl) -3-butynyl] -2'-isobutyl-2 '-( methanesulphonyl) 4-phenyl-3-butynyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 452 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.42 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was prepared as follows:
(i) In a similar manner to that described in Example 107, parts (i) and (ii) above, 1,2-dibenzyl 1-3-butyl- Starting from 2 (R) - [1 (S) -t-butoxycarbonyl) -4-phenyl-3-butynyl] -carbamic acid tert- -4-methylvaleric acid in the form of a light yellow solid.
(S) - (tert-butoxycarbonyl) -4-phenyl-3- (2-fluorophenyl) propanoate in a similar manner to that described in Example 2, Parts (iii) (RS) -pyranyloxy) carbamoyl] -4-phenyl-butyric &lt; / RTI &gt; yl) -4-methylvaleric acid and isobutylhydrazine, 3-butynyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 536 (M + H) &lt; ⁺ & gt ^; .
Example 116
2 (S) - (hydroxycarbamoyl) -3-phenoxypropyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.23 g of 2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Yl) -propyl] -2'-isobutyl-2'- (methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.143 g of 2 (R) - [l (S) - (hydroxycarbamoyl ) -3-phenoxypropyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a creamy white solid.
MS: 458 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.89 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was prepared as follows:
(i) Cyclohexylamine salt The title compound was prepared in analogy to example 107, parts (i) and (ii), except that instead of crystallization of the salt, the product was purified by flash chromatography on silica gel using hexane / ether (4: 1) Starting from 1,2-dibenzyl 1-3-butyl 4-methyl-1,1,2 (R) -pentanetricarboxylate and (2-iodoethoxy) benzene in a manner analogous to that described, 4-tert-Butyl hydrogen 3 (S) - (2-phenoxy) ethyl-2 (R) -isobutyl succinate as a light yellow oil.
MS: 351 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 2, parts (iii) - (v), tert-butyl hydrogen 3 (S) - (2- phenoxy) ethyl- (RS) -pyranyloxy) carbamoyl] -3-phenoxypropyl] -2 ' - iso &lt; / RTI &gt; Butyl-2 &apos;-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 542 (M + H) &lt; ⁺ & gt ^; .
Example 117
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) Methyl-3-oxetanyl) methyl] valerohydrazide
(RS) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Methyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' - [ (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) - [(3-methyl-3-oxetanyl) methyl] valerohydrazide in the form of a white solid.
MS: 482 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.76 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - (tert-butoxycarbonyl) -4 -Phenyl-3-butenyl] -4-methylvalerohydrazide and 3-methyl-3-oxetanecarboxaldehyde.
Example 118
2 (S) - (hydroxycarbamoyl) -3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide
(RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -3- &lt; / RTI &gt; (R) - [1 (S) - (hydroxycarbamoyl) - 2 '- (methanesulfonyl) -4-methyl-2'- phenylvalerohydrazide, 3-butenyl] -2 &apos;-( methanesulfonyl) -4-methyl-2 &apos; -phenylvalerohydrazide as a white solid.
MS: 398 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.97 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -3-butenyl] -2 '-( methanesulfonyl) -4 -Methyl-2-phenylvalerohydrazide was prepared as follows:
(R) - [1 (S) - (tert-Butoxycarbonyl) - (tert-butoxycarbonyl) - (RS) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -3-butenyl] -2 - (methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide in the form of a white solid.
MS: 482 (M + H) &lt; ⁺ & gt ^; .
Example 119
2 (R) - [1 (S) - (hydroxycarbamoyl) -butyl] -2 '-( methanesulfonyl) -4-methyl-2 ' -phenylvalerohydrazide
(R) - [1 (S) - [(benzyloxy) carbamoyl] butyl] -2 '-( methanesulfonyl) - &lt; / RTI &gt; -Methyl-2'-phenylvalerohydrazide there was obtained 0.36 g of 2 (R) - [1 (S) - (hydroxycarbamoyl) butyl] -2 &apos;-( methanesulfonyl) -4- Methyl-2 &apos; -phenylvalerohydrazide in the form of a white solid.
MS: 400 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution increasing from 5% solvent A to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 10.14 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The 2 (R) - [1 (S) - [(benzyloxy) carbamoyl] butyl] -2 '- (methanesulfonyl) -4-methyl-2'- phenylvalerohydrazide used as a starting material was &Lt; / RTI &gt;
(i) A solution of 3.0 g of 2 (R) - [1 (S) - (tert-butoxycarbonyl) -3-butenyl] -4-methylvaleric acid in 30 ml ethanol was treated with 0.3 g of 5 % &Lt; / RTI &gt; palladium for 4 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was dissolved in 30 ml of toluene and the solvent was again evaporated. This procedure was repeated to obtain 2.83 g of 2 (R) - [1 (S) - (tert-butoxycarbonyl) butyl] -4-methylvaleric acid as a colorless oil.
(R) - [1 (S) - (tert-Butoxycarboxy) -carbamic acid tert-butyl ester in a manner analogous to that described in Example 1, Part (i) and Example 65, 2 (S) - [(benzyloxy) carbamoyl] butyl] -2 '-( methanesulfonyl) -4-methyl- Apos; -phenylvalerohydrazide &lt; / RTI &gt; in the form of a white solid.
MS: 490 (M + H) &lt; ⁺ & gt ^; .
Example 120
(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-N-phthalimido valeric amide
(E) -2 (R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3 -Butenyl] -4-methyl-N-phthalimido valeramide, 0.034 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) Butenyl] -4-methyl-N-phthalimido valeric amide as a white solid.
MS: 450 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Time of stay: 12.00 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -4-methyl-N-phthalimido Valeramide was prepared as follows:
(i) To a solution of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] -4- methylvalerohydrazide in 50 ml toluene And 0.41 g of phthalic anhydride was heated to reflux for 2 hours. The mixture was allowed to cool and the solvent was evaporated and replaced with ethyl acetate. The ethyl acetate solution was washed with 2M aqueous hydrochloric acid, 5% aqueous sodium bicarbonate and then brine. The ethyl acetate phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was triturated with diethyl ether to give 0.60 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl- Phthalimido valeramide in the form of a white solid.
MS: 443 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 2, Part (iv) and (v), 0.44 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) Starting from 0.13 g of (E) -2 (R) - [(tetrahydro-2 (RS) -pyranyloxy ) Carbamoyl] -4-phenyl-3-butenyl] -4-methyl-N-phthalimido valeric amide as a white solid.
MS: 534 (M + H) &lt; ⁺ & gt ^; .
Example 121
Methyl (E) -3- [2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutylcarbazate
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy Starting from 0.19 g of methyl (E) -3- [2 (R) - [2-methyl- 1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutyl carbazate as a white solid.
MS: 434 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.08 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl ] -4-methylvaleryl] -2-isobutylcarbazate was prepared as follows:
(i) To a solution of 0.50 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] -2'-isobutyl- Valerohydrazide and 0.12 mL of pyridine were dissolved in 10 mL of dichloromethane and cooled to 0 &lt; 0 &gt; C under nitrogen. 0.12 mL of a small amount of crystals of methyl chloroformate and 4-dimethylaminopyridine was added successively, and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with dichloromethane, washed successively with 5% aqueous sodium hydrogen carbonate solution, water, 2M aqueous hydrochloric acid and water, and then dried over magnesium sulfate. The solvent was evaporated to give 0.54 g of methyl (E) -3- [2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl-3-butenyl] Yl] -2-isobutylcarbazate in the form of a white foam.
MS: 475 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 2, Part (iv) and (v), 0.54 g of (E) -3- [2 (R) - [1 (S) - (tert- Starting from 0.27 g of methyl (E) -3- [2 (R) - [1 &lt; RTI ID = 0.0 &gt; -4-methylvaleryl] -2-isobutylcarbazate was prepared as a white solid (22 mg) from (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl- Lt; / RTI &gt;
MS: 518 (M + H) &lt; ⁺ & gt ^; .
Example 122
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl Valero Hydrazide
2'-cycloheptyl-2 (R) - [1 (S) -tetrahydropyran-2-yl) -ethanone in a similar manner to that described in Example 45, but using cycloheptanone instead of isobutyraldehyde in step (i) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 494 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.99 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 123
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- Lohia Dragaj
(R) - [1 (S) - (hydroxycarbamoyl) piperidin-1-yl) -ethanone in a similar manner to that described in Example 45, but using pivaloaldehyde instead of isobutyraldehyde in step (i) Phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2-neopentylvalerohydrazide in the form of a white solid.
MS: 468 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.79 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 124
(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2'- (trifluoroacetyl) -4- Methylvalerohydrazide
(E) -2 (R) - [1 (S) - (Hydroxy-phenyl) Carbamoyl) -4-phenyl-3-butenyl] -2 ' -isobutyl-2 '-( trifluoroacetyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 472 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.36 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 125
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl- ) Valero Hydrazide
In a similar manner to that described in Example 59, but using phenylacetyl chloride instead of isobutyric anhydride in step (i), (E) -2 (R) - [1 (S) - (hydroxycarbamoyl ) -4-phenyl-3-butenyl] -2'-isobutyl-4-methyl-2 '- (2-phenylacetyl) valerohydrazide in the form of a white solid.
MS: 494 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.03 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 126
(S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -N- (2-isothiazolidinyl) -4-methylvaleramide S, S-dioxide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Starting from 0.03 g of (E) -2 (R) - [1, 1 -benzonitrile (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -N- (2-isothiazolidinyl) -4-methylvaleramide S, S-dioxide in the form of a white solid.
MS: 424 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.90 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -N- (2-isothiazolidinyl) -4-methylvaleramide S, S-dioxide was prepared as follows:
(i) 1.85 g of 3-chloropropylsulfonyl chloride and 0.85 g of pyridine were added to a solution of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4 -Phenyl-3-butenyl] -4-methylvalerohydrazide in 10 ml of dichloromethane. After stirring at room temperature for 2 hours, the solvent was evaporated and the residue was triturated with diethyl ether. The mixture was filtered and the solvent was evaporated to give 1.92 g of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl- 3-chloropropylsulfonyl) -4-methylvalerohydrazide in the form of a pale yellow oil.
^{MS: 445 (M + H- t} Bu) +.
(ii) 1.59 g of potassium carbonate was added to a solution of (E) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl- -2 '-( 3-chloropropylsulfonyl) -4-methylvalerohydrazide in 10 ml of dichloromethane was added. After stirring at room temperature overnight, the solvent was evaporated and the residue was dissolved in diethyl ether and washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate / hexane (1: 2) to elute. (E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -4-phenyl-3-butenyl] -N- (2-isothiazolidinyl) -4 -Methylvaleramide &lt; / RTI &gt; S, S-dioxide as a pale yellow oil.
^{MS: 409 (M + H- t} Bu) +.
(E) -2 (R) - [1 (S) - (tert-Butoxycarbonyl) -methanone) in a similar manner as described in example 2, part (iv) Starting from 0.12 g of (E) -2 (R) - [1, 2-dihydro- (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] S-dioxide &lt; / RTI &gt; in the form of a white solid.
MS: 508 (M + H) &lt; ⁺ & gt ^; .
Example 127
(E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] amides
(R) - [1 &lt; RTI ID = 0.0 &gt; (R) -2 &lt; / RTI &gt; (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methyl-N- (2-oxo-3-oxazolidinyl) valeramide in the form of a white solid.
MS: 390 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.79 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 128
2 (S) - [1 (RS) - (hydroxycarbamoyl) (phenylthio) methyl] -2'-isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydrazide
(RS) - (Phenylthio) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2, Methyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide there was obtained 1.92 g of 2 (S) - [1 (RS) - (hydroxycarbamoyl) (Phenylthio) methyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 446 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.36 and 12.64 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(RS) - (phenylthio) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2'-isobutyl- Methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
In a manner similar to that described in Example 131, Part (v), Example 1, Part (iii) and Example 2, Parts (iii) and (v), 3.45 g of 2 (S) -isobutyl- Starting from (RS) -phenylthiobutane-1,4-dioic acid-4-tert-butyl ester (prepared as described in WO 97/42168), 2.98 g of 2 (S) - [ (RS) - (phenylthio) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2'-isobutyl-2 '- (methanesulfonyl) -4- methylvalerohydra The zide was obtained in the form of a white solid.
MS: 530 (M + H) &lt; ⁺ & gt ^; .
Example 129
2 (S) - (hydroxycarbamoyl) -4-methylpentyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydrazide
In a manner similar to that described in the first paragraph of Example 2, 0.77 g of 2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] (S) - (hydroxycarbamoyl) -4-methylvalerohydrazide, starting from 0.48 g of 2 (R) - [ -4-methylpentyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 408 (M + H) &lt; ⁺ & gt ^; .
HPLC: Accelerated gradient elution with increasing solvent B to 80% solvent B over 10 minutes in solvent A containing 40% solvent B for 5 minutes; Flow rate of 1 ml / min. Retention time: 5.61 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERSIL 120A.
(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-methylpentyl] -2'-isobutyl-2 '-( Methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(i) To a solution of 2 (R) - [1 (S) - (tert-butoxycarbonyl) -4-methyl-3-pentenyl] -2'- Fluoro) -4-methylvalerohydrazide in 50 ml of tetrahydrofuran was hydrogenated for 6 hours in the presence of 0.15 g of 10% palladium on carbon. The catalyst was removed by filtration and the solvent was evaporated to give 1.5 g of 2 (R) - [1 (S) - (tert-butoxycarbonyl) -4-methylpentyl] -2'- (Methanesulfonyl) -4-methylvalerohydrazide in the form of a colorless oil.
MS: 449 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 1, Part (iii) and Example 2, Part (v), 1.5 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl ) - 4-methylpentyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.77 g of 2 (R) (RS) -pyranyloxy) carbamoyl] -4-methylpentyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide as a white solid Lt; / RTI &gt;
MS: 492 (M + H) &lt; ⁺ & gt ^; .
Example 130
2 (R) - [1 (S) - (hydroxycarbamoyl) -4-methyl-3-pentenyl] -2'-isobutyl- Jed
(RS) - [(RS) -pyranyloxy) carbamoyl] -4-methyl-pyrimidine -3-pentenyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.16 g of 2 (R) Methylcarbamoyl) -4-methyl-3-pentenyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 406 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.59 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(RS) -pyranyloxy) carbamoyl] -4-methyl-3-pentenyl] -2 ' -isobutyl- 2 '-( methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(i) To a solution of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-methyl-3-pentenyl] -2 ' -isobutyl- A solution of 1.5 g of 2 '- (methanesulfonyl) -4-methylvalerohydrazide, 0.51 g of triethylamine and 0.93 g of trimethylsilyltriflate was heated to reflux for 4 hours under a nitrogen atmosphere. The mixture was cooled and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with 2M aqueous hydrochloric acid, water and brine. The ethyl acetate phase was then dried over anhydrous magnesium sulfate and the solvent was evaporated to give 1.31 g of 2 (R) - [1 (S) - (carboxy) -4-methyl-3-pentenyl] 2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a yellow foam.
MS: 391 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 2, Part (v), 1.31 g of 2 (R) - [1 (S) - (carboxy) -4-methyl-3-pentenyl] Starting from isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide 0.25 g of 2 (R) - [1 (S) - [(tetrahydro- (RS) -pyranyloxy ) Carbamoyl] -4-methyl-3-pentenyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a light yellow foam.
MS: 490 (M + H) &lt; ⁺ & gt ^; .
Example 131
2 (R) - [(S) - (benzyloxy) - (hydroxycarbamoyl) methyl] -2'-isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydrazide
(S) - (Benzyloxy) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2-methylpropionic acid was prepared in a manner analogous to that described in Example 45, Methyl) -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.07 g of 2 (R) - [(S) - (benzyloxy) Methylcarbamoyl) methyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 444 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution increasing from solvent A containing 5% solvent B to 98% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.86 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(RS) -pyranyloxy) carbamoyl] methyl] -2 ' -isobutyl-2 '-( (S) - (benzyloxy) Methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(i) 4.48 g of 3 (R) -carboxy-2 (S) -hydroxy-5-methylhexanoic acid were stirred in 10 ml of trifluoroacetic anhydride under nitrogen for 1.5 hours. The solvent was evaporated and the residue was dissolved in 20 mL of anhydrous methanol and stirred overnight at room temperature. The solvent was evaporated, yielding 5.3 g of methyl 3 (R) -carboxy-2 (S) -hydroxy-5-methylhexanoate in the form of an orange oil.
(ii) 2.1 ml of allyl bromide was added to a solution of 4.52 g of methyl 3 (R) -carboxy-2 (S) -hydroxy-5-methylhexanoate and 7.9 g of cesium carbonate in 30 ml of dimethylformamide. The mixture was stirred overnight and evaporated. The residue was dissolved in dichloromethane and washed with 2M aqueous hydrochloric acid. The dichloromethane phase was then dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate / hexane (1: 9, increased to 2: 8) to elute. 2.88 g of methyl 3 (R) - (allyloxycarbonyl) -2 (S) -hydroxy-5-methylhexanoate were obtained in the form of a pale yellow oil.
(iii) 0.51 g of silver oxide I and 0.33 ml of benzyl bromide are added to a solution of methyl 3 (R) - (allyloxycarbonyl) -2 (S) -hydroxy-5-methylhexanoate Was added to a solution of 0.27 g. The mixture was stirred for 24 hours, then 0.36 g of cesium carbonate was added and stirring was continued for 3 hours. The mixture was diluted with diethyl ether and filtered. The filtrate was then washed successively with 5% aqueous citric acid, water, 5% aqueous sodium bicarbonate, water and brine. The diethyl ether phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate / hexane (1: 19) to elute. 0.16 g of methyl 3 (R) - (allyloxycarbonyl) -2 (S) -benzyloxy-5-methylhexanoate was obtained in the form of a clear oil.
(iv) 0.39 ml of morpholine and 0.05 g of tetrakis (triphenylphosphine) -palladium (0) were added to a solution of methyl 3 (R) - (allyloxycarbonyl) -2 S) -benzyloxy-5-methylhexanoate (0.15 g). The mixture was stirred for 0.5 h and then the solvent was evaporated. The residue was dissolved in dichloromethane and washed successively with 2M aqueous hydrochloric acid and water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was dissolved in diethyl ether and filtered. The diethyl ether solution was evaporated to give 0.16 g of methyl-3 (R) -carboxy-2 (S) -benzyloxy-5-methylhexanoate in the form of a yellow oil.
(v) By a similar method to that described in Example 1, part (i), and part (ii) except using isobutylhydrazine instead of phenylhydrazine, 0.43 g of methyl-3 (R) -carboxy- Starting from (S) -benzyloxy-5-methylhexanoate, 0.34 g of 2 (R) - [(S) - (benzyloxy) - (methoxycarbonyl) methyl] -2'- 2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a yellow oil.
MS: 443 (M + H) &lt; ⁺ & gt ^; .
(vi) 0.530 ml of a 2M solution of trimethylaluminum in toluene is added to a solution of 0.124 g of O- (tetrahydro-2H-pyran-2 (RS) -yl) hydroxylamine in 5 ml anhydrous toluene at 0 & Respectively. The mixture was stirred at 0 &lt; 0 &gt; C for 0.5 h, and then 0.335 g of 2 (R) - [(S) - (benzyloxy) - (methoxycarbonyl) methyl] -2'-isobutyl- Phenyl) -4-methylvalerohydrazide was added in one portion. The mixture was then allowed to warm to room temperature overnight. The mixture was diluted with ethyl acetate and washed successively with 2M aqueous hydrochloric acid and 5% aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was triturated with hexane / diethyl ether (2: 1) to give 0.119 g of 2 (R) - [(S) - (benzyloxy) - [(tetrahydro-2 (RS) -pyranyloxy ) Carbamoyl] methyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 528 (M + H) &lt; ⁺ & gt ^; .
Example 132
2 (R) - [1 (S) - (hydroxycarbamoyl) -2-phenylethyl] -2'-isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydrazide
(S) - (Benzyloxycarbamoyl) -2-phenylethyl] -2 ' -isobutyl-2 ' - (methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.014 g of 2 (R) - [1 (S) - (hydroxycarbamoyl) -2-phenylethyl] -2'- Butyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 428 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution increasing from solvent A containing 5% solvent B to 95% solvent B over 10 minutes; Flow rate of 2 ml / min. Retention time: 7.55 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent B: H ₂ O / 90% CH ₃ CN / 0.085% TFA. Column type: DYNAMAX 300A.
2 (S) - [(benzyloxycarbamoyl) -2-phenylethyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalero The hydrazide was prepared as follows:
(R) - [1 (S) -tetrahydropyran-2-yl) -ethanone in a similar manner to that described in Example 2, Parts (i) and (ii), except that benzyl bromide was used instead of cinnamyl bromide in step (i) - (tert-butoxycarbonyl) -2-phenylethyl] -4-methylvaleric acid in the form of a clear oil.
MS: 321 (M + H) &lt; ⁺ & gt ^; .
(ii) In a similar manner to that described in Example 131, Part (v) and Example 65, Parts iii) and iv), 1.49 g of 2 (R) - [1 (S) - (tert- (S) - (benzyloxy-carbamoyl) -2-phenylethyl] -4-methylvaleric acid was prepared 0.063 g of 2 (R) Butyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 518 (M + H) &lt; ⁺ & gt ^; .
Example 133
2 (R) - [1 (S) - (hydroxycarbamoyl) -2- (phenylthio) ethyl] -2'-isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- ( Phenyl] thio) ethyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide there was obtained 0.116 g of 2 (R) Carbamoyl) -2- (phenylthio) ethyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 460 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 11.95 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
2- (phenylthio) ethyl] -2'-isobutyl-2 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -2- '- (methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(i) 7.8 ml of piperidine and 20 ml of a 40% formaldehyde aqueous solution were added to a solution of 1-tert-butyl dihydrogen 4-methyl-1 (RS), 1,2 (R) -pentane Tricarboxylate in 6.0 g, and the mixture was stirred overnight under a nitrogen atmosphere. The solvent was evaporated and the residue was dissolved in ethyl acetate. The ethyl acetate phase was washed successively with 1 M aqueous hydrochloric acid, warm water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 3.94 g of 2 (R) - [1- (tert-butoxycarbonyl) vinyl] -4-methylvaleric acid in the form of a clear oil.
(ii) In a manner similar to that described in Example 131, Part (v), starting with 3.4 g of 2 (R) - [1- (tert-butoxycarbonyl) vinyl] -4-methylvaleric acid , 3.27 g of 2 (R) - [1- (tert-butoxycarbonyl) vinyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide as a clear oil Lt; / RTI &gt;
(iii) 0.183 g of thiophenol and 0.356 ml of triethylamine were added to a solution of 2 (R) - [1- (tert-butoxycarbonyl) vinyl] -2'- Methanesulfonyl) -4-methylvalerohydrazide in 5 ml of dichloromethane, and stirring was continued for 48 hours under a nitrogen atmosphere. 0.183 ml of thiophenol was further added to the mixture and stirring was continued at 60 &lt; 0 &gt; C for 48 hours. The mixture was then cooled to room temperature and diluted with ethyl acetate. The mixture was washed successively with 1M aqueous hydrochloric acid, 1M aqueous sodium hydroxide and brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated. Trituration with hexane afforded 0.307 g of 2 (R) - [1 (S) - (tert-butoxycarbonyl) -2- (phenylthio) ethyl] -2'-isobutyl- ) -4-methylvalerohydrazide in the form of a white solid.
MS: 501 (M + H) &lt; ⁺ & gt ^; .
(iv) In a similar manner to that described in Example 2, parts (iv) and (v), 0.307 g of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -2- Starting from 0.315 g of 2 (R) - [1 (S) - [(tetrahydroisoquinolin-2-ylmethyl) -2 (RS) -pyranyloxy) carbamoyl] -2- (phenylthio) ethyl] -2'-isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydrazide as a white solid .
MS: 544 (M + H) &lt; ⁺ & gt ^; .
Example 134
(R) - [1 (S) - (hydroxycarbamoyl) -4- (1-naphthyl) -3-butenyl] -2'-isobutyl- ) -4-methylvalerohydrazide
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4-methylvalerohydrazide, 0.155 g of (E) - (1-naphthyl) -3-butenyl] -2'- 2 (R) - [1 (S) - (hydroxycarbamoyl) -4- (1-naphthyl) -3-butenyl] -2'-isobutyl- Methylvalerohydrazide in the form of a white solid.
MS: 504 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 13.19 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (1-naphthyl) -3- 2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide was prepared as follows:
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -3-butenyl] -2 '-( methane Methyl-2'-phenylvalerohydrazide, 0.449 g of 1-bromo-naphthalene, 0.219 g of triethylamine, 0.012 g of palladium (II) acetate and 0.033 g of tri -o-tolylphosphine was dissolved in 5 ml of dimethylformamide and stirred at 100 &lt; 0 &gt; C for 24 hours. The mixture was cooled to room temperature and partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using dichloromethane / methanol (9.5 / 0.5) to elute. (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- (1-naphthyl) -3-butenyl] ] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 504 (M + H) &lt; ⁺ & gt ^; .
Example 135
(R) - [1 (S) - (hydroxycarbamoyl) -4- (5-pyrimidinyl) -3-butenyl] -2'- Trifluoromethyl-phenyl) -4-methylvalerohydrazide
-2 (R) - [1 (S) - (hydroxycarbamoyl) piperidin-1-yl] -methanone in a similar manner to that described in Example 134, but using 5-bromopyrimidine instead of 1- (5-pyrimidinyl) -3-butenyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methylvalerohydrazide in the form of a white solid.
MS: 456 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.89 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Example 136
2 '-( methanesulfonyl) -4-methylvalerohydrazide and 2 (R) - [(S) - (cyclopentyl) (hydroxycarbamoyl) methyl] ) - [(S) - (cyclopentyl) (hydroxycarbamoyl) methyl] -2'-isobutyl-2 '-( methanesulfonyl) -4-methyl-3-pentenoylhydrazide
[(S) - (cyclopentyl) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2 - (S) - (cyclopentyl) [(tetrahydro-2 (RS) -pyranyloxy) -2 '-( methanesulfonyl) -4-methylvalerohydrazide and 2 (R) ) - [(S) - (R) - [2- (4-fluorophenyl) carbamoyl] methyl] -2'-isobutyl-2 '-( methanesulfonyl) (Compound A) and 2 (R) - [(S) -methyl-2-isobutyl-2 '-( methanesulphonyl) -4-methylvalerohydrazide Methyl-3-pentenohaidrazide (Compound B) was obtained as a white solid, mp &lt; RTI ID = 0.0 &gt;Lt; / RTI &gt; The compound was then isolated by preparative high performance liquid chromatography on a DYNAMAX 5 mu m C18 300A column with a diameter of 21.4 x 50 mm using the gradient elution method shown below:
Compound A: MS: 405 (M + H) &lt; ⁺ & gt ^; . HPLC: gradient elution with solvent B for 15 min; Flow rate of 1 ml / min. Time of stay: 11.00 minutes.
Compound B: MS: 403 (M + H) &lt; ⁺ & gt ^; . HPLC: gradient elution as described for compound A; Flow rate of 1 ml / min. Retention time: 10.77 min.
[(S) - (cyclopentyl) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2'-isobutyl-2 Methyl) valerohydrazide and 2 (R) - [(S) - (cyclopentyl) [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] methyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methyl-3-pentenohalide was prepared as follows.
(i) In a similar manner to that described in Example 131, Part (v), 1.1 g of 2 (S) -cyclopentyl-3 (R) - (2-methylallyl) succinic acid 4- 19503), starting from 1.14 g of 2 (R) - [(S) - (benzyloxycarbonyl) (cyclopentyl) methyl] -2'-isobutyl- Methanesulfonyl) -4-methyl-4-pentenoylhydrazide in the form of a white foam, which can be recrystallized from hexane.
(ii) To a solution of 2 (R) - [(S) - (benzyloxycarbonyl) (cyclopentyl) methyl] -2'-isobutyl-2 '-( methanesulfonyl) -Pentenoic &lt; / RTI &gt; hydrazide in 50 ml of tetrahydrofuran was hydrogenated for 48 hours in the presence of 0.05 g of 10% palladium on carbon. Removal of the catalyst by filtration and evaporation of the solvent afforded 2 (R) - [(S) - (carboxy) (cyclopentyl) methyl] -2'-isobutyl-2 '-( methanesulfonyl) (R) - [(S) - (carboxy) (cyclopentyl) methyl] -2'-isobutyl-2 &apos;-( methanesulfonyl) -4-methyl-3-pentenoylhydrazide Lt; / RTI &gt; as a white foam.
(iii) In a manner similar to that described in Example 2, Part (v), 2 (R) - [(S) - (Methylsulfonyl) -4-methylvalerohydrazide and 2 (R) - [(S) - (carboxy) (cyclopentyl) methyl] -2'- (RS) -pyranyloxy) carbamoyl] methyl] - (2-methyl-3-pentenoylhydrazide) (S) - (cyclopentyl) [(tetrahydro-2 (RS) -pyranyl) -2 '-( methanesulfonyl) -4-methylvalerohydrazide and 2 (R) Oxy) carbamoyl] methyl] -2'-isobutyl-2 '- (methanesulfonyl) -4-methyl-3-pentenohydrazide in the form of a white solid.
MS: 512 (M + Na) &lt; ⁺ & gt ^; and 510 (M + Na) &lt; ⁺ & gt ^; .
Example 137
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -4- Starting from (E) -2 &lt; RTI ID = 0.0 &gt; (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'- ) -4-methylvalerohydrazide methanesulfonic acid in the form of a white solid.
MS: 492 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.84 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
(R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Methyl valerohydrazide was prepared in a manner similar to that described in Example 15, Part (iii) from (E) - [2- (1-imidazolyl) ethyl] -2 '-( methanesulfonyl) -2 (R) - [(S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] Prepared by reaction with 1- (2-bromoethyl) imidazole starting from methyl valero hydrazide.
Example 138
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-( methanesulfonyl) Valero Hydrazide
(Z) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) carbamoyl] -methanone in a manner analogous to that described in the first paragraph of Example 2, Starting from 0.047 g of (Z) -2 (R) - (4-Phenyl-3-butenyl] -2 ' -isobutyl-2 '-( methanesulphonyl) Phenyl] -3-butenyl] -2 ' -isobutyl-2 '-( methanesulfonyl) -4-methylvalerohydrazide as a white solid Lt; / RTI &gt;
MS: 454 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 12.19 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material was prepared as follows:
(i) To a solution of 2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl-3-butynyl] -2 ' -isobutyl- A solution of 0.1 g of Drazide was shaken in the presence of 5% palladium catalyst on barium sulphate in hydrogen atmosphere. After 45 minutes, the catalyst was filtered off and the pyridine was evaporated. The residue was further evaporated three times from toluene to obtain 0.1 g of (Z) -2 (R) - [1 (S) - (tert- butoxycarbonyl) -4-phenyl- Isobutyl-4-methylvalerohydrazide in the form of a straw-colored solid.
MS: 417 (M + H) &lt; ⁺ & gt ^; .
(R) - [1 (S) - (tert-Butoxycarbonyl) -4-tert- (R) - [1 (S) - [(tetrahydro-2 (RS) ) -Pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2'-isobutyl-2 '-( methanesulfonyl) -4- methylvalerohydrazide in the form of a white solid Respectively.
MS: 538 (M + H) &lt; ⁺ & gt ^; .
Example 139
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) 2-pyridyl) methyl] valerohydrazide methanesulfonate
In a manner similar to that described in the first paragraph of Example 2, but using methanesulfonic acid instead of p-toluenesulfonic acid, 0.266 g of (E) -2 (R) - [1 (S) - [ (Methylsulfonyl) -4-methyl-2 '- [(2-pyridyl) methyl) -2 '-( methanesulphonyl) ] Valerohydrazide, 0.24 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- Sulfonyl) -4-methyl-2 '- [(2-pyridyl) methyl] valerohydrazide methanesulfonate as an off-white solid.
MS: 489 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Retention time: 9.95 min. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
Starting material was prepared from (E) -2 (R) - [1 (S) - [(tetrahydro-2 (RS) -pyranyloxy) (Methanesulfonyl) -4-methylvalerohydrazide and 2-bromomethylpyridine hydrobromide in an analogous manner as described in example 15, part (iii).
Example 140
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- , 6-dimethyl-4-pyrimidinyl) valerohydrazide methanesulfonate
In a manner similar to that described in the first paragraph of Example 2 but using methane sulfonic acid instead of p-toluenesulfonic acid, 0.049 g of (E) -2 (R) - [1 (S) - [ (RS) -pyranyloxy) carbamoyl] -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl-2 '-( 2,6-dimethyl- -Pyrimidinyl) valerohydrazide, 0.039 g of (E) -2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl- - (methanesulfonyl) -4-methyl-2 '- (2,6-dimethyl-4-pyrimidinyl) valerohydrazide methanesulfonate as a gray solid.
MS: 504 (M + H) &lt; ⁺ & gt ^; .
HPLC: gradient elution, increasing from solvent A containing 5% solvent B to 95% solvent B over 15 minutes; Flow rate of 1 ml / min. Time of stay: 12.00 minutes. Solvent A: H ₂ O / 0.1% TFA; Solvent _{B: CH 3 CN / 0.085%} TFA. Column type: HYPERPEP 300A.
The starting material is a mixture of (E) -2 (R) - [1 (S) - (tert-butoxycarbonyl) -4-phenyl-3-butenyl] -4-methylvaleric acid and 2,4- (Iii) to (v) starting from 5-chloro-6-hydrazinopyrimidine.
Example A
Tablets containing the following ingredients can be prepared in a conventional manner:
ingredientThe amount of refined sugar (mg) Hydrazine derivative10.0 Laktos125.0 Corn starch75.0 talc4.0 Magnesium stearate1.0 Gross weight215.0
Example B
Capsules containing the following ingredients can be prepared in a conventional manner:
ingredientAmount per capsule (mg) Hydrazine derivative10.0 Laktos165.0 Corn starch20.0 talc5.0 Capsule filling weight200.0

权利要求:
Claims (25)
[1" claim-type="Currently amended] Claims 1. Compounds of the general formula &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &
Formula I

In this formula,
Y signifies CO or SO ₂ ;
R ¹ means lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl;
R ² means lower alkyl, halo-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl or aryl when Y signifies SO ₂ ; When Y is meant a CO is lower alkyl, halo-lower alkyl, lower alkoxy, lower alkoxycarbonyl, acyl, lower cycloalkyl, aryl, aryl-lower alkyl, aryl-represents lower alkoxy or NR ⁵ R ^6, and;
R ³ is hydrogen,
Lower alkyl substituted or unsubstituted with cyano, amino, hydroxy, lower alkoxy, lower alkoxycarbonyl, heterocyclyl or heterocyclylcarbonyl,
Lower alkenyl, lower alkynyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl-lower alkenyl, aryl or heterocyclyl; or
R ² and R ³ together form a moiety of a 5-, 6- or 7-membered cyclic amide, cyclic imide, cyclic sulfonamide or cyclic urethane group;
R ⁴ is lower alkyl, lower alkenyl, lower cycloalkyl, lower cycloalkyl-lower alkyl or a group of the general formula X-aryl, X-heteroaryl or - (CH ₂ ) _1-2 -CH = CR ⁷ R ⁸ Means;
X represents a spacer group;
R ⁵ and R ⁶ are each independently hydrogen, lower alkyl or aryl-lower alkyl;
R ⁷ and R ⁸ together represent a lower alkylene group in which one methylene group is substituted or unsubstituted by a hetero atom.
[2" claim-type="Currently amended] The method according to claim 1,
Y represents a CO or SO _2, and; R ^{1 means} lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl or aryl-lower alkyl; R ² means lower alkyl, aryl-lower alkyl or aryl when Y signifies SO ₂ and lower alkyl, lower alkoxy, lower cycloalkyl, aryl-lower alkoxy or NR ⁵ R ⁶ ; R ³ is hydrogen; Lower alkyl substituted or unsubstituted with cyano, amino or phthalimido; Lower alkenyl, lower alkynyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl or heterocyclyl; Or R ² and R ³ together form a 5-, 6- or 7-membered cyclic amide, cyclic imide or cyclic sulfonamide group; R ⁴ is phthalimido-lower alkyl or a group of the general formula X-aryl or X-heteroaryl; X represents a spacer group; Heteroaryl is C-linked; R ⁵ and R ⁶ are each independently hydrogen, lower alkyl or aryl-lower alkyl, or a pharmaceutically acceptable salt thereof.
[3" claim-type="Currently amended] 3. The method according to claim 1 or 2,
Y signifies CO, R ² signifies lower alkoxy, or Y signifies SO ₂ and R ² signifies lower alkyl.
[4" claim-type="Currently amended] The method of claim 3,
Y is CO, and R &lt; ² &gt; is methoxy.
[5" claim-type="Currently amended] The method of claim 3,
Y is SO ₂ , and R ² is methyl.
[6" claim-type="Currently amended] 6. The method according to any one of claims 1 to 5,
Wherein R &lt; ^{1 &gt;} is lower alkyl.
[7" claim-type="Currently amended] 7. The method according to any one of claims 1 to 6,
And R &lt; ¹ &gt; represents isobutyl.
[8" claim-type="Currently amended] 8. The method according to any one of claims 1 to 7,
R <^3> is lower alkyl, lower alkenyl, aryl-lower alkyl or aryl.
[9" claim-type="Currently amended] 9. The method of claim 8,
R ³ is isobutyl, 2-methylbutyl, 2-methylallyl, unsubstituted benzyl or unsubstituted phenyl.
[10" claim-type="Currently amended] 10. The method according to any one of claims 1 to 9,
X represents the formula _{- (CH 2) 1-5 -,} -CH 2 -CH = CH-, -CH 2 -C≡C-, -CH 2 NHCO-, - (CH 2) 1 _{or 2} NHCONH-, - _{(CH 2) 1-5 -S-, -CH} 2 NHSO 2 -, -CH 2 NHCH 2 -, - (CH 2) 1-5 -O-, -O- (CH 2) 1-5 - or - S-. &Lt; / RTI &gt;
[11" claim-type="Currently amended] 11. The method of claim 10,
X represents the formula _{- (CH 2) 1-5 -,} -CH 2 -CH = CH-, -CH 2 -C≡C-, -CH 2 NHCO-, - (CH 2) 1 _{or 2} NHCONH-, - CH ₂ S-, -CH ₂ NHSO ₂ - or -CH ₂ NHCH ₂ -.
[12" claim-type="Currently amended] 12. The method according to any one of claims 1 to 11,
R &lt; ⁴ &gt; represents a group of the general formula X-aryl.
[13" claim-type="Currently amended] 13. The method of claim 12,
Compound X refers to a group of the formula -CH ₂ -CH = CH-, and aryl means an unsubstituted phenyl beach.
[14" claim-type="Currently amended] A compound selected from the group consisting of:
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2'-isobutyl-2 '-( methanesulfonyl) Valero Hydrazide,
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- Lohia Drazed,
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- (S) -methylbutyl] valerohydrazide,
(R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -2 '-( methanesulfonyl) -4-methyl- -Methylallyl) valerohydrazide and &lt; RTI ID = 0.0 &gt;
Methyl (E) -3- [2 (R) - [1 (S) - (hydroxycarbamoyl) -4-phenyl-3-butenyl] -4-methylvaleryl] -2-isobutylcarbazate .
[15" claim-type="Currently amended] A compound of formula II:
(II)

In this formula,
Y, R ¹ , R ² , R ³ and R ⁴ have the meanings given in claim 1,
R ⁹ means a protecting group.
[16" claim-type="Currently amended] 16. The method of claim 15,
R ⁹ is tetrahydropyranyl, 4-methoxybenzyl, benzyl or tri (lower alkyl) silyl.
[17" claim-type="Currently amended] A carboxylic acid of formula (IX)

In this formula,
Y, R ¹ , R ² , R ³ and R ⁴ have the meanings indicated in claim 1.
[18" claim-type="Currently amended] 15. The method according to any one of claims 1 to 14,
A compound for use as a therapeutically active substance in the treatment of inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis.
[19" claim-type="Currently amended] 14. A process for the preparation of a compound according to any one of claims 1 to 14, comprising deprotecting a compound of formula &lt; RTI ID = 0.0 &gt; (II) &lt; / RTI &gt; and optionally converting the obtained compound of formula (I) into a pharmaceutically acceptable salt Way:
(II)

In this formula,
Y, R ¹ , R ² , R ³ and R ⁴ have the meanings given in claim 1,
R ⁹ means a protecting group.
[20" claim-type="Currently amended] 15. A medicament containing a compound according to any one of claims 1 to 14 and a therapeutically inert carrier material.
[21" claim-type="Currently amended] 14. A medicament for the treatment of inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis, comprising a compound according to any one of claims 1 to 14 and a therapeutically inert carrier substance.
[22" claim-type="Currently amended] 15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 in a herbal dosage form together with a therapeutically inert carrier material and, optionally, one or more additional therapeutically active substances, Bleeding, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis.
[23" claim-type="Currently amended] 15. The use of a compound according to any one of claims 1 to 14 in the treatment of diseases including inflammation, fever, hemorrhage, sepsis, rheumatoid arthritis, osteoarthritis, multiple sclerosis or psoriasis.
[24" claim-type="Currently amended] 15. The method according to any one of claims 1 to 14,
20. A compound according to claim 19 or an equivalent method.
[25" claim-type="Currently amended] Novel compounds, intermediates, processes, agents and methods as described above.

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同族专利:

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公开号 | 公开日

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GB9803335D0|1998-04-15|

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KR100371122B1|2003-02-05|

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PE86099A1|1999-09-17|

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AR012258A1|2000-09-27|

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YU70899A|2002-06-19|

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CO4940511A1|2000-07-24|

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GB9713833D0|1997-09-03|

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HRP980366A2|1999-02-28|

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ZA9805469B|1998-12-30|

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EA199901111A1|2000-08-28|

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:
1997-06-30|Priority to GBGB9713833.3A

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1998-02-17|Priority to GB9713833.3

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1998-02-17|Priority to GB9803335.0

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1998-02-17|Priority to GBGB9803335.0A

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1998-06-18|Application filed by 프리돌린 클라우스너, 롤란드 비. 보레르, 에프. 호프만-라 로슈 아게

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2001-02-26|Publication of KR20010014331A

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2003-02-05|Application granted

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2003-02-05|Publication of KR100371122B1

优先权:

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申请号 | 申请日 | 专利标题

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GBGB9713833.3A|GB9713833D0|1997-06-30|1997-06-30|Novel hydrazine derivatives|

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GB9713833.3|1998-02-17|

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GB9803335.0|1998-02-17|

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GBGB9803335.0A|GB9803335D0|1997-06-30|1998-02-17|Novel hydrazine derivatives|