[go: up one dir, main page]

MXPA00012599A - Amino acid derivatives and drugs containing the same as the active ingredient - Google Patents

Amino acid derivatives and drugs containing the same as the active ingredient

Info

Publication number
MXPA00012599A
MXPA00012599A MXPA/A/2000/012599A MXPA00012599A MXPA00012599A MX PA00012599 A MXPA00012599 A MX PA00012599A MX PA00012599 A MXPA00012599 A MX PA00012599A MX PA00012599 A MXPA00012599 A MX PA00012599A
Authority
MX
Mexico
Prior art keywords
cyclohexylmethylthio
propanamide
benzylpiperidin
substituted
ylcarbonylamino
Prior art date
Application number
MXPA/A/2000/012599A
Other languages
Spanish (es)
Inventor
Takuya Seko
Masashi Kato
Original Assignee
Ono Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ono Pharmaceutical Co Ltd filed Critical Ono Pharmaceutical Co Ltd
Publication of MXPA00012599A publication Critical patent/MXPA00012599A/en

Links

Abstract

Compounds represented by general formula (I) and salts thereof, wherein each symbol is as defined in the specification. Because of inhibiting the N type calcium channel, the compounds of general formula (I) are useful as preventives and/or remedies for brain infarction, transient ischemic attack, cerebrospinal failure following heart operation, spinal vascular failure, stress hypertension, neurosis, epilepsy, asthma, frequent urination, etc. or analgesics.

Description

Amino acid derivatives and pharmaceutical composition that comprise them as active ingredients Field of Art The present invention relates to amino acid derivatives of the formula (I), the process for the preparation thereof and the pharmaceutical composition thereof as active ingredients.
More particularly, it refers to amino acid derivatives of the formula (I) (where all the symbols have the same meanings as those described below), non-toxic salts thereof and the hydrates thereof, the processes for the preparation thereof, and the calcium channel blocker type N who understand them as active ingredients. (125727) Background of Related Arts The calcium ion has been known as an intracellular messenger for signal transduction, and it is suggested that several physiological events are activated by the elevation of the intracellular calcium concentration. The calcium flux of the extracellular fluid is one of the mechanisms for the elevation of the intracellular calcium concentration. The influx of calcium flux are the voltage-dependent calcium channels. The voltage-dependent calcium channel is opened by polarization of the plasma membrane, and the calcium ion flows selectively from the extracellular fluid into the cell through the channel, according to the electrochemical gradient. Voltage-dependent calcium channels are classified as N-, L-, P-, Q- and the present type ^ T. It is known that calcium channels of type T and L- are distributed within the various tissues in a ubiquitous manner, and especially, the calcium channel type L is enriched in smooth muscle cells or cardiac muscle cells. On the other hand, calcium channels type P and N- are located mainly within the nervous system, and are related to the neurotransmitter release. This neurotransmitter is stored inside synaptic vesicles of the nerve terminals in the resting state. When the potential action is conducted by means of signal transmission on the nerve in the pre-synaptic fiber and reaches up to the nerve terminal, the voltage-dependent calcium channels are activated and subsequently, the calcium ion flows inward. of the nerve terminals. By means of these mechanisms, the synaptic vesicles fuse with the pre-snaptic membrane, and the neurotransmitters in the vesicles are released. The neurotransmitters released are related to signal transmission at the synapse due to the binding of their receptors in the post-synaptic membrane. From the above, a N-type calcium channel blocker is considered to be effective in several diseases induced by an excessive release of neurotransmitter. For example, it may be useful as an agent for the prevention and / or treatment of cerebral infarction (J. Cereb Blood Flow Metab., Vol.17, 421-429, 1997), transient ischemic attack, encephalomyelitis after the operation. cardiac, spinal angiopathy, hypertension with stress (Science, 239, 57-61, 1988) neurosis, epilepsy, asthma or pollakiuria etc. or agent for the treatment of pain (Pain, ß_0, 83-90, 1995).
Isolated poisons of the genus Conus, o-conotoxin GVIA, MVIIA, are well known as calcium channel blockers type N.
But, these? -conotoxins are composed of peptides, so it is expected that these have several problems (for example, these are not absorbed into the living body in an easy way). Thus. There is a demand for the arrangement of these blockers towards the non-peptide compounds ie the small molecule. There are some reports that relate to the small molecule as follows: ~~ For example, it is described in the specification of Japanese Patent Kokai Hei 8-217671 that the glycine derivatives of the formula (A) , 1A, R, MCH (OCOR 2) CH2CONHCH2CO2H (A) (wherein R1A and R2A are, identical or different, linear or branched C1-19 alkyl or linear or branched C2-19 alkenyl) and salts thereof are N-type calcium channel blockers.
It is described in the specification of EP 805147 that the compounds of the formula (B) (wherein R1B is alkyl, R2B is hydrogen, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl, R38 is hydrogen, CN, XB is linked or S02, R B, R6B, R8B, RSB and R10B are each hydrogen or alkyl, AB is CH2 or YBCQ (in which YB is linked), R7B is C substituent to amino acid or ester thereof, R6B and R7B join to form a C3-5 alkylene chain optionally substituted by C1-4 alkyl or hydroxy or CH2-ZB -CH2 (wherein Z is CO, S, SO, S02), R7B and R8B join to form the C3-5 alkylene chain optionally substituted by C1-4 alkyl or hydroxy, BB is CON (R21B), mB is 0- 2, R11B is hydrogen or alkyl, R12B is hydrogen, alkyl, optionally substituted aryl or optionally substituted heteroaryl, R13B is alkyl, optionally substituted aryl or optionally substituted heteroaryl, R12B and R13B are joined to form C3-8 cycloalkyl), the salts of the same or the ester thereof are modulators of calcium channel (the necessary part is extracted in the explanation of the group).
Also, it is described in the specification of Japanese Patent okai Sho 61-200950 that the compound of the formula (C) (wherein Rc and Rl each independently, is lower alkyl, aryl lower alkyl or phenyl optionally substituted by one or more donor or electron withdrawing groups, R2C and R3C each independently, is hydrogen, lower alkyl, aryl lower alkyl or phenyl optionally substituted with one or more donor or electron withdrawing groups, and nC is 1-4) and pharmaceutically acceptable salts thereof are anti-convulsant agents.
In addition, the present inventors (s) have filed an international application with In addition, 098/54123 is listed as an application that relates to a type N calcium channel inhibitor.
In addition to the above applications, 099/25686 (cyclic amino derivatives that possess inhibitory action on chemokine) is listed.
Description of the invention As a result of energetic investigations to find compounds possessing inhibitory action on the N-type calcium channel, the present invention has found that the purpose has been carried out by means of the compound of the formula (I).
The present invention relates to (1) an amino acid derivative of the formula (I) < (I) [wherein, R1 is, 1) Cl-15 alkyl, 2) Cl-8 alkoxy, 3) phenyl, 4) C3-8 cycloalkyl, 5) heterocyclic ring, 6) Cl-4 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring, 7) Cl-4 alkoxy substituted with femlo, C3-8 cycloalkyl or heterocyclic ring or _ _ 8) C2-4 alkenyl substituted with phenyl, cycloalkyl C3-8 or heterocyclic ring, wherein all phenyl, C3-8 cycloalkyl and heterocyclic ring in R1 can be substituted with 1-3 substituents of the group consisting of the following (i) - (ix): (i) alkyl Cl-4, (ii) alkoxy Cl-4, (iii) phenyl, (iv) phenoxy, (v) benzyloxy, (vi) -SR5 (wherein R5 is hydrogen or alkyl Cl-4), (vii) acyl C2-5, (viii) halogen, (ix) alkoxycarbonyl Cl-4, (x) nitro and (xi) -NRSR7 (in which R6 and R7 are independently, hydrogen , alkyl Cl-4 or alkoxycarbonyl C1-4, or R6 and R7 are taken together with the nitrogen atom, to which these are bonded represents the 5-7 membered saturated heterocyclic ring which necessarily contains a nitrogen atom and additionally optionally contains a nitrogen atom or an oxygen atom), A is a single bond, -CO- or -SO; -, R2 is hydrogen or alkyl Cl-4, which can be substituted with a phenyl, D is alkylene Cl-4 or alkenylene C2-4, E is 1) -COO-, 2) -OCO-, 3) -CONR8- (wherein R8 is hydrogen or C1-4 alkyl), 4) -NR9C0- (wherein R9 is hydrogen or C1-4 alkyl), ) -0-, 6) -S-, 7) -SO-, 8) -SO¿-, 9) -NR10- (wherein R10 is hydrogen or Cl-4 alkyl), 10) -CO- 11 ) -SO-NR11- (wherein R11 is hydrogen or Cl-4 alkyl; 12) -NR12S0_- (wherein R12 is hydrogen or Cl-4 alkyl), R3 is 1) carbocyclic ring, 2) heterocyclic ring or 3) Cl-4 alkyl substituted with carbocyclic ring or heterocyclic ring, wherein all carbocyclic ring and heterocyclic ring in R3 may be substituted With 1 ~ 3 substituent (s) selected from the group consisting of the following (i) - (ix): (i) - (ix): (i) Cl-4 alkyl, (ii) Cl-4 alkoxy, (iii) phenyl, (iv) phenoxy, (v) benzyloxy, (vi) -SR13 (wherein R13 is hydrogen-alkyl Cl-4), (vii) acyl C2-5, (viii) halogen, (ix) alkoxycarbonyl Cl-4, (x) nitro and (xi) -NR14R "(in which R14 and R1S are independently, hydrogen, C1-4 alkyl or alkoxycarbonyl Cl-4, or R14 and R1S are taken together with the nitrogen atom, to which these are linked represents the 5-7 membered saturated heterocyclic ring which necessarily contains a nitrogen atom and additionally optionally contains a nitrogen atom or an oxygen atom), J is J1 or J2, J1 is l) -0- or 2) -NR16- (wherein R16 is hydrogen or C1-4 alkyl), J2 is 1) -NR17- (wherein R17 is Cl-4 alkyl substituted with a phenyl, NR18R19 (in which R18 and R19 are independently, hydrogen or Cl-4 alkyl), hydroxy, Cl-4 alkoxy, - (Cl-4 alkylene) -OH, - (Cl-4 alkylene) -O- ( alkyl Cl-4) or - (alkylene Cl-4) -O- (C2-5 acyl)), 2) -NR20-NR21- (in which R20 and R21 are independently, hydrogen or alkyl Cl-4, which can be substituted with a phenyl), 3) -NR22- (Cl-4 alkylene) -NR23- (wherein R22 and R23 are independently, hydrogen or Cl-4 alkyl, which can be substituted with a phenyl), 4) - NR24- (alkylene Cl-4) -O- (wherein R24 is hydrogen or Cl-4 alkyl, and which can be substituted with a phenyl) or 5) -NR 25- (C 1-4 alkylene) -S- (wherein R 2 S is hydrogen or C 1-4 alkyl, which can be substituted with a phenyl), R 4 is R 4"1 , R4"2 or R4" 3, R4"1 is 1) Cl-8 alkyl, 2) carbocyclic ring, 3) heterocyclic ring or 4) Cl-8 alkyl substituted with 1 ~ 3 selected substituent (s) of the group consisting of the following (i) - (v); (i) carbocyclic ring, (ii) heterocyclic ring, (iii) COOR26 (wherein R26 is hydrogen or Cl-4 alkyl substituted with a phenyl (in which the phenyl can be substituted with alkoxy Gl-4), (iv) SR27 (wherein R27 is hydrogen or Cl-4 alkyl) and (v) 0R28 (wherein R28 is hydrogen or Cl-4 alkyl), with the proviso that when J is -NR17-, -NR20-NR21- 0-NR22- (Cl-4 alkylene) -NR23-, each of R4"1 and R17, R4 ~ 1 and R21 and R4"1 and R23 are taken together with the nitrogen atom to which these link represent the heterocyclic ring, wherein all carbocyclic ring heterocyclic ring in R" heterocyclic ring represented by each R4"1 and R17, R4"1 and R21 and R4" 1 and R23 are taken together with the nitrogen atom to which they are bonded and can be substituted with 1 ~ 3 their selected constituent (s) from the group consisting of the following i) - ( xi): i) Cl-4 alkyl, ii) Cl-4 alkoxy, (iii) phenyl, iv) phenoxy, v) benzyloxy, vi) -SR29 (wherein R29 is hydrogen or Cl-4 alkyl), vii) acyl C2-5, (viii) halogen, ix) alkoxycarbonyl Cl-4, x) nitro and xi) -NR30R31 (in which R30 and R31 are independently, hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R30 and R31 are taken together with the nitrogen atom, to which these are bonded represents the 5-7 membered saturated heterocyclic ring which necessarily contains a nitrogen atom and also contains optionally a nitrogen atom or an oxygen atom), R 4 is 1) carbocyclic ring, 2) heterocyclic ring or 3) Cl-8 alkyl substituted with 1 ~ 3 substituents selected from the group consisting of the following (i) - ( v): (i) carbocyclic amyl, (ii) heterocyclic ring, (iii) COOR32 (wherein R32 is hydrogen or Cl-4 alkyl substituted with a phenyl (wherein the phenyl can be substituted with Cl-4 alkoxy), (iv) SR33 (wherein R33 is hydrogen or Cl-4 alkyl) and (v) 0R34 (wherein R34 is hydrogen or Cl-4 alkyl), with the proviso that when J is -NR16-, -NR17-, -NR20-NR21- or -NR22- (alkylene Cl-4) -NR23-, each of R4"2 and R16, R4" 2 and R16 , R4"2 and R17, R4" 2 and R21, and R4"2 and R23 are together with the nitrogen atom to which these are linked can represent the heterocyclic ring, in dande at least one ring of all carbocyclic ring and heterocyclic ring in R4"2 and heterocyclic ring represented by each R4" 2 and R16, R4"2 and R17, R4" 2 and R21, and Y4"2 and R23 are taken together with the nitrogen atom to which these are they are substituted with a hydroxy or an -O- (alkylene Cl-4) -O- (alkyl Cl-4) and can be further substituted with 1 ~ 2 substituents selected from the group consisting of the following (i) - (xiii): (i) alkyl Cl-4, (ii) alkoxy Cl-4, (iii) phenyl, (iv) phenoxy, (v) benzyloxy, (vi) -SR35 (wherein R35 is hydrogen or alkyl Cl-4), (vii) C2-5 acyl, (viii) halogen, (ix) alkoxycarbonyl Cl-4, (x) nitro and (xi) -NR3SR37 (in which R36 and R37 are independently, hydrogen , alkyl Cl-4 or alkoxycarbonyl Cl-4, or R36 and R37 are taken together with the nitrogen atom, to which these are bonded represents the 5-7 membered saturated heterocyclic ring that necessarily contains a nitrogen atom and also contains optionally a nitrogen atom or an oxygen atom), (xii) hydroxy and (xiii) -O- (alkyleneCl-4) -O- (alkylCl-4), R4"3 is LM, -L- is 1) - (carbocyclic ring, which can be substituted with 1 ~ 3 its constituent (S)) -, 2)) - (heterocyclic ring, which can be substituted with 1 ~ 3 its (S)) - or 3) - (alkylene Cl-4) - (carbocyclic indigo) or heterocyclic ring, which can be substituted with 1 ~ 3 substituent (s)), with the proviso that when J is -NR16-, -NR17-, - NR20-NR21- or -NR22- (alkylene Cl-4) -NR23-, each L and R16, L and R17, L and R21 and L and R23 are taken together with the nitrogen atom to which they are bonded represents - (heterocyclic ring, which can be substituted with 1 ~ 3 substituent (s)), M is 1) carbocyclic ring or heterocyclic ring, which can be substituted with 1 ~ 3 substituent (s) (with the proviso that when the carbocyclic ring is phenyl, such ring is substituted with at least one substituent (s), and when the heterocyclic ring is 5-7 membered saturated heterocyclic ring, in which the nitrogen atom in the heterocyclic ring is linked to the L group as shown And wherein it may additionally contain a nitrogen atom or an oxygen atom, subsequently such a ring is substituted with at least one substituent or its substituents, 2) Cl-4 alkyl substituted with 1 ~ 2 its selected donor (s) ( s) of the group consisting of the following (i) - (ii); (i) carbocyclic ring, which can be substituted with 1-3 substituent (s), (ii) heterocyclic ring, which can be substituted with 1 ~ 3 its ti tiyente (s), 3) -0- (carbocyclic ring or heterocyclic ring, which can be substituted with 1 ~ 3 substituent (s)) (with the proviso that when the carbocyclic ring is phenyl, such ring is substituted with at least one substituent or substituents, 4) -S- (carbocyclic ring or heterocyclic ring, which can be substituted with 1 ~ 3 substituent (s)), 5) -NR38- (carbocyclic ring or heterocyclic ring, which can be substituted with 1 ~ 3 substituent (s) (in which R38 is hydrogen or Cl-4 alkyl which can be substituted with a phenyl), 6) -0-CH_- (carbocyclic ring, which can be substituted with 1 ~ 3 substituent (s)) (with the proviso that when the carbocyclic ring is phenyl, such ring is substituted with at least one or more substituent (s)), 7) -0- (C 2-4 alkylene) - (carbocyclic ring , which can be substituted with 1 ~ 3 its ti tiyente (s)), 8) -O- (alkylene Cl - 4) - (indigo the heterocyclic, which can be substituted with 1 ~ 3 its ti tiyente (s)), 9) -S- (alkylene Cl-4) - (carbocyclic ani lio or heterocyclic ring, which can be substituted with 1 ~ 3 substituent (s)), 10) -NR39- (alkylene Cl-4) - (carbocyclic ring or heterocyclic ring, which can be substituted with 1 ~ 3 substituent (s)) (in which R39 is hydrogen, alkyl Cl-4 can be substituted with a phenyl or acyl C2-5 that can be substituted with 1 ~ 3 of halogen) or 11) -CO- (carbocyclic ring or heterocyclic ring, which can be substituted with 1 ~ 3 its constituent (s)), where the substituent (s) ) of the carbocyclic ring and heterocyclic ring in L and M, and the heterocyclic ring represented by L and R16, L and R17, L and R21, and L and R23 are taken together with the nitrogen atom to which these are linked is selected of the following (i) - (xiv): (i) Cl-4 alkyl, (ii) C2-4 alkenyl, (iii) hydroxy, (iv) Cl-4 alkoxy, (v) - (alkylene Cl-4) -0H, (vii) allogen, (viii) NR 0R41 (in which R40 and R41 are independently, hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R40 and R41 are taken together with the nitrogen atom to which they are attached represents the 5-7 membered saturated heterocyclic ring that necessarily contains an atom of nitrogen, and in addition additionally contains a nitrogen atom or an oxygen atom), (ix) SR42 (wherein R42 is hydrogen or Cl-4 alkyl), (x) nitro, (xi) trifluoromethyl, (xii) alkoxycarbonyl Cl-4, (xiii) oxo and (xiv) C2-5 acyl, with the proviso that when J is J1, R4 does not represent R4"1 or salts non-toxic thereof, or hydrates thereof, (2) the N-type calcium channel inhibitor comprising, as an active ingredient, amino acid derivatives of the formula (I) or non-toxic salts thereof, or hydrates of the same. the same and (3) the process for the preparation of the amino acid derivatives of the formula (I) or non-toxic salts thereof, or hydrates thereof.
Detailed Explanation of the Invention Unless otherwise specified, all isomers are included in the present invention. For example, the alkyl, alkenyl, alkynyl and alkylene group include both linear and branched. In addition, the isomers of double bond, ring, fused ring (E-, Z-, cis and trans isomer), isomers generated from asymmetric carbon atom (s) (R-, S-, isomer and β, enantiomer , diastereomer), "optically active isomers (D-, L-, d-, I- isomer), polar compounds generated by chromatography separation (more polar compound, less polar compound), equilibrium compounds, mixtures of the same a. voluntary relationships and racemic mixtures in the present invention.
In the formula (I), the alkyl Cl-15 represented by R 1 means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and isomers thereof In formula (I), the alkoxy Cl-4 represented by R17 means methoxy, ethoxy, propoxy, butoxy and isomers thereof.
In the formula (I), the alkoxy Cl-8 represented by R 1 signifies methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and isomers of the isms.
In the formula (I), the C3-8 cycloalkyl represented by R1, the C3-8 cycloalkyl as a substituent of C1-4 alkyl, C1-4 alkoxy and alkenyl C2-4 in R1 means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In the formula (I), the alkyl Cl-4 represented by Rs, R6, R7, R8, R9, R10, R11, R12, R53, R14, R15, R16, R18, pl9 p27 p28 p29 R30 p31 R33 p34 p 35 p36 p 37 p40 -,? , J, J, J? , J, K,? , Í \, J? , I \, K, R41, and R42 means methyl, ethyl, propyl, butyl and isomers thereof.
In the formula (I), the alkyl Cl-4 as a substituent of phenyl, the cycloalkyl C3-8 and the heterocyclic ring in R1, the carbocyclic ring and the heterocyclic ring in R3, R4, L and M and the heterocyclic ring depicted for each R4"1 and R17, R21, R4" 1 and R23, R4"2 and R16, R4" 2 and R17, R4"2 and R21, R4" 2 and R23, L and Rlβ, L and R17, L and R21, and L and R23 are taken together with the nitrogen atom to which these are linked via methyl, ethyl, propyl, butyl and isomers thereof.
In the formula (I), the Cl-4 alkyl substituted with phenyl, the C3-8 cycloalkyl or the -heterocyclic ring represented by R1 means methyl, ethyl, propyl, butyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring and isomers of the same.
In the formula (I), the alkyl Cl-4, which can be substituted with a phenyl represented by R2, R20, R21, R22, R23, R24, R25, R38 and R39 means methyl, ethyl, propyl, butyl, which they can be substituted with a phenyl and isomers thereof. In the formula (I), the Cl-4 alkyl substituted with a phenyl represented by R 17, R 26 and R 32 means methyl, ethyl, propyl, butyl, which can be substituted with a phenyl and isomers thereof.
In the formula (I), the Cl-4 alkyl substituted with the carbocyclic ring or heterocyclic ring represented by R 3 means methyl, ethyl, propyl, butyl, substituted with the carbocyclic ring or heterocyclic ring and isomers thereof.
In the formula (I), the alkyl Cl-4 in - (alkylene Cl-4) -0- (alkyl Cl-4) represented by R17 and the alkyl Cl-4 in -O- (alkylene Cl-4) -O - (Cl-4 alkyl) as a carbocyclic ring substituent or heterocyclic ring on R4-2, L and M and the heterocyclic ring represented by each R4"2 and R16, R17, R4" 2 and R21 and R4"2 and R23 , L and R16, L and R17, L and R21, L and R23, are taken together with the nitrogen atom to which these are bonded means methyl, ethyl, propyl, butyl and isomers thereof.
In the formula (I), the Cl-4 alkyl substituted with 1 &sub2; &submin; &sub2;, the group (s) selected from the group consisting of the group (i) - (ii) represented by means of M means methyl, ethyl, propyl, butyl substituted with 1 ~ 2 their constituent (s) selected from the group consisting of group (i) - (ii) and isomers thereof.
In the formula (I), the alkyl Cl-8 represented by R 4"1 means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
In the formula (I), the alkyl Cl-8 substituted with 1 ~ 3 its constituent (s) selected from the group consisting of the group (i) - (v) represented by R4"1 and R4-2 mean methyl , ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl substituted with 1 to 3 their constituent (s) selected from the group consisting of group (i) - (v) and isomers thereof.
In formula (I), Cl-4 alkoxy substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring represented by R1 means methoxy, ethoxy, propoxy, butoxy substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring and isomers thereof.
In the formula (I), the alkoxy Cl-4 as a substituent of phenyl, C3-8 cycloalkyl and heterocyclic ring in R1, alkoxy Cl-4 as a carbocyclic ring substituent and heterocyclic ring in R3, R4, L and M, and Cl-4 alkoxy as a heterocyclic ring substituent represented by each R4"1 and R17, R21 and R4" 1 and R23, R4-2 and R16, R4"2 and R17, R4" 2 and RZ1, R4"2 and R23, L and R17, L and R21, and L and R23 are taken together with the nitrogen atom to which they are bonded means methoxy, ethoxy, propoxy, butoxy and isomers thereof In the formula (I), the Cl-4 alkoxy as a substituent of phenyl in Cl-4 alkyl substituted with a phenyl in R26 and R32 means methoxy, ethoxy, propoxy, butoxy and isomers thereof.
In the formula (I), the C2-4 alkenyl substituted with phenyl, cycloalkyl or heterocyclic ring represented by R1 means ethenyl, propenyl, butenyl substituted with phenyl, cycloalkyl or heterocyclic ring and isomers thereof.
In formula (I), C2-4 alkenyl as a carbocyclic ring substituent, the heterocyclic ring in L and M, and C2-4 alkenyl as a carbocyclic ring substituent, the heterocyclic ring in L and M, and the C2-4 alkenyl as a heterocyclic ring substituent represented by each L and R16, L and R17, L and R21, and L and R23 are taken together with the nitrogen atom to which they are attached mean ethenyl, propenyl, butenyl and isomers thereof.
In the formula (I), the acyl C2-5 in - (alkylene Cl-4) -O- (acyl C2-5) represented by R17 means acetyl, propionyl, butyryl, valeryl and isomers thereof.
In the formula (I), the acyl C2-5 can be substituted with 1 ~ 3 of halogen represented by R39 means acetyl, propionyl, butyryl, valeryl can be substituted with 1 ~ 3 of halogen and isomers thereof.
In the formula (I), the C2-5 acyl as a phenyl substituent, the C3-8 cycloalkyl and heterocyclic ring in R1, C2-5 acyl as a carbocyclic ring substituent, the heterocyclic ring in R3, R4, L and M, and C2-5 acyl as a heterocyclic ring substituent represented by each R4"1 and R17 and R21, R4" 1 and R23 and R16, R4"2 and R17, R4'2 and R21, R4" 2 and R23, L and R16, L and R17, L and R21, and L and R23 are taken together with the nitrogen atom to which they are attached means acetyl, propionyl, butyryl, valeryl and isomers thereof.
In the formula (I), the halogen as a substituent of C2-5 acyl represented by R39, the halogen as a substituent of phenyl, C3-8 cycloalkyl and heterocyclic ring on R1, the halogen as a carbocyclic ring substituent and heterocyclic ring in R3, R4, L and M, the halogen as a heterocyclic ring substituent represented by each R4-1 and R17 and R21, R4"1 and R23 and R16, R4-2 and R17, R4" 2 and R21, R4" 2 and R23, L and R16 'L and R17, L and R21, and L and R23 are taken together with the nitrogen atom to which they are bonded means fluoride, chloride, bromide and iodide.
In the formula (I), the alkoxycarbonyl Cl-4 represented by R6, R6, R14, R1S, R30, R31, R36, R37, R40 and R41 means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and isomers thereof.
In the formula (I), the alkoxycarbonyl Cl-4 as a substituent of phenyl, the cycloalkyl C3-8 and heterocyclic ring in R1, the alkoxycarbonyl Cl-4 as a substituent of carbocyclic ring and heterocyclic ring in R3, R4, L and M, and alkoxycarbonyl Cl-4 as a heterocyclic ring substituent represented by each R4"1 and R17 and R21, R4" 1 and R23 and R16, R4"2 and R17, R4-2 and R21, R4" 2 and R23, L and R16, L and R17, L and R21, and L and R23 are taken together with the nitrogen atom to which they are bonded means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and isomers thereof.
In the formula (I), the alkylene Cl-4 represented by means of D means methylene, ethylene, propylene, butylene and isomers thereof.
In the formula (I), the alkylene Cl-4 in -NR22- (alkylene Cl-4) -NR23-, -NR24- (alkylene Cl-4) -O- and -NR25- (alkylene Cl-4) -S - represented by J2, the alkylene Cl-4 in - (alkylene Cl-4) -OH, - (alkylene Cl-) -O- (alkyl Cl-4) and - (alkylene Cl -4) -O- (acyl C2 -5) represented by R17, C1-4 alkylene in - (C1-4 alkylene) - (carbocyclic ring or heterocyclic ring which can be substituted with 1 ~ 3 substituent (s)) -represented by L, or alkylene Cl-4 in - O- (Cl-4 alkylene) - (heterocyclic ring, which can be substituted with 1 ~ 3 its constituent (s)), -S- (Cl-4 alkylene) - (carbocyclic ring or heterocyclic ring which can be substituted with 1 ~ 3 substituent (s)) and -NR39- (Cl-4 alkylene) - (carbocyclic ring or heterocyclic ring which can be substituted with 1 ~ 3 its constituent (s)) represented by means of D means methylene, ethylene, propylene, butylene and isomers thereof.
In the formula (I), C2-4 alkylene in -0- (alkylene) C2-4) - (carbocyclic ring, which can be substituted with 1 ~ 3 substituent (s)) represented by means of M signifies ethylene, propylene, butylene and isomers thereof.
In the formula (I), the alkylene Cl-4 in -0- (alkylene Cl-4) -O- (alkyl Cl-4) as a substituent of carbocyclic ring or heterocyclic ring in R4, L and M and the heterocyclic ring represented by each R4_2 and R16, R4'2 and R17, R4"2 and R21, R4" 2 and R23, L and R16, L and R17, L and R21, and L and R23 are taken together with the nitrogen atom to which they are linked means methylene, ethylene, propylene, butylene and isomers thereof.
In the formula (I), the alkylene Cl-4 en- (alkylene Cl-4) -OH as a carbocyclic ring substituent or heterocyclic ring in L and M and the heterocyclic ring represented by each L and R16, L and R17, L and R21, and L and R23 are taken together with the nitrogen atom to which they are attached means methylene, ethylene, propylene, butylene and isomers thereof.
In formula (I), C2-4 alkenylene represented by D means ethenylene, propenylene, butenylene and isomers thereof. In the formula (I), the saturated 5-7 membered heterocyclic ring necessarily contains a nitrogen atom and furthermore contains additionally a nitrogen atom or an oxygen atom represented by each R6 and R7, R14 and R1S, R30 and R31, R36 and R37, and R40 and R41 are taken together with the nitrogen atom to which they are attached means, for example, pyrrolidine, piperidine, piperazine, morpholine, perhydroazepine.
In formula (I), the carbocyclic ring in R3, R4, L and M means mono- and bi-carbocyclic ring C3-10 and fused carbocyclic ring. The mono- and bi-carbocyclic ring and fused carbocyclic ring mean, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodentane, cyclopentane, cyclohexanediene, cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene , dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, indane (dihydroindene), perhydroindene, bicyclopentane, bicyclohexane, bicycloheptane (bicyclo [2.2.1] heptane), bicycloheptane (bicyclo [2.2.1] hep-2-ene), bicyclooctane, biciclononane, bicyclodecane, adamantene, etc.
In the formula (I), the heterocyclic ring in R 1, R 3, R 4, L and M means a 5 ~ 15 membered mono-bi-heterocyclic ring containing 1 ~ 2 atom (s = nitrogen, 1 ~ 2 atom ( s) of oxygen and / or a sulfur atom that is unsaturated or partially saturated or completely saturated (abbreviated as the heterocyclic ring (A)). The 5 ~ 15 membered mono-bi-heterocyclic ring containing 1-2 atom ( s) of nitrogen, 1 ~ 2 oxygen atom (s) and / or a sulfur atom which is unsaturated or partially saturated or completely saturated - means, for example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiazine (dihydrothiopyran), tetrahydrothiazine (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihidroisooxazol, tetrahidroisooxazol, dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazol, tetraisot'iazol, morpholine, t iomorfolina, indoline, isoindoline, dihydroindazole, peridroíndazol, dihydroquinoline, tetrahydroquinoline, peridroquinolina, dihldroisoquinolina, tetrahidroí soquinolina, peridroisoquinolina, dihydrophthalazine tetrahidroftalazina, perhydro phthalazine, dihidronaftilidina, tetrahidronaftilidina, ylidine perhidronaf, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhi droquinazolina, dihydrocinnoline, tetrahidrocino lina, perhidrocinolina, dihidrobenzooxazol, perhidrobenzooxazol, dihydrobenzothiazol, perhidrobenzotiazol, dihydrobenzoimidazole, perhidrobenzoimidazol, dihidrobenzooxazina, dioxaindano, benzodioxane, quinuclidine, pyrrole, imidazole , pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridazine, azepine, diazepine, phrano, pyran, oxapine, oxazepine, thiophene, tialna (thiopir anus), tiepine, oxazole, isooxazole, thiazsl, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindol, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline , phthalazine, naphthylidine, quinoxaline, quinazoline, cinoline, benzooxazole, benzothiazole, benzoimidazole, oxatetrahydrofuran etc.
In the formula (I), the heterocyclic ring represented by each R4"1 and R17 and R21, R4" 1 and R23 and R16, R4"2 and R17, R4" 2 and R21, R4"2 and R23, L and R16 , L and R17, L and R21, and L and R23 are taken together with the nitrogen atom to which they are attached means the 5- or 15-membered mono- or bi-heterocyclic ring containing a nitrogen atom as an indispensable and furthermore it contains additionally a nitrogen atom, - n oxygen atom and / or a sulfur atom, which is unsaturated or partially saturated or completely saturated.The 5- or 15-membered mono- or bi- or heterocyclic ring containing an atom of hydrogen as an indispensable and furthermore optionally containing a nitrogen atom, 1 ~ 2 oxygen atom and / or a sulfur atom which is unsaturated or partially saturated or fully saturated means, for example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropi rimidina, tetrahidropirida z ina, hexahydropyridazine, hexahydroazepine, tetrahydrooxazole, tetrahidroisooxazol, etrahidrotiazol, ahidroisotiazol tet, morpholine, thiomorpholine, indoline, isoindoline, dihydroindazole, perhídroindazol, dihydroquinoline, tetrahydroquinol ine, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, phthalazine dihydro, tetrahidroftalazina, perhidroftala z ina, dihidronaftilidina, tetrahidronaftilidina, perhidrona ftilidina, dihydroquinoxaline, rahidroquinolina tet, perhydroquinoxaline, dihydroquinazoline, tetrahidroquinazoline, perhidroquinazoline, dihydrocinnoline, tetrahidrocinolina, perhidrocinolina, dihidrobenzooxazol, perhidrobenzooxazol, azole dihidrobenzotí, perhidrobenzAtiazol, dihydrobenzoimidazole, perhidrobenzoimidazol, pyrrole, imidazole, pyrazole, indole, Isoindole, indazole, benzoimidazole etc.
R1 is preferably Cl-8 alkoxy, phenyl, C3-8 cycloalkyl, heterocyclic ring or Cl-4 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring, and more preferably ~ heterocyclic ring (with the proviso that all phenyl, cycloalkyl and heterocyclic ring can be substituted). The heterocyclic ring (A) is listed as a heterocyclic ring. More preferably, such a ring is a 5-15 membered mono- or bi-heterocyclic ring containing from 1-2 nitrogen atom (s), 1-2 oxygen atom (s) and / or sulfur atom which is unsaturated or partially saturated or fully saturated (eg, dihydrooxazole, tetrahydrooxazole, dihydroisooxazole, tetrahydroisoxazole, dihydro-iazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetraisothiazole, morphillin, t iomor folin, dihydrobenzooxazole, perhydrobenzooxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzooxazine, oxazepine, oxazole, isooxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, tiadiazepine, benzooxazole, benzothiazole etc.), more preferably, a 5-7 membered mono-heterocyclic ring containing a Nitrogen atom and an oxygen atom or a sulfur atom that is unsaturated or partially saturated or completely saturated (eg, dihydrooxazole , tetrahydrooxazole, dihydroisooxazole, tetrahydroisooxazole, dihydro thiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetraisothiazole, morpholine, thiomorpholine, oxazapine, oxazole, isooxazole, thiazole, isothiazole, oxazine, oxazepine, thiazine, thiazepine, etc.) and more preferably, tetrahydrothiazole (thiazolimidine) ).
A is preferably single bond or -CO-, and more preferably -CO-.
D is preferably in each group, more preferably alkylene Cl-4, more preferably methylene.
R2 is preferably in each group, more preferably hydrogen or methyl substituted with a phenyl, and more preferably hydrogen.
E is preferably -COO-, -O-, -S-, -SO- or -SO-, more preferably -O- or -S-, and more preferably -S-.
R3 is preferably carbocyclic ring or C1-4 alkyl substituted with carbocyclic ring (all carbocyclic ring can be substituted), more preferably C3-10 cycloalkyl such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane or Cl-4 alkyl substituted with C3-10 cycloalkyl (all cycloalkyl can be substituted), much more preferably cyclopentyl or cyclohexyl or methyl substituted with cyclopentyl or cyclohexyl, and more preferably methyl substituted with cyclohexyl.
J is preferably -NR16- (wherein R16 has the same meaning as previously defined) or -NR22- (Cl-4 alkylene) -NR23- (wherein R22 and R23_ have the same meanings as previously defined), and more preferably -NR16-.
R4 is preferably (-L-M) represented by R4"3.
In the above symbol, L is preferably in each group, and more preferably the heterocyclic ring that can be substituted with 1-3 substituent (s). The heterocyclic ring (A) is listed as a heterocyclic ring. More preferably, such a ring is a 5-15 membered mono- or bi-heterocyclic ring containing 1-2 nitrogen atom (s) which is unsaturated or partially unsaturated or completely unsaturated (eg, pyrroline, pyrrolidine, imidazoline, imidazoline) , pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazepine, indoline, isoindoline, dihydroindazole, perhidroindazol, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine tetrahidroftalazina, perhidroftalazina, dihidronaftilidina, tetrahidronaftilidina, perhidronaftilidina , dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinoline, tet ahidrociño li a, perhidrociño lina, dihidrobenzoimidazol, perhidrobenzoimidazol, quinuclidina, pyrrole, imidazole, pirrazol, pyridine, pyrazine, pyrimidine, pyridazine, pyridazine, azepine, diazepine, indole, isoindol, indazol, quinoline, isoquinoline, phthalazine , naphthylidine, quinoxaline, quinazoline, cinoline, benzoimidazole et.), and more preferably, 5-7 membered mono-heterocyclic ring containing 1-2 nitrogen atom (s) which is unsaturated or partially saturated or fully saturated (by example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazepine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridazine, azepine, diazepine et.) and more preferably piperidine. M is preferably in each group, more preferably Cl-4 alkyl substituted with 1-2 substituent (s) selected from the group consisting of carbocyclic ring or heterocyclic ring which can be substituted with 1-3 its parent (s), and more preferably Cl-4 alkyl substituted with 1-2 substituent (s) selected from the group consisting of phenyl and C3-10 cycloalkyl which can be substituted with 1-3 their constituent (s), and more preferably methyl substituted with a phenyl.
Each ring in R1 is preferably the ring, which is unsubstituted or substituted, more preferably the ring that is substituted or substituted with C1-4alkyl, halogen, C1-4alkoxycarbonyl, and more preferably ring substituted with C1-4 alkoxycarbonyl.
The ring substituent on R4 or heterocyclic ring substituent represented by J and R4 is preferably in each group (in the case of the unsubstituted ring, such unsubstituted ring is also preferable).
In R4, preferably at least one of the carbocyclic ring and heterocyclic ring in R4-2 and the heterocyclic ring represented by each R4"2 and R16, R4" 2 and R17, R4"2 and R21, and R4" 2 and R23 are taken together with the nitrogen atom to which these are bound is substituted with a -hydroxy and heterocyclic ring which can be substituted with 1-2 substituent (s) selected from the group consisting of the following (i) - (xii): i ) alkyl Cl-4, ii) alkoxy Cl-4, (iii) phenyl, iv) phenoxy, v) benzyloxy, vi) -SR3S (in which R35 is hydrogen or alkyl Cl-4), vii) acyl C2-5 (viii) halogen, ix) alkoxycarbonyl Cl-4, x) nitro, xi) -NR36R37 (in which R36 and R37 are independently, hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R 36 R37 are taken together with the nitrogen atom to which these link represent the 5-7 membered saturated heterocyclic ring, which necessarily contains a nitrogen atom and additionally contains additionally a nitrogen atom or an oxygen atom) and ( xii) hydroxy is preferable. In addition, in R4, the substituent of the carbocyclic ring and heterocyclic ring in L and M, and the substituent of the heterocyclic ring represented by each L and R16, L and R17, L and R21, and L and R23 are taken together with the nitrogen atom to which these are linked is to the group selected preferably from the following (i) - (v) and (vii) - (xiv): (i) alkyl Cl-4, (ii) C 2-4 alkenyl, (iii) hydroxy , (iv) Cl-4 alkoxy, (v) - (Cl-4 alkylene) -OH, (vii) halogen, (viii) NR40R41 (where R40 and R41 are independently, hydrogen, Cl-4 alkyl or Cl-alkoxycarbonyl -4, or R40 and R41 are taken together with the nitrogen atom to which they are bonded represents the 5-7 membered saturated heterocyclic ring, which necessarily contains a nitrogen atom and additionally contains a nitrogen atom or an atom oxygen), (ix) SR42 (where R42 is hydrogen or Cl-4 alkyl), (x) nitro, (xi = tri fluoromethyl, (xii) alkoxycarbonyl Cl-4, (xiii) oxo y (x iv) C2-5 acyl.
[You go out] All non-toxic salts are also included in the present invention. For example, the compounds of the formula (I) of the present invention can be converted to the corresponding salts by known methods. Water-soluble and non-toxic salts are preferable. Suitable salts, for example, are the following: alkali metal salts (potassium, sodium etc.), alkaline earth metal salts (calcium, magnesium etc.), ammonium salts, salts of pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, dicyclohexylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-met il-D-glucamine etc.). The compounds of the formula (I) of the present invention can be converted to the corresponding acid addition salts by methods known per se. Water-soluble and non-toxic addition salts are preferable. Suitable acid addition salts, for example, are the salts of organic acids, eg, hydrochloride, hydrobromide, sulfate, phosphate, nitrate etc., or salts of organic acids, eg, acetate, trifluoroacetate, lactate, "- tartarate, oxalate , fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfanate, benzenesul fanate, toluenesulfanate, isethioate, glucuronate, glucinate etc. The compounds of the formula (I) of the present invention or salts thereof can be converted to hydrates thereof by methods known per se In the compounds of the formula (I), the compounds of the formula (Ia) (la) (where all the symbols have the same meanings as those described above), the compounds of the formula (Ib) (where all the symbols have the same meanings as those described above), the compounds of the formula (le) (ic) (where all the symbols have the same meanings as those described above), the compounds of the formula (Id) (where all the symbols have the same meanings as those described above), the compounds of the formula (le) (you) where all the symbols have the same meanings as those described above), the compounds of the formula (If) (where all the symbols have the same meanings as those described above), the compounds of the formula (Ig) (ig) wherein all the symbols have the same meanings as those described above), the compounds of the formula (Ih) (where all the symbols have the same meanings as those described above), the non-toxic salts thereof or hydrates thereof are preferable. The compounds of the formula (la) or (Ib) (wherein all the symbols have the same meanings as those described above), the non-toxic salts thereof or hydrates thereof are more preferable.
The particular compounds are those shown in the following Tables 1-40, the non-toxic salts thereof and the hydrates thereof and those described in the Examples. Also, the following concrete compounds include isomers generated by means of asymmetric carbon atom (s), i.e., R, S and RS form. In the following each table, Me is methyl, Boc is t-butoxycarbonyl, i-Bu is isobutyl and Ac is acetyl.
Table 1 ~ No. R1 No. R No. R1 B | O H N ^ A 8 xt 16 H2N- J 24 OA Table 2 No. R1 No. R1 No.
Boc 8 16 HzNH J 24 ox- Table 3 No. R1 No. R1 No. R1 H 8 (X 16 H2N- J 24 (XA No. R1 No. R1 No. R1 H 8 or 16 H2N? * T 24 (XX Table 5 No. R No. R1 No. R1? Cd- Table 6 No. R1 No. R1 No. R1 | oc H 8 or 16 H2N- < T 24 c - Table 7 No. R1 No. R1 No. R1 Table No. R1 No. R1 No. R1 No. R1 No. R1 No. R1 Table 10 No. R1 No. R1 No. R1 H NA 7 ° < sr 15 r 23 - Table 11 No. R1 No. R1 No. R1 Table 12 No. R1 No. R1 No. R1 Table 13 No. R1 No. R1 No. R1 H N-A ° < sr NA 7 15 23 Table 14 No. R1 No. R1 No. R1 Table 15 - No. R1 No. R1 No. R1 Table 16 - "_- No. R1 No. R No. R1 ox Table 17 No. R1 No. R1 No. R1 Table 18 No. R1 No. R1 No. R1 - Table 19 - No. R1 No R1 No. R1 ÑA NA 8 16 H2N- < J 24 OCA Table 20 No. R1 No. R1 No. R1 Table 21 No. R1 No. R1 No. R1 Table 22 No. R1 No. R1 No. R1 Table 23 - No. R1 No. R1 No. R1 No. No. No. R1 V Table 25 No. R1 No. R1 No. R1 Table 2 ( No. R1 No. R1 No. R1 H N- / 8 or 16 H2N- J 24 OA- Table 27 No. R1 NO. R1 No. R1 Table 28 No. R1 No. R1 No. R1 Table 29 No. R1 No. R1 No. R1 Table 30 No. R1 No. R1 No. R1 Table 31 No. R1 No. R1 No. R1 | oc H N to 8 cAr 16 H2N- J 24 co- Table 32 No. R1 No. R1 No. R Table 33 No. R1 No. R1 No. R1 Table 34 No. R1 No. R1 No. R1 Table 35 No. R1 No. R1 No. R1 Table 36 No. R1 No. R1 No. R1 Table 37 No. R1 No. R1 No. R1 Table 3 No. No. R1 No R1 No. R1 Table 39 No. R1 No. R1 No. R1 Table 40 No. R1 No. R No. R1 H or toy 8 16 H2N-T 24 oy [Processes for the preparation of the compounds of the present invention] (a) the compounds of the formula (I), wherein E is -COO-, -OCO-, -CONR8-, -NR? CO-, -O-, -S- or -CO-, ie, the compounds of the present invention of the formula (I-AT (wherein, R '"1 has the same meaning as that described above for R1, with the proviso that the amino group in R1_1 is protected with the protecting group, if necessary, R3_i has the same meaning as that which described above for R3, with the proviso that the amino group in R3_1 is protected with the protecting group, if necessary, R4-4 has the same meaning as that described above for R, with the proviso that the --COOH, hydroxy or amino group in R4-4 is protected with the protecting group, if necessary, J3 has the same meaning as that described above for J, with the proviso that the hydroxy or amino group in j "is protected with the protecting group , if necessary, E1 is -COO-, -OCO-, -cONR8-, -NR9CO-, -O-, -S- or -CO- and the other symbols have the same meanings as those described above) can prepared by amidation or esterification of the compounds of the formula (II) (where all the symbols have the same meanings as those defined above) with the compounds of the formula (III) -R < (lll) (wherein, J4 is -OH, -NHR1", -NHR17, -NR21-NHR2r ?, -NR23- (alkylene Cl-4) -NHR22, -0- (alkylene Cl-4) -NHR24, -S- ( alkylene Cl-4) -NHR2"or heterocyclic ring possessing NH (this heterocyclic ring has the same meaning as the one described above for the heterocyclic ring represented by each R_z and R16, L and R1", R4_1 and R1, R4-2 and R, and L and R- are taken together with the nitrogen atom to which they are bonded) (in which all symbols have the same meanings as those described above), R4 ~ "has the same meaning as described above), or by amidation or esterification of the compounds of the formula (IV) (where, E ~ is -COOOH, -NHR- (in which RJ has the same meaning as the one described above) or -OH and the other symbols have the same meanings as the one described above) with the compounds of the formula (V) EJ-R ° (V) (wherein, E3 is -OH, -NHRP (in which R8 has the same meaning as that described above) or -COOH and the other symbols that have the same meanings as those defined above). the amidation is well known, for example, it can be carried out (1) by means of the method using acid halide, (2) by means of the method using mixed acid anhydride, (3) by means of the method using a driving agent etc. "~~ The concrete description of these methods is the following: (1) The method by using the acid halide for example can be carried out, for example; Reacts carboxylic acid with an acid halide (oxalyl chloride, thionyl chloride or isobutyl chloroformate etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran or ethyl acetate etc.) or without solvents -a From -20 ° C to a reflux temperature to give an acid halide, the acid halide obtained and an amine are reacted in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or N-methylmorpholine etc.) at 0 ~ 40 ° C. (2) The method using mixed acid anhydride can be carried out, for example; carboxylic acid is reacted with an acid halide (pivaloyl chloride, tosyl chloride, silyl chloride, ethyl chloroformate, isobutyl chloroformate etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, Etc. ) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or N-methylmorpholine etc.) at ~20 ~ 40 ° C to give mixed acid anhydride. The resulting mixed acid anhydride and the corresponding "amine are reacted in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.) at 0 ~ 40 ° C. (3) The method using the condensing agent can be carried out, for example; a carboxylic acid and an amine are reacted in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran, etc.) or without solvents in the presence or absence of tertiary amine (pyrridine, triethylamine, dimethylaniline or dimethylaminopyridine etc. .) which are used with the condensing agent (1,3-dicyclohexylcarbodiimido (DCC) -, 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimido (EDC), 2-chloro-1-methylpriridinium iodide, 1,1'-carbonidiimidazole (CDI) etc.) using or without 1-hydroxybenztriazole (HoBt) at 0 ~ 40 ° C.
Preferably, the above reactions Al), (2) and (3) described above are carried out under an atmosphere of an inert gas (argon, nitrogen -etc.) In anhydrous condition.
The esterification can be carried out by the same procedure as the amidation described above.
The compounds of the formula (I-A), wherein E, the compounds of the formula (I-A-1) (wherein all symbols have the same meanings as "those described above) can be prepared by reacting the compounds of the formula (VI) (where all the symbols have the same meanings as those described above) with the compounds of the formula (VII) 3-1 (Vil) (where, X is halogen and the other symbols have the same meanings as those described above).
The reaction of the compounds of the formula (VI) and the compounds of the formula (VII) can be carried out by known methods. For example, it can be carried out in an organic solvent (dimethylformamide, acetone etc.) in the presence of the base (potassium carbonate etc.) at 0 ~ 40 ° C. (b) The compounds of the formula (I), wherein E is -SO-, -S0_-, i.e., the compounds of the formula (I-B) (wherein, E4 is -SO- or -SO: - and the other symbols have the same meanings as those defined above) can be prepared by oxidation of the compounds of the formula (I-A) wherein E1 is -S-. oxidation is known per su. In the case of the oxidation of sulphide to sulfoxide, it can be carried out, for example, in an organic solvent (methylene chloride, chloroform, benzene, hexane, t-butyl alcohol, etc.) in the presence of an equivalent of oxidizing agent ( hydrogen peroxide, sodium periodate, acyl nitrate, sodium perborate, peracid (eg, m-chloroperbenzoic acid, peracetic acid, etc.) etc.) for a few minutes at -78 ~ 0 ° C. in the case of the oxidation of sulfur to sulfon, it can be carried out, for example, in an organic solvent (methylene chloride, chloroform, benzene, hexane, t-butyl alcohol, etc.) in the presence of an excessive amount of oxidizing agent (hydrogen peroxide, sodium periodate, potassium permanganate, potassium perbromate, potassium peroxymonosulfate, peracid (eg, m-chloroperbenzoic acid, peracetic acid, etc.Jetc.) for a few hours at -78 ~ 40 ° C. c) The compounds of the formula (I), wherein E is -NR10-, ie, the compounds of the formula (IC) (wherein all symbols have the same meanings as those described above) can be prepared by reacting the compounds of the formula (VIII) where all the symbols have the same meanings as those described above) with the compounds of the formula (IX) NHR10-R3"1 (IX) (where all the symbols have - the same meanings as - those described above). the reaction of the compounds of the formula (VIII) and the compounds of the formula (IX) can be carried out by known methods, for example, by reacting the compounds of the formula (VIII) and the compounds of the formula (IX) ) in an organic solvent (methanol, ethanol etc.) that uses reducing agent (sodium cyanoborohydrate-, sodium borohydrate, etc.) or, which uses a pH adjusting agent (acetic acid etc.) if necessary, to 0 ~ 40 ° C. (d) The compounds of the formula (I), wherein E is SO2NR1"-, i.e., the compounds of the formula (I-D) (where all the symbols have the same meanings as those described above) can be prepared by reacting the compounds of the formula (X) (wherein all symbols have the same meanings as those described above) with the compounds of the formula (XI) NHR11-R3"1 (XI) (where all the symbols have the same s igni fincados as those described above) the reaction of the compounds of the formula (X) and the compounds of the formula (XI) can be carried out by known methods, for example, by reacting the compounds of the formula (X) with the base (triphenylphosphine etc.) and acid halide (oxazolyl chloride, thionyl chloride, etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.), from -20 ° C to reflux temperature, and subsequently in this way reacting the obtained compounds and the compounds of the formula (XI) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) at 0 ~ 40 ° C. (e) The compounds of the formula (I), wherein E is -NR12SO: -, i.e., the compounds of the formula (I-E) (where all the symbols have the same meanings as those described above) can be prepared by reacting the compounds of the formula (XII) (wherein all the symbols have the same meanings as those described above) with the compounds of the formula (XIII) (where, X is halogen and the other symbols have the same meanings as those described above).
The reaction of the compounds of the formula (XII) and the compounds of the formula (XIII) can be carried out, for example, by reacting the compounds of the formula (XII) and the compounds of the formula (XIII) in an organic solvent '(chloroform, methylene chloride, diethyl ether, tetrahydrofuran et.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) at 0 ~ 40 ° C. (f) The compounds of the formula (I), wherein A is -CO- or -SO; -, i.e., the compounds of the formula (I-F) (l-F) (wherein, A1 is -CO- or -SO; - and the other symbols have the same meanings as those defined above) can be prepared by the amidation or sulphonation of the compounds of the formula (XIV) (where all the symbols have the same meanings as those described above) with the compounds of the formula (XV) .1-1 (XV) (where, A2 is -COOH or -S03H and the other symbols have the same meanings as those defined above). the amidation and the sulfonamidation can be carried out by means of the same procedure as described above. (g) The compounds of the formula (I), wherein A is single bond and R1 is Cl-4 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring, i.e., the compounds of the formula (I-G) (R1- "is Cl-4 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring (with the proviso that when the amino group exists as a substituent of each ring, such amino group is protected with the protecting group, if it is necessary) and the other symbols have the same meanings as those defined above) can be prepared by reacting the compounds of the formula (XIV) (where all the symbols have the same meanings as those defined above) with the compounds of the formula (XVI) R1 ^ 3 CHO (XVI) (wherein, R1-3 is phenyl, C3-8 cycloalkyl, heterocyclic ring or Cl-3 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring (with the proviso that when the amino group exists as a substituent of each ring , such amino group is protected with the protecting group, if necessary).}. ".
This reaction can be carried out by means of the same procedure, as described in the reaction of the compounds of the formula (VIII) "and the compounds of the formula (IX) (h) The compounds of the formula (I), wherein R 1 is heterocyclic anion containing at least one nitrogen atom or Cl-4 alkyl substituted with heterocyclic ring containing at least one nitrogen atom, and the heterocyclic ring is substituted with C2-5 acyl or C1-4 alkoxycarbonyl, ie, the compounds of the formula (IH) (wherein, R43 is a single bond or C1-6 alkylene, C44 is alkoxycarbonyl Cl4 or C2-5 acyl., R r 'is Cl4 alkyl, Cl4 alkoxy, phenyl, phenoxy, benzyloxy, - SR5, halogen, nitro or -NR R7, n is 0-2 and has the same meaning for the heterocyclic ring in R1, with the proviso that such a heterocyclic ring contains at least one nitrogen atom, and that when the amino group exists as a substituent represented by R4-, such an amino group is protected with the protector, if necessary and the other symbols have the same meaning as those defined above) can be prepared by -amidation of the compounds of the formula (XVII) (where all the symbols have the same meanings as those defined above) with the compounds of the formula (XVIII) , 44 OH (XVIII) (where, R "has the same meaning as the one defined above).
The amidation can be carried out by means of the same procedure as described above. (i) Among the compounds of the formula (i) the compounds of the formula (I-I) (il) (where, R1_C R ~ ~, R4-5 and J have the same meanings as those described above for R1, R3, R4 and J respectively, with the proviso that at least one of them is a group containing -COOH, hydroxy or amino and the other symbols have the same meanings as those defined above) can be prepared by removal of the protecting group according to alkaline hydrolysis, by removal of the protecting group in an acidic condition and / or by hydragenolysis of the compounds of the formula (IA), (IAl), (IB), (IC), (ID), (IE), (IF), (IG) O (IH).
The removal of a protecting group according to alkaline hydrolysis is well known. For example, it can be carried out in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.) which uses hydroxide of an alkali metal (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), the hydroxide of an alkaline earth metal ( calcium hydroxide etc.) or carbonate (sodium carbonate, potassium carbonate etc.) or in an aqueous solution thereof or a mixture thereof at 0 ~ 40 ° C. The removal of a protective group in an acidic condition is well known. For example, it can be carried out in an organic solvent (methylene chloride, chloroform, dioxane, ethyl acetate, anisole, etc.) or without a solvent, in the presence of organic acid (trifluoroacetic acid, methanesulfonic acid, tri-ethylsilylide etc.) or organic acid, hydrochloric acid, etc.) or mixtures thereof (hydrobromic acid, etc.) at 0 ~ 90 ° C.
Hydrogenolysis is well known. For example, it can be carried out in an organic solvent (tetrahydrofuran, dioxane, ethyl ether, ethyl acetate, methanol, ethanol etc.), in the presence of a hydrogenated catalyst (eg, Pd-C, palladium, palladium hydroxide, acetate of palladium, palladium black, platinum black, Ni, Raney nickel etc.) at an ordinary or increased pressure lowers an atmosphere of hydrogen gas to or ~ 80 ° C.
As is well known to the person skilled in the art, a carboxy or hydroxy protecting group includes, for example, t-butyl, benzyl, etc. In addition, such a group includes the other protecting groups that can be removed in a selective and easily manner, for example, that described in T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1991. An amino protecting group including, for example, benzyloxycarbonyl, t-butoxycarbonyl. In addition, such a group includes the other protective groups - which can be removed selectively and easily. In addition, the white compounds of the present invention can be easily prepared by the choice of these protecting groups.
The compounds of the formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), ( XIII), (XIV), (XV), (XVI), (XVII), (XVIII) can be known per se or can be prepared by known methods or by the methods described in the Examples. But, the above compounds can be prepared by other methods.
For example, the compounds of the formula (X) can be prepared by the method described in Liebigs Ann. Chem, 776-783, 1979.
For example, the compounds of the formula (XII) can be prepared by the method described in J_Org. Chem., Vol. 44, No. 10, 1979.
For example, the compounds of the formula (XIV), wherein E is -O-, -S-, -SO-, S0: -, ie, the compounds of the formula (XIV) and the compounds of the formula (XVII) ), wherein E is -O-, -S-, -SO-, -S0-, ie, the compounds of the formula (XVII ') can be prepared by the method shown in the following Reaction Schemes 1 and 2.
In addition, among the compounds of the formula (II), the compounds of the formula (II ') -A (where all the symbols have the same meanings as those defined above) can be prepared by the method to be shown in the following Reaction Scheme 3.
Reaction Scheme 1 B Boc removal (XIV) Reaction Scheme 2 (xvir) Reaction Scheme 3 (II1) (in each Reaction Scheme, E: is -O-, -S-, -SO- or -S0_-, Boc is t-butoxycarbonyl, (Boc), O is di-t-butyl dicarbonate, R46 is single bond or alkylene Cl-3, R4"* is hydroxy or 2,5-dioxopyrrolidin-1-yloxy and the other symbols have the same meanings as defined above) The reactions described in the Schemes mentioned above can be carried out by known methods. In the Schemes mentioned above, the compounds used by the initiator materials can be known per se or can be easily prepared by known methods.
In the present invention, the other starting materials and each reagent known per se can be prepared by known methods.
In each reaction in the present specification, the products can be purified by a conventional manner. For example, it can be carried out by distillation under reduced or atmospheric pressure, high yield by liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, by washing or by recrystallization. The purification can be carried out after each reaction or after a series of reactions.
[Pharmacological Activity] It has been confirmed that the compounds of the present invention of the formula (I) possess "an inhibitory activity on the N-type calcium channel according to the following experiment.
Determination of the inhibitory activity on the calcium channel type N: The cell line is differentiated according to the method described in EEBS Letters, 235, 178-182, 1988. The cell line is loaded with fluorescent reagent, Fura-2'AM (in the final concentration of 10 fM), at 37 ° C for 30 minutes and suspended in a Krebs buffer containing HEPES (25 mM) to obtain the cell suspension. The resulting cell suspension is incubated in the presence or absence of the compounds of the present invention with nifedipine for 5 minutes. The cell is depolarized by adding to the same potassium chloride solution (in the final concentration of 80 mM) and subsequently a fluorescent intensity is emitted at the emission at a wavelength of 500 nm excited by means of UV of 340 nm and 380 nm alternately it is measured using the intracellular calcium analyzer (Nippon Bunko Co., CAF-110). The inhibitory activity of the compound of the present invention (at the final concentration of 3 juM.) On the luxury of calcium within the cells is calculated from the difference in the change of the maximum value of the fluorescent intensity (? R) of according to the following equation.
Mean of? R in the case of (%) Inhibitory effect a solution containing the compound of the compound of the present invention (3 μM.) Present invention x 100 on the calcium flux of? R in the case of a solution not containing the compound of the present invention X The results are shown in Table 41. Table 41 Example No Inhibitory Effect on Calcium Flow C-) 95 From the results of an experiment using the patch-clamp technique (technique in electrophysiology, in which a microelectrode is inserted inside a cell) described in Pflüngers Archives, 391, 85-100, 1981, the compounds of the present invention at the concentration of 10 μM. clearly show the inhibitory action on the flow of barium ion (current calcium) that passes through a calcium channel type N. The cells used in this experiment have been incubated according to the method described in FEBS Letters, 235, 178-182 , 1988.
[Toxicity] The toxicity of the compounds of the present invention is very low and therefore, the compounds of the present invention can be considered safe for pharmaceutical use.
Industrial Application The compounds of the formula (I) have an inhibitory action on the N-type calcium channel, so they are useful as agents for the prevention and / or treatment of cerebral infarction, transient ischemic attack, encephalomyelpatia after the cardiac operation, angiopathy spinal, hypertension and stress, neurosis, epilepsy, asthma and pollakiuria etc., or agent for the treatment of pain.
For the purpose described above, the compounds of the present invention of the formula (I), non-toxic salts thereof and acid addition salts thereof and hydrates thereof can usually be administered systematically? local, usually by oral or parenteral administration.
The doses to be administered are determined depending on the age, body weight, symptoms, desired therapeutic effect, route of administration, and duration of treatment etc. In human adults, doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, several times per day, "and between 0.1 mg and 100 mg, by means of parenteral administration (preferred via intravenously) several times per day, or by continuous administration between 1 and 24 hours per day intravenously.
As mentioned above, the doses to be used depend on various conditions. Therefore, there are cases in which lower or larger doses than the ranges specified above can be used.
The compounds of the present invention can be administered as internal solid compositions or internal liquid compositions for oral administration, or as injections, liniments or suppositories etc. By parenteral administration.
Internal solid compositions by oral administration include compressed tablets, pills, capsules, dispersible powders and granules etc. The capsules contain hard capsules and soft capsules.
In such internal solid compositions, one or more of the compound (s) is (are) mixed with at least one inert diluent (lactose, mannitol, glucose, microcrystalline cellulose, starch etc.), connecting agents (hydroxypropyl cellulose) , polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.), disintegrating agents (calcium glycollate cellulose etc.), lubricating agents (magnesium stearate, etc.), stabilizing agents, assist agents to dissolve (glutamic acid, acid asparagic etc.) etc. To prepare pharmacists by known methods. The pharmaceuticals can, if desired, be coated with material such as sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl cellulose phthalate etc., or they can be coated with one or more films. And in addition, the coating may include the containment within the capsules of absorbable materials such as gelatin.
The internal liquid compositions and oral administration include pharmaceutically acceptable water agents, suspensions, emulsions, syrups and elixirs etc. In such liquid compositions, one or more of the active compound (s) is (are) compressed in inert diluent (s) commonly used in the art (purified water, ethanol or mixtures thereof). of them etc.). In addition to the inert diluents, such compositions also comprise adjuvants such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, perfuming agents, preservatives and buffering agents etc.
Injections by parenteral administration include solutions, suspensions and emulsions and solid injections that are dissolved or suspended in solvent when they are used. One or more compound (s) is (are) dissolved, suspended (s) or emulsified (s) in a solvent when such compositions are used. Aqueous solutions or suspensions include distilled water by injection and physiological saline, vegetable oil, propylene glycol, polyethylene glycol and alcohol such as ethanol etc., and mixtures thereof. Such compositions may comprise additional diluents such as a stabilizing agent, assisting agents for dissolving (glutamic acid, asparaginic acid, POLYSOLBATE80 (trademark) et.), Suspending agents, emulsifying agents, dispersing agents, buffering agents, agents of preservation etc. These can be sterilized, for example, by filtration through a filter that retains bacteria, by the incorporation of sterilization agents in the compositions or by irradiation. They can also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile diluent by injection before immediate use.
Other compositions by parenteral administration include liquids for external use, ointments, endermic liniments, aerosols, spray compositions, suppositories and pessaries for vaginal administration etc. Which comprise one or more active compound (s) and can be prepared by known methods.
The spray compositions may comprise additional substances instead of inert diluents: e.g- stabilizing agents such as sodium acid sulfate, stabilizing agents to give isotonicity, isotonic buffer such as sodium chloride, sodium citrate, citric acid. For example, for the preparation of such spray compositions the method described in U.S. Patent No. 2,868,691 or 3,095,355 may be used.
The best way to carry out the invention The following Reference Examples and Examples are intended to illustrate, but not to limit the present invention The solvents within the parentheses show the levigating or developing solvents and the ratios of the solvents used are in volume in the separations by chromatography and TLC.
The solvents inside the parentheses in the NMR show the solvents used for the measurement.
Reference Example 1 (2R) -2-t-Butoxycarbonylamino-3-cyclohexylmethylthiopropanoic acid To a solution of L-cysteine (133 mg) in ethanol (10 ml), an aqueous solution of 2N NaOH is added. (1: 1), (bromomethyl) cyclohexane (0.17 ml). The mixture is stirred for 2.5 hours at room temperature, to the reaction mixture, an aqueous solution of 2N NaOH (0.6 ml) and di-t-butyl dicarbonate (0.28 ml) are added.
The mixture is stirred for 1 hour. After the ethanol is distilled, the mixture is acidified by addition of HCl to IN and extracted with ethyl acetate. The extract is washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (chloroform: methanol = 19: 1) to obtain the title compound (135 mg) having the following physical data.
TLC: Rf 0.21 (ethyl acetate, acetic acid, water = 9.1: 1); NMR (CDC13): d 4.42-4.28 (HH, m), 3.01 (HH,,, J = 14.2, 5.2Hz), 2.92 (HH,,, J = 14.2, 3.4Hz), 2.45 (2H, d, J = 7.0Hz =, 1.91-0.81 (20H, m Reference Example 2 (2S) -2-t-Butoxycarbonylamino-3-cyclohexyl-methoxypropanoic acid To a solution of (2S) -3-hydroxy-2-l-butoxycarbonylaminopropanoic acid (10.11 q) in dimethylformamide (200 mal, abbreviated as DMF), sodium hydrate (60%, 3.95 g) is added in cold water. The mixture is stirred for 30 minutes at 0 ° C. to the reaction mixture, (bromomethyl) cyclohexane (9.0 ml) is added dropwise in cold water, and tetra-n-butylammonium iodide (910 mg) is added thereto. The reaction mixture is stirred for 23 hours at room temperature, and (bromomethyl) cyclohexane (2.1 ml) is added dropwise to the reaction mixture, and the mixture is stirred for 4 hours. to this ibimomethyl) cyclohexane (2.1 ml) dropwise. The mixture is stirred for 25 hours at room temperature. After concentration of the reaction mixture, the residue is diluted with HCl to IN and extracted with ethyl acetate. The extract solution is washed with water and saturated sodium chloride solution in successive manner, dried over anhydrous sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel (chloroform: methanol = 97: 3) to obtain the title compound (2.52 g) having the following physical data.
TLC: Rf 0.21 (chloroform: methanol = 9: 1) NMR (CDC1;): d 5.59-5.40 (lH, m), 4.46-4.27 (lH, m), 3.89A3.76 (lH, m), 3.64 ( lH, dd, J = 9.4, 4.6Hz), 3.27 (2H, d, J = 6.2Hz), 1.79-0.79 (20H, m).
Example 1 (2R) -N- (1-beneylpiperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide To a solution of the compound prepared in the Reference Example 1 is added (726 mg) and 4-amino-1-benzylpiperidine (0.47) in methylene chloride (12 ml), l-ethyl-3- (3-dimethylaminopropyl) -carboimide hydrochloride (527 mg) and 1-hydroxybenzotriazole in cold water, in a successive manner. The reaction mixture is stirred for 3 hours. The reaction mixture is washed with a saturated solution of sodium hydrogen carbonate, water and saturated sodium chloride solution in successive manner, dried over anhydrous sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel (methanol: chloroform = 3: 97) to obtain the compound (1.05 g) of the present invention having the following physical data.
TLC: Rf 0.62 (methanol: chloroform = 1: 9); NMR (CDC13): d 7.34-7.22 (m, 5H), 6.31 (d, J = 7.8Hz, 1H), 5.37 (d, J = 6.0Hz, ÍH), 4.17-4.11 (m, ÍH), 3.49 ( s, 2H), 2.94 (dd, J = 13.5, 5.4Hz, ÍH), 2.80-2.73 (, 3H), 2.47 (dd, J = 12.6, 6.9Hz, ÍH), 2.43 (dd, J = 12.6, 6.9 Hz, 1H), 2.19-2.10 (m, 2H), 1.95-1.60 (m, 8H), 1.58-1.38 (m, 13H), 1.30.1.05 (m, 3H), 1.00-0.85 (m, 2H).
Example 1 (1) ~ Example 1 (30) By means of the same procedure as described in Example 1 to react the compounds prepared in Reference Example 1 or Reference Example 2 and 4-amino-1-benzylpiperidine or corresponding amine derivatives in Example 1, the following compounds of the present invention were obtained.
Example 1 (1) (2R) -N- (4-Hydroxybenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide TLC: Rf 0.52 (ethyl acetate: hexane = 1: 1); NMR (CDC13): d 7.13-7.06 (2H, m), 6.78-6.67 (3H, m), 6.20 (ΔH, d, J = 7.2Hz), 4.36 (2H, d, J = 6.0Hz), 4.29- 4.19 (1H, m), 2.96 (1H, dd, J = 14.0, 6.0Hz), 2.83 (HI, dd, J = 14, 6.6Hz), 2.42 (2H, d, J = 6.6Hz), 1.85-0.78 (20H, m).
Example 1 (2) (2S) -N- (l-benzylpiperidin-4-yl) -2- t-butoxycarbonylamino -3-cyclohexylmethoxypanamide TLC: Rf 0.23 (methanol: methylene chloride = 1: 19); NMR (CDC1;.): d 7.37-7.23 (m, 5H), 6.47-6.35 (m, H), 5.45-5.32- (m, 1H), 4.20-4.10 (m, 1H), 3.88-3.73 (m , 2H), 3.50 (s, 2H), 3.50-3.40 (m, ÍH), 3.26 (d, J = 6Hz, 2H), 2.84-2.72 (m, 2H), 2.22-2.10 (, 2H), 1.95- 1.84 (m, 2H), 1.76-1.61 (m, "5H), 1.50-1.37 (m, 12H), 1. SILOS (m, 12H), 1.31-1.06 (m, 3H), 1.00-0.83 (m, 2H).
Example 1 (3) (2R) -N- (l-benzylpiperidin-4-ylmethyl) -2-t-butoxycarbonyl amino-3-cyclohexylmethylthiopropanamide TLC: Rf 0.41 (methanol: chloroform = 1: 9); NMR (CDC13): d 7.31-7.20 (m, 5H), 6.47 (t, J = 5.4Hz, ÍH), 5.36 (d, "J = 7.2Hz, 1H) 4.16 (dd, J = 12.6, 7.5Hz, 1H), 3.59 (s, 2H), 3.23-3.09 (m, 2H), 2.95 (dd, J = 14.1, 5.7Hz, 1H (, 2.90-2.86 (m, 2H) 2.78 (dd, J = 14.1 7.2 Hz, ÍH), 2.47 (dd, J = 12.6, 6.9Hz, ÍH), 2.42 (dd, J = 12.6, 6.6Hz, 1H) 1.99-1.90 (m, 2H), 1.84-1.65 (, 7H), 1.55 -1.05 (M, 16H), 0.98 -0.86 (m, 2H).
Example 1 (4) _ _ _ -. _ (2R) -N- (3-methoxymethoxy-4-methoxybenzyl) -2- t-butoxycarbo nylamino-3-cyclohexylmethylthiopropanamide TLC: Rf 0.36 (hexane: ethyl acetate = 2: 1); NMR (CDC13): d 7.07 (d, j = 1.8Hz, ÍH), 6.93 (dd, J = 8.4, 1.8Hz, ÍH), 6.84 (d, J = 8.4Hz, 1H), 6.65 (t, J = 6.0Hz, 1H), 5.37 (d, J = 6.66Hz, 1H), 5.23 (s, 2H), 4.28 (d, J = 6.0Hz, 2H), 4.29-4.19 (m, ÍH), 3.87 (s, 3H), 3.52 (s, 3H), 2.98 (dd, J = 13.8, 5.4Hz, ÍH), 2.82 (dd, J = 13.8, 7.0Hz, ÍH), 2.52-2.35 (m, 2H), 1.86-1.59 (m, 5H), 1.53 1.36 (m, 10H), 1.34-0.80 (m, 5H).
Example 1 (5) (2R) -N- (1- (4-methoxybenzyl) piperidin-4-ylmethyl) -2-t-butoxycarboni lamino-3-cyclohexylmethylthiopropanamide _ _TLC: Rf 0.39 (methanol: chloroform = 1: 9) and NMR (CDC13): d 7.25-7.19 (m, 2H), 6.89-6.81 (, 2H), 6.48 (t, J = 5.8Hz, ÍH), 5.35 (d, J = 7.4Hz, ÍH), 4.21-4.11 (m, ÍH) 3.80 (s, 3H), 3.46 (s, 2H), 3.19-3.11 (m, 2H), 3.00-2.72 (m, 4H ), 2.44 (d, J = 6.6Hz, 2H), 2.04-0.79 (m, 27H).
E n gle 1 (6) (2R) -N-methyl-N (1-benzylpyrrole idin-3-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide TLC: Rf 0.49 (chloroform: methanol = 9: 1); NMR (CD, OD): d 7.33-7.20 (m, 5H), 5.17-4.68 (, 2H), 3.73-3.49 (m, 2H), 3.16 and 2.91 -2.03 (m, 12H), 1.98- 1.59 (m , 6H), 1.48-0.80 (m, 15H).
Example 1 (7) (2R) -N- (1- (4-methoxybenzyl) piperidin-4-yl) -2-t-butoxycarbonyl-3-cyclohexylmethylthiopropanamide TLC: Rf 0.37 (methanol: chloroform = A: 9) A NMR (CDC13): d 7.25-7.18 (m, 2H) 6.89-6.82 (, 2H), 6. 31Ad, J = 6.4Hz, ÍH), 5.36 (d, J = 7.4Hz, ÍH), 4.19-4.09 (my h) . 3.91-3.70 (m, 4H), 3.43 (s, 2H), 2.84 (dd, J = 13.-6, 5.2Hz, 1H), 2.81-2.71 (m, 3H), 2.45 (d, J = 6.6Hz) , 2H), 2.19-2.05 (m, 2H), 1.85-0.81 (m, 24H) A Example 1 (8) (2R) -N- (1- (4-methoxybenzoyl) piperidin-4-yl) -2-t-butoxy carboylamino-3-cyclohexylmethyl thiopropanamide TLC: Rf 0.17 (ethyl acetate: hexane = 1.2); NMR (CDC13): d 7.40-7.33 (m, 2H), 6.93-6.89 (, 2H), 6.45 (d, J = 7.5Hz, ÍH), 5.35 (d, J = 7.5Hz, ÍH), 4.16 (dd) , J = 12.9, 7.2Hz), 4.09-3.93 (m, 1H), 3.83 (s, 3H), 3.14-3.04 (, 2H), 2.95 (dd, J = 13.8, 5.4Hz, ÍH), 2.78 (dd) , J = 7.2Hz, ÍH), 2.47 (dd, J = 13.8, 7.2Hz, ÍH), 2.43 (dd, J = 13.8, 6.9Hz, ÍH), 2.03-1.91 (m, 2H), 1.85-1.78 ( m, 2H), 1.75-1.63 (m, 4H), 1.54.1.38 (m, 13H), 1.30-1.06 (m, 3H), 1.00-0.85 (m, 2H).
Example 1 (9) (2R) -JST- (1- (4-flourobenzyl) piperidin-4-ylmethyl) -2-t-butoxycarboni lamino-3-cyclohexylmethylthiopropanamide TLC: Rf 0.28 (methanol: chloroform = 1:19); NMR (CDC13): d 7.31-7.20 (m, 2H), 7.05-6.93 (m, 2H), 6.48 (t, J = 5.8Hz, ÍH), 5.36 (d, J = 7.2Hz, 1H), 4.17 (td, J = 7.0, 5.4Hz, ÍH), 3.46 (s, 2H), 3.20-3.13 (m, 2H), 3.00-2.73 (m, 4H)), 2.45 (d, J = 6.6Hz, 2H), 2.00- 0.78 (m, 27H).
Example 1 (10) N- ((IR) -2-cyclohexylmethylthio-1- (4-benzylpiperazin-1-ylcarbonyl) ethyl) carbamic acid t-butyl ester ^ TLC: Rf 0.45 (hexane: ethyl acetate = 1.1); NMR (CD3OD): d 7.34-7.22 (m, 5H), 4.70 (t, J = 6.9Hz, 1H), 3.74-3.44 (m, 6H), 5.83 (dd, J = 13.5, 6.9Hz, ÍH), 2. 63 -I (dd, J = 13.5, 6.9Hz, ÍH), 2.57-2.41 (m, 6H, 1.86-1.64 (m, 5H), 1.50-1.36 (m, 10H), 1.33-1.09 (m, 3H) , 1. 01-0.87 (m, 2H).
Example 1 (11) ^ _ ^ t-Butyl ester of N- ((IR) -2-cyclohexylmethylthio-1- (4-diphenylmethylpiperazin-1-ylcarbonyl) ethyl) carbamic acid TLC: Rf 0.22 (ethyl acetate: chloroform = 1:39); NMR (CDCI3): d 7 ^ 41 (d, J = 7.5Hz, "4H), 7.28 (d, J = 7.5Hz, 4H), 7.21-7.17 (m, 2H), 5.42 (d, J = 10.2Hz , ÍH), 4.76-4.68 (m, 2HP, 4.23 (s, 2H), 3.69-3.50 (m, 4H), 2.81 (dd, J = 14.4, 9.0Hz, 1H) 2.68 (dd, J = 14.4, 6.9 H, ÍH), 2.45-2.32 Cm, 6H), 1.86-1.57 (m, 5H), 1.49-1.34 (, 10H), 1.30-1.05 (m, 3H), 0.98-0.83 (, 2H).
Example 1 (12) (2R) -N- (2-benzylaminoethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide TLC: Rf (chloroform: methanol = 9: 1); NMR (CDC13): d 7.34-7.22 (m, 5H), 6.88-6.72 (br, 1H), 4.25-4.15 (m, ÍH), 3.79 (s, 2H), 3.42-3.33 (m, 2H), 2.94 (dd, J = 13.6, 6.6Hz, 1H), 2.85-2.75 (, 3H), 2.43 _ (d, J = 6.6Hz, 2H), 1.86-1.58 (m, 5H), 1.55-1.35 (m, 10H), 1.33-0.81 (, 5H).
Example 1 (13) N- ((IR) -2-cyclohexylmethylthio-1- (4- (4-methoxyphenyl) piperazin-1-ylcarbonyl) ethyl) carbamic acid t-butyl ester _ TLC Rf: 0.33 (ethyl acetate: hexane = 1: 2); NMR (CDClj): d 6.92-6.83 (m, 4H), 5.43 (d, J = 9.0Hz, 1H), 4.82 (dd, J = 15.0, 7.5Hz, ÍH), 3.83 - 3.72 (, 7H), 3.15-3.04 (, 4H), 2.87 (dd, J = 13.5, 7.2Hz, ÍH), 2.75 (d, J = 13.5, 6.0Hz, ÍH), 2.44 (d, J = 6.9Hz, 2H), 1.88-0.85 (m, 20H).
Example 1 (14) (2R) -N- (1- (4-flurobenzyl) piperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide TLC: Rf (ethyl acetate: hexane = 1: 9); NMR (CDC1): d 7.31-7.23 (m, 2H), 7.03-6.95 (m, 2H), 6.32 (d, J = 7.8Hz, ÍH), 5.37 (d, J = 6.6Hz, 1H), 4.14 ( dd, J = 12.9, 6.6Hz, 1H), 3.8 -3.73 (m, ÍH), 3.45 (s, 2H) 72.94 (dd, J = 13.8, 5.4Hz, 1H), 2.80-2.73 (, 3H), 2.47 (dd, J = 12.6, 6.9Hz, 1H), 2.17-2.08 (m, 2H), 1.95-1.60 (m, 7H), 1.55-1.38 (m, 12H), 1.30-1.05 (m, 3H), 1.00 -0.85 (M, 2H).
Example 1 (15) __ (2R) -N- (1- (4-f lur oben z oil) piperidin-4-? L) -2-t-butoxycarbon? Lamino-3-c? Clohexylmethylthiopropanamide TLC: Rf 0.33 (ethyl acetate: hexane = 1: 2); NMR (CDC13): d 7.44-7.37 (M, 2H), 7.14.7.06 (m, 2H), 6.46- (d, J = 7.5Hz, ÍH), 5.35 (d, J = 6.9Hz, 1H), 4.52 (br.s, 1H) 4.20-4.13 (m, 1H), 4.07-3.96 (m, 1H), 3.75 (br.s, ÍH), 3.22-3.00 (m, 2H), 2.95 (dd, J = 13.8 , 5.4, ÍH), 2.78 (dd, J = 13.8, 7.2Hz, 1H), 2.51-2.39 (M, 2H), 2.08-1.60 (m, 7H), 1.54- 1.06 (M, 15H), 1.00-0.84 (M, 2H).
Example 1 (16) N- ((IR) -2-cyclohexylmethylthio-1- (4- (pyridin-2-yl) piperazin-1-ylcarbonyl) ethyl) carbamic acid t-butyl ester TLC: Rf 0.73 (ethyl acetate: hexane = 2: 1); NMR (CDC1): d 8.23-8.20 (m, ÍH), 7.56-7.47 (m, 1H), 6.71-6.64 (, 2H), 5.44 (d, J = 8.8Hz, ÍH), 4.82 (dd, J = 14.6, 6.6Hz, 1H), 3.83-3.52 (m, 8H), 2.88 (dd, J = 13.3, 7.6Hz, 1H), 2.75 (dd, J = 13.4, 5.8Hz 1H), 2.44 (d, J = 6.8 Hz, 2H), 1.89-0.80 (m, 20H).
Example 1 (17) N- ((IR) -2-cyclohexylmethylthio-1- (4- (pyridin-4-yl) piperazin-1-ylcarbonyl) ethyl) carbamic acid t-butyl ester TLC: Rf 0.35 (methanol: chloroform = A: 9) ~~ NMR (CDC1): d 8.325 (dd, J = 4.8, 1.8Hz, ÍH), 6.67 (dd, J = 4.8, 1.8Hz, lh), 5.40 (d, J = 9.2Hz, ÍH), 4.86-4.74 ( m, ÍH), 3.86-3.75 (m, 4H), 3.50-3.30 (m, 4H), 2. 87 (dd, J = 13.6, 7.8Hz, 1H), 2.76 (dd, J = 13.6, 5.8Hz, 1H), 2.44 (d, J = 6.6Hz, 2H), 1.88-0.80 (m, 20H).
Example 1 (18) (2R) -N- (4- (morpholin-4-ylmethyl) phenyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide TLC: Rf 0.40 (methanol: chloroform = 1:19); NMR (CDCl 3) 8.40 (s, 1H), 7.47 (d, J = 8.4Hz, 2H), 7.28 (d, J = 8.4Hz, 2H), 5.47 (d, J = 6.9Hz, ÍH), 4.37-4.30 (m, 4H), 3.46 (s, 2H), 3.04 (dd, J = 13.8, 5.7Hz, ÍH), 2.88 (dd, J = 13.8, 6.9Hz, 1H), 2.48 (d, J = 6.6Hz, 2H), 2.44-2.39 (m, 4H), 1.86-1.60 (m, 5H), 1.53-1.38 (m, 10H), 1.29-1.04 (m, 3H), OR .99- OR .85 (M, 2H) ).
Example 1 (19) _- t-Butyl ester of N- ((IR) -2-cyclohexylmethyl thio-1- (4-phenylaminopiperidin-1-ylcarbonyl) ethyl) carbamic acid TLC: Rf 0.40 (hexane: ethyl acetate = 2.1); NMR (CDCI3): d 7.19 (t, J = 8.4Hz, 2H), 6.72 (t, J = 7.2Hz, ÍH), 6.61 (d, J = 8.4Hz, 2H), 5.43 (d, J = 8.4Hz , 1H), 4.84-4.77 (m, ÍH), 4.52-4.42 (br, ÍH), 4.07-3.95 (br, ÍH), 3.66-3.44 (m, 2H), 3.32-3.23 (, ÍH] ", 3.00 -2.82 (m, 2H9, 2.75-2.69 (m, ÍH), 2.46-2.42 (, 2H), 2.21-2.07 (m, 2H), 1.87-1.07 (m, 20H), 0.99-0.86 (m, 2H) .
Example 1 (20) (2R) -N- (4- (N '-methyl-N' -phenylamino) benzyl) -2-t-butoxy-carbonylamino-3-cyclohexylmethylpropanamide TLC: Rf 0.55 (ethyl acetate: hexane = 1: 2); NMR (CDCl 3): d 7.31-7.24 (m, 2H), 7.21-7.15 (m, 2H), 7.04-6.93 (m, 5H), 6.64 (t, J = 5.1Hz, 1H), 5.36 (d, J = 6.0Hz, ÍH), 4.40 (d, J = 5.4Hz, 2H), 4.24 (dd, J = 12.9, 6. 6Hz, lh), 3.30 (s, 3H), 2.99 Ad "" d, "J = 14.1, . 7Hz ", 1H), 2.82 (dd, J = 14.1, 6.9Hz, ÍH) 2.46 (dd, J = 12.-6, 6.9Hz, 1H), 2.41 (dd, J = 12.6, 6.9Hz, ÍH), 1.85-0.83"(m, 20H).
Example 1 (21) (2R) -N- ((4-methoxyphenyl) amino) -2- t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide TLC: Rf 0.26 (ethyl acetate: hexane = 1.2); NMR (CDC1.): D 8.22 (s, ÍH), 6.86-6.76 (m, 4H), 6.05-5.90 (b, 1H) 5.36 (d, J = 8Hz, ÍH), 4.35- 4.25 (, ÍH), 3.76 (s, 3H), 2.95 (dd, J = 14, 6Hz, ÍH), 2.84 (dd, J = 14, 8Hz, ÍH), 2.45 (d, J = 8Hz, 2H), 1.85-1.55 (m, 5H), 1. 55-1.35 (m, 10H), 1.32-1.03 (m, 3H), 1.00-0.84 (m, 2H).
Example 1 (22) (2R) -N-amino-N-enci 1-2- 1-butoxycarboni 1 amino-3-cycloheptylmethylthiopropanamide TLC: Rf 0.28 (ethyl acetate: hexane = 1: 2); NMR (CDC13): d 7.77 (s, ÍH), 7.42-7.25 (m, 5H), 5.32-5.22 (d, J = 8Hz, 1H), 5.00-4.75 (b, ÍH), 4.23-4.13 (m, 1H), 3.98 (s, 2H), 2.91 (dd, J = 14, 6Hz, ÍH), 2.78 (DD, J = 14, 8Hz, 1H), 2.50-2.35 (m, 2H) ~, 1.85-1.55 ( m, 5H), 1.50-1.35 (m, 10H), 1.35-1.04 (m, 3H), 1.00-0.83 (m, 2H).
Example 1 (23) (2S) -N- (l-benzylpiperidin-4-yl-) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide TLC: Rf 0.40 (methanol: chloroform = 1: 9); NMR (CDCl 3): d 7.34-7.20 (m, 5H), 6.32 (d, J = 7.8Hz, 1H), 5.37 (d, J = 7.0Hz, 1H), 4.19-4.07 (m, ÍH), 3.90- 3.71 (m, ÍH), 3.49 s, 2H), 2.94 (dd, J = 13.6, 5.6Hz, ÍH), 2.84.2.69 (m, 3H), 2.45 (d J = 6.6Hz, 2H), 2.21-2.08 (m, 2H), 1.95-0.79 (m, 24H).
Example 1 (24) (2R) -N- (l-benzylpiperidin-4-yl) -2-t-butoxy-r -bonylamino -3-cyclopentylmethylthiopropanamide TLC: Rf 0.54 (chloroform: methanol = 9: 1); NMR (CDC1): d 7.32-7.20 (, 5H), 6.23 (d, J = 8.2Hz, 1H), 5.37 (d, J = 7.4Hz, 1H), 4.20-4.10 (m, ÍH), 3.90- 3.71 (m, ÍH), 3.49 (s, 2H), 2.96 (dd, J = 13.8, 5.4Hz , 1H), 2.83-2.73 (, 3H), 2.57 (d, J = 6.4Hz, 2H), 2.21- 1.68 (M, 7H), 1.66-1.40 (m, 15H), 1.28-1.13 m, 2H).
Example 1 (25) (2R) -N- (1-benzylpiperidin-4-yl) -2-t-butynylcarbonylamino-3-cycloheptylmethyl thiopropane amide TLC: Rf (methylene chloride: methanol = 19: 1); NMR (CDCl 3): d 7.40-7.20 (m, 5H), 6.31 d, J = 8.0Hz, ÍH), 5.36 (d, J = 7.0Hz, ÍH), 4.19-4.09 (m, ÍH), 3.89- 3.70 (m, 1H), 3.49 (s, 2H), 2.94 (dd, J = 13.4, 5.4Hz , 1H), 2.81-2.71 (, 3H), 2.48 (d, J = 6.6Hz, 2H), 2.21- 2.09 (m, 2H), 1.92-1.13 (m, 26H).
Example 1 (26) (2R) -N- (l-benzylpiperidin-4-yl) -N-methyl 1-2- t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide TLC: Rf 0.46 (methanol: chloroform ^ 1.19); NMR (CDCl 3): d 7.36-7.20 (m, 5H), 5.39 (d, J = 8.7Hz, 1H), 4.83-4.72 (m, ÍH), 4.51-4.40 and 3.87-3.73 (m, 1H), 3.52 (s, 2H), 3.04-2.66 (m, 7H), 2.44-2.41 (, 2H), 2.16-0.84 (m, 26H).
Example 1 (27) (2R) -N- (2-acetoxyethyl) -N- (1-benzylpiperidin-4-yl) -2-t-butoxy carboni lamino-3-cyclohexylmethyl thiopropane amide TLC: Rf 0.42 (methanol: chloroform = 1:19); NMR (CDC13): d 7.38-7.20 (m, 5H), 5.36-5.26 (, 1H), 4.28-4.09 (m, 2H), 3.87-3.24 (m, 5H), 3.06-2.65 (m, 4H), 2.44-2.38 (m, 2H), 2.16-0.80 (m, 29H).
E emplo 1 (28) (2R) -N- (l-benzylpiperidin-4-yl) -2-t-butoxycarbonylamino -3-cyclohexymethyl thio-3-methylbutanamide TLC: Rf 0.34 (methanol: methylene chloride = 1.19); NMR (CDCl 3): d 7.38-7.20 (m, 5H), 6.65 6.55 (m, 1H), 5.66-5.57 (m, 1H), 4.14-4.04 (m, 1H), 3.89-3.75 (m, ÍH), 3.49 (s, 2H), 2.83-2.72 (m, 2H), 2.49 (d, J = 7Hz, 2H), 2.21-2.09 (m, 2H), 1.98-1.60 (m, 7H), 1.60- 1.33 (, 15H), 1.33-1.10 (m, 6H), 1.05-0.88 (m, 2H).
Example 1 (29) N- ((IR) -2-cyclohexylmethylthio-1- (4- (N '-benzyl-N' -trifluoroacetylamino) piperidin-1-ylcarbonyl) ethyl) carbamic acid t-butyl ester or TLC: Rf 0.60 (ethyl acetate: hexane = 1: 2); NMR (CDC1): d 7.41-7.11 (, 6H), 5.39-5.23 (m, ÍH), 4.84-4.48 (m, 4H), 4.34-3.93 (m, 2H), 3.21-2.23 0 (m, 6H) , 1.98-0.75 (m, 23H).
Example 1 (30) __ t-Butyl ester of N- ((IR) -2-cyclohexylmethylthio-1- (4- (N '-benzyl-N' -methylamino) piperidin-1-5-ylcarbonyl) ethyl) carbamic acid - TLC: Rf 0.26 (methanol: chloroform = 1.49); NMR (CDCl 3): d 7.40-7.20 (m, 5H), 5.44 (d, J = 8.4Hz, 1H), 4.86-4.56 (m, 2H), 4.16-3.99 (m, ÍH), 3.58 (s, 2H) ), 3.16-2.40 (m, 7H), 2.19 (s, 3H), 2.00-Ü.80 Xm, 24H).
Reference Example 3 2 (2R) -N- (1-benzylpiperidin-4-yl) -2-amino-3-cyclohexylmethylthiopr hydrochloride To a solution of the compound prepared in the Example 1 (993 mg) is added in dioxane (2 ml), dioxane in HCl at 4N (10 ml). The mixture is stirred for 30 minutes at room temperature. The reaction mixture is concentrated to obtain the titled crude compound (916 mg). In this way the resulting compound is used in the next reaction without purification.
Example 2 (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethyl thio-2- ((4R) -3-t-butoxycarbonyl-thiazolidin-4-yl-carbonyl-lamino) propanamide To a solution of the compound prepared in Reference Example 3 (916 mg) and (4R) -3-t-butoxycarbonylthiazolidin-4-ylcarboxylic acid (0.30 ml) in methylene chloride (llml), hydrochloride- • l-ethyl- 3- (3-dimethylaminopropyl) -carbodiimide (495 mg) and 1-hydroxybenzotriazole (396) are added successively in cold ice. The mixture is stirred for 3 hours. The reaction mixture is washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel (methanol: chloroform = 3: 97) to obtain the compound (1.17 g) of the present invention having the following physical data.
TLC: Rf 0.44 (methanol: chloroform = 1: 9); NMR (CDC1: d 7.34-7.21 (5H, m), 7.15 (lh, d, J = 6.6Hz), 6.77 (ÍH, br.s), 4.67-4.40 (4H, m), 3.81-3.69 (1H, m), 3.49 (2H, s), 3.35-3.12 (3H, m), 2.82 -2.69 (3H,), 2.49-2.37 (2H, m), 2.16-2.09 (2H, m), 1.93-1.36 (19H,), 1.30-1.05 (3H, m), 0.96-0.85 (2H, m).
Example 3 ~ 3 (36) _ _ By means of the same procedure described in Reference Example 3 A- Example 2, using the compounds prepared in Example 1 ~ Example 1 (30) (in Example 2, using acid (4R) -3-t-butoxycarbonyl thiazolidin-4-ylcarboxylic acid or the corresponding derivatives), the following compounds of the present invention are obtained, with the proviso that when the compound of Example 3 (36) is prepared, it is used (+) - 3 - t-Butoxycarbonylthiazolidin-2-ylcarboxylic acid.
Example 3 (2R) -N- (4-hydroxybenzyl) -3-cyclohexylmethylthio-2- ((2-RS-3-t-butoxycarbonyl-thiazolidin-2-yl carbon and lamium) propan ami da TLC: Rf 0.36 (ethyl acetate: hexane = 1: 1); NMR (CD3OD): d 7.12 (2H, d, J = 8.4Hz), 6.71 (2H, d, J = 8.4Hz), 5.22 (1H, br.s), 4.53-4.44 (1H, m), 4.34 ( ÍH, d, J = 14.8Hz), 4.23 (ÍH, d = 14.8Hz), 3.98-3.86 (1H, m), 3. 77-3.64 (ÍH, m), 3.34-2.69 (4H,), 2.42 (2H, d, J = 7.0Hz), 1.90-0.83 (20H, m) Eg emplo_ 3 (1) - «• (2R) -N- (4-hydroxybenzyl) -3-cyclohexylmethylthio-2- ((4RS-3-butoxycarbonyl ti zol idin-4-ylcarbonylamino) propanamide TLC: Rf 0.36 (ethyl acetate: hexane = 1: 1); NMR (CD3OD): d 7.12 (2H, d, J = 8.4Hz), 6.74-6.68 (2H,), 4.65-4.44 (4H, m), 4.31 (ÍH, J = 14.8Hz), 4.23 (ÍH, d, J = 14.8Hz), 3.35 81H, dd, J = 12.2, 7.4Hz), 3.12 (ÍH, dd, J = 12.2, 4.8Hz), 2.99-2.68 (2H, m), 2.41 (2H, d, J07.0HZ), 1.88-0.81 (20H, m). Example 3 (2) (2R) -N- (l-benzylpiperidin-4-ylmethyl) -3-cyclohexylmethyl-2- ((4R) -3-t-butoxycarbonyl thiazole and din-4-ylcarbonylamino) propanamide TLC: Rf 0.28 (methanol: chloroform = 1:19); NMR (CDC13): d 7.32-7.20 (5H, m), 7.11 (ÍH, d, J = 8.1Hz), 6.96 (1H, br.s), 4.65-4.44 (4H, m), 3.49 (2H, s), 3.30-3.20 (4H, m), 3.08-2.93 (ÍH, m), 2.91 -2.81 (2H, m), 2.74 (1H, dd, J = 13.8, 6.6Hz), 2.49-2.32 (2H, m), 1.98-1.88 (2H, m), 1.84-1.04 (23H,), 0.98- 0.82 (2H, m).
E emplo 3 (3) (2R) -Ñ- (3-hydroxy-4-methoxybenzyl) -3-cyclohexylmethylthio-2- ((4R) -3- t-butoxycarbonylthiazolidin-4-yl carboni lamino) propan ami da TLC: Rf 0.38 (hexane: ethyl acetate = 1: 1); NMR (CD3OD): d 6.86-6.70 (3H, m), 4.65-4.45 (4H, m), 4. 25 (2H, s), 3.81 (3H, s), 3.35 (ÍH, dd, J = 7.2, 12.0Hz "), 3.12 (ÍH, dd, J = 4.8, 12.0Hz), 3.03-2.67 (2H, br ), 2.41 (2H, d, J = 7.0Hz), 1.84-1.58 (5H, m), 1.53-1.34 (10H, m), 1.32-0.83 (5H,).
Example 3 (4) (2R) -N- (1- (4-methoxybenzyl) piperidin-4-ylmethyl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl thiazolidin-4-ylcarboni lamino) propanamide TLC: Rf 0.44 (methanol: chloroform = 1: 9); NMR (CDC1: d 7.22 (2H, d, J = 8.7Hz), 7.11 (1H, d, J = 8.1Hz), 6.97 (1H, br.s), 6.87-6.82 (2H, m), 4.65-4.45 (4H, m), 3.80 (3H, s), 3.45 (2H, s), 3.30-3.21 (4H, m), 3. 04-2.86 (3H, m), 2.74 (ÍH, dd, J = 13.8, 6.3Hz), 2.48- 2.34 (2H, m), 1.98-0.82 (27H, m).
Example 3 (5) (2R) -N-methyl-N- (l-benzylpyrrolidin-3-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-buto-icarbonylthi-zolidin-4-l -carbonylamino) propanamide TLC: Rf 0.46 (methylene chloride: methanol = 19: 1); NMR (CDC13): d 7.33-7.22 (m, 5H), 7.19-6.79 (br, 1H9, 5.24-4.97 (br, 1.5H), 4.83-4.52 (br, 2.5H, 4.38 (d, J = 9.6Hz , 1H), 3.71-3.64 (, 1H), 3.50 (d, J = 12.9Hz, 1H), 3.37-3.16 (m, 3.5H), 2.96-2.11 (m, 10.5H), 1.93-1.64 (m, 6H), 1.48-1.33 (m, 10H), 1.28-0.81 (m, 5H).
Example 3 (6) (2R) -N- (4-methoxybenzyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl-1-thiazole idin-4-ylcarbonyl-lamino) propanamide TLC: Rf 0.34 (methanol: chloroform = 1: 9); NMR (CDC13): d 7.25-7.21 (m, 2H), 7.14 (d, J = 6.6Hz, ÍH), 6.87-6.83 (m, 2H), 6.72 (br.s, 1H), 4.66-4.43 (, 4H), 3.81-3.67 (m, 4H), 3.44 (s, 2H), 3.35-3.14 (m, 3H), 2.81-2.69 (m, 3H), 2.50-2.35 (m, 2H), 2.16-2.05 (, 2H), 1.94-1.35 (m, 19H), 1.30-1.04 (m, 3H), 0.98- 0.93 (m, 2H). Example 3 (7) (2R) -N- (1- (4-methoxybenzoyl) piperidin-4-yl) -3-cyclo? -hexylmethylthio-2- ((4R) -3-t-buxylcarbonyl thiazole idin - 4-yl carboni lamino) propanamide TLC: Rf 0.36 (ethyl acetate); NMR (CDCl 3): d 7.38-7.34 (m, 2H), 7.12 (d, J = 6.6Hz, ÍH), 7.04 (br.s, ÍH), 6.91-6.87 (m, 2H), 4.64-4.48 (m , 4H), 4.05-3.92 (m, ÍH), 3.83 (m, 3H), 3.37-3.25 (m, 3H), 3.16-2.97 (m, 2H), 2.75 (dd, J = 13.8, 5.7Hz, 1H ), 2.47-2.34 (m, 2H), 2.06-1.35 (m, 21H), 1.31-1.06 (ra, 3H), 0.98-0.83 (m, 2H).
Example 3 (8) (2S) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethoxy-2- ((4R) -3- t-butoxycarbonyl) thiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.19 (metansl: methylene chloride = 1:19); NMR (CDCl 3): d 7.40-7.20 (m, 5H), 6.99 (d, J = 7Hz, ÍH), 6.83-6.65 (m, ÍH), 4.67-4.54 (m, 2H), 4.45-4.36 (m, 2H), 4.02-3.87 (m, 1H), 3.85-3.70 (m, 1H), 3.54-3.40 (m, 3H), 3.33-3.15 (m, 4H), 2.87-2.74 (m, 2H), 2.20- 2.05 (m, 2H), 1.94-1.80 (m, 2H), 1.78-1.62 (m, 5H), 1.62-1.40 (m, 12H), 1.31-1.06 (m, 3H), 1.00-0.82 (m, 2H); Example 3 (9) (2R) -N- (1-benzylaminoet il) -3-cyclohexylmethylthio-2 - ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.37 (chloroform: methanol = 9: 1); NMR (CD3OD): d 7.36-7.21 (m, 5H), 4.62 (d, J = 9.0Hz, 1H9, 4.61-4.54 (br, ÍH), 4.45 (d, J = 9.0Hz), 4.42 (t, J = 6.9Hz, 1H), 3.75 (s, 2H), 3.48-2.27 (m, 3H), 3.13 (dd, j = 12.0, 4.8Hz, ÍH), 2.96-2.75 (br, 2H), 2.74 (t, J = 6.0Hz, 2H), 2.42 (d, J = 6.9Hz, 2H), 1.84-1.61 (m, 5H), 1.57-1.34 (m, 10H), 1.32-1.08 (m, 3H), 0.99-0.86 (m, 2H).
Ex emp_l __ 3 (10) (4R) -TST- ((IR) -2-cyclohexylmethylthio-l- (-benzylpiperazin-1-ylcarbonyl) ethyl) -3-t-butoxycarbonylthiazolidin-4- i 1 carboxamide TLC: Rf 0.40 (chloroform: methanol = 19: 1); NMR (CD3OD): d 7.33-7.22 (m, 5H), 4.99 (t, J = 6.9Hz, ÍH), 4.64-4.52 (m, 2H), 4.46 (d, J = 9.0Hz, ÍH), 3.72- 3.43 (m, 6H), 3.41-3.29 (br, 1H), 3.10 (dd, J = 12.0, 4.5Hz, 1H), 2.92 (dd, J = 13.5, 7.5 Hz, ÍH), 2.68 (dd, J = 13.-5, 6.3Hz, ÍH), 2.52-2.42 (m, 6H), 1.85-1.63 (m, 5H), 1.52-1.36 (m, 10H), 1.33-1.09 (m, 3H), 1.03-0.87 (m, 2H).
EXAMPLE 3 (11) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4-diphenylmethylpiperazin-1-ylcarbonyl) ethyl) -3-t-butoxycarbonyl iazole idin-4-ylcarboxamide TLC: Rf 0.38 (ethyl acetate: hexane = 1: 2); NMR (CDC13): d 7.48-6.90 (m, 11H), 5.04-4.97 (m, 1H), 4.84-4.55 (m, 2H), 4.38 (d, J = 9.3Hz, ÍH), 4.24 (s, 1H) ), 3.77-3.52 (m, 4H), 3.40-3.34 (m, ÍH), 3.26-3.14 (m, 1H), 2.85 (dd, J = 13.5, 6.9Hz, ÍH), 2.70 (dd, J = 13.5 , 5.4Hz, 1H), 2.54-2.34 (m, 6H), 1.84-1.32 (m, 15H), 1.29-1.04 (m, 3H), 0.98-0.82 (m, 2H). Example _3 (12) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4- (4-methoxyphenyl) piperazin-1-ylcarbonyl) ethyl) -3-t-butoxycarbonyl thiazolidin-4-ylcarboxamide TLC: Rf 0.45 (ethyl acetate: hexane = 1: 1); NMR (CDC10): d 7.15 (br.s, ÍH), 6.92-6.83 (, 4H), 5.13-5.07 (m, ÍH), 4.72-4.66 (m, 2H), 4.40 (d, J = 9.3Hz, ÍH), 3.85-3.71 (m, 7H), 3.37 (dd, J = 11.4, 2.7Hz, ÍH), 3.28-3.17 (m, 1H), 3.12-3.03 (m, 4H), 2.90 (dd, J = 13.5, 7.2Hz, 1H), 2.76 (dd, J = 13.5, 6.0Hz, 1H), 2.44 (d, J = 6.6Hz, 2H), 1.86-1.59 (m, 5H), 1.54-1.36 (m, 10H) ), 1.29-1.05 (m, 3H), 0.98-0.85 (m, 2H).
Example 3 (13) (2R) -N- (1- (4-fluorobenzyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.56 (methanol: chloroform = 1: 9); NMR (CDC13): d 7.32-7.23 (m, 2H), 7.14 (d, J = 6.9Hz, 1H), 7.02-6.95 (m, 2H), 6.79 (br.s, ÍH), 4.67-4.40 (m , 4H), 3.82-3.6í [, 1H), 3.45 2H; 3.35-3.16, m, 3H), 2.79-2.69 (m, 3H), 2.50-2.34 (m, 2H), 2.16-2.06 (m, 2H), 1.93-1.36 (m, 19H), 1.30-1.04 (m, 3H), 0.98- 0.82 (m, 2H).
Example 3 (14) (2R) -N- (1- (4-fluorobenzoyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-buto and carbonylthiazole idin-4-ylcarboni lamino) propanamide TLC: Rf 0.50 (ethyl acetate); NMR (CDC1: d 7.43-7.36 (m, 2H), 7.12-7.05 (m, 4H), 4.63-4.48 (m, 5H), 4.07-3.94 (m, ÍH), 3.73 (br.s, ÍH), 3.37-3.25 (m, 3H), 3.07 (br.s, 2H) 7 2.75 (dd, J = 14-l, 6.0Hz, ÍH), 2.47-2.34 (m, 2H), 2.05-1.36 ( m, 19H), 1.32-1.05 (m, 3H), 0.98-0.82 (m, 2H).
Ex empl.o 3 (15) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4- (pyridin-2-yl) piperazin-1-ylcarbonyl) ethyl) -3-t-butocarbonyl ti azolidin-4-yl carboxamide TLC: Rf 0.42 (ethyl acetate: hexane = 2: 1); NMR (CDC13): d 8.22-8.19 (m, ÍH), 7.55-7.49 (, ÍH), 7.26 (br.s, ÍH), 6.70-6.65 (m, 1H), 5.14-5.07 (m, 1H), 4.86-4.50 (m, 2H), 4.40 (d, J = 9.3Hz, ÍH), 3.84-3.54 (m, 8H), 3.88 (dd, J = 11.7, 2.7Hz, ÍH), 3.26-3.16 (m, ÍH), 2.91 (dd, J = 13.5, 7.2Hz, 1H), 2.77 (dd, J = 13-5, 5.7Hz, ÍH), 2.44 (d, J = 6.9Hz, 2H), 1.85-1.58 (m , 5H), 1.54-1.35 (m, 10H), 1.28-1.05 (m, 3H), 0.98-0.83 (m, 2H).
Example 3 (16) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4- (pyridin-4-yl) piperazin-1-ylcarbonyl) ethyl) -3-t-butoxycarbonyl thiazole id- 4-ylcarboxamide TLC: Rf 0.42 (methanol: chloroform = 1:19); NMR (CDCl 3): d 8.33-8.31 (m, 2H), 7.10 (br.s, 1H), 6.68-6.66 (, 2H), 5.12-5.04 (m, ÍH), 4.79-4.50 (, 2H), 4.39 (d, J = 9.3Hz, 1H), 3.91-3.61 (m, 4H "), 3.49-3.19 (m, 6H), 2.90 (dd, J = 13.5, 7.8Hz, ÍH), 2.77 (dd, J = 13.5, 5.7Hz, 1H), 2.44 (d, J = 6.9Hz, 2H), 1.89-1.60 (m, 5H), 1.53-1.35 (m, 10H), 1.30-1.05 (m, 3H), 0.99-0.83 _ (m, 2H) Example 3 (17) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((3RS) -4- t-butoxycarbonyl thiomor folin-3-ylcarboni lamino) propanamide TLC: Rf 0.39 (methylene chloride: methanol = 93: 7); NMR (CDC1,): d 7.40-7.20 (m, 1H), 6.68-6.45 (m, ÍH), 5.11-4.93 (m, 1H), 4.54-4.18 (m, 2H), 3.86-3.70 (m, ÍH), 3.49 (s, 2H), 3.34-2.60 (m, 8H), 2.57-2.37 (m, 3H), 2.21-2.07 (m, 2H), 1.96-1.35 (m, 19H), 1 ~ 31-1.05 (m, 3H), 1.03-0.84 (m, 2H).
Example 3 (18) (2R) -N- (4- (morpholin-4-ylmethyl) phenyl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazole idin-4-ylcarbonylamino) propanamide TLC: Rf 0.38 (methanol: chloroform = 1:19); NMR (CD3OD): d 7.57 (d, J = 8.1Hz, 2H), 7.31-7.27 (m, 2H), 4.66-4.56 (m, 3H), 4.50 (d, J = 9.3Hz, ÍH), 3.68- 3.65 (m, 4H, 3.48 (s, 2H), 3.39 (dd, J = 12.0, 8.1Hz, ÍH), 3.22 (dd, J = 12.0, 4.8Hz, ÍH), 3.06-2.80 (m, 2H), 2.47-2.42 (m, 6H), 1.86-1.75 (m, 2H), 1.73-1.58 (m, 3H), 1.54-1.36 (m, 10H), 1.30-1.05 (m, 3H), 0.98-0.83 (m, 2H).
Example 3 (19) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4-phenylaminopiperidin-1-ylcarbonyl) ethyl) -3-t-butoxycarbonyl thiazolidin-4-ylcarboxamide TLC: Rf 0.50 (hexane: ethyl acetate = 1: 1); NMR (CDC1A: d 7.22-7.04 (m, 3H), 6.77-6.71 (br, ÍH), 6.67-6.59 (br, 2H), 5.12-5.05 (m, 1H), 4.86-4.55 (br, 2H), 4-48-4.37 (m, 2H), 4.09-3.94 8br, ÍH), 3.59-3.50 (m, ÍH), 3.39-3.19 Cm, 3H), 2.95-2.85"Tm, 2H), 2.78-2.70 (m , 1H), 2.45-2.41 (m, 2H), 2.22-2.06 (br, 2H), 1.83-1.06 (m, 20H), 0.98-0.85 (m, 2H).
Example 3 (20) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4RS) -3-t-butoxycarbonyl-l, 3-perhydrothiazin-4-ylcarbonylamino) propanamide TLC: Rf 0.33 (ethyl acetate: hexane = 1: 2); NMR (CD3OD): d 7.40-7.23 (m, 5H), 4.93-4.38 (m, 4H), 3.73-3.57 (m, ÍH), 3.53 (s, 2H), 3.05-2.71 (m, 5H), 2.65-2.52 (m, ÍH), 2.50-2.34 (m, 3H), 2.23-2.06 (m, 2H), 2.06-1.78 (m, 5H), 1.78-1.35 (m, 15H), 1.31- 1.07 (m, 3H), 1.05-0.85 (m, 2H). Example 3 (21) (2R) -N- (4- (N '-methyl-N' -phenylamino) benzyl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl thiazolidin-4 -carbonylamino) propanamide TLC: Rf 0.28 (ethyl acetate: hexane = 1: 2); NMR (CDCl 3): d 7.32-7.12 (m, 6H), 7.00 (d, J = 8.4Hz, 2H), 6.97-6.92 (m, 3H), 4.65 (dd, J = 6.6, 4.2Hz, 1H), 0.8 (m, 2H), 4.45 (d, J = 9.6Hz, ÍH), 4.41-4.30 (m, 2H), 3.36- ^ 3.12 (m, 6H), 2.79 (dd, J = 13.8, 6.3Hz, ÍH ), 2.47-2.30 (m, 2H), 1.84-1.56 (m, 5H), 1.47-1.38 (m, 10H), 1.30-1.04 (m, 3H), 0.97-0.78 (m, 2H).
Example 3 (22) (2R) -N- ((4-methoxyphenyl) amino) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide .-- TLC: Rf 0.20 (ethyl acetate: hexane = 2: 3); NMR (CDCl 3): d 8.85-8.63 (b, ÍH), 7.22-7.08 (m, ÍH), 6.88-6.75 (m, 4H), 6.07-5.90 (m, ÍH), 4".77-4.45 (m , 4H), 3.74 (s, 3H), 3.40-3.10 (m, 3H), 2.82 (dd, J = 14, 7Hz, ÍH), 2.50-2.28 (m, 2H), 1.84-1.58 (m, 5H) , 1.55-1.36 (m, 10H), 1.31-1.04 (m, 3H), 0.99-0.83 (m, 2H: Example 3 (23) _ (2R) -N-amino-N-benzyl-3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl-thiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.20 (ethyl acetate: hexane = 2: 3); NMR (CDC13): d 8.40-8.15 (b, 1H), 7.39-7.24 (m, 5H), 7.15-7.00 (m, 1H), 4.64-4.40 (m, 4H), 3.96 (s, 2H), 3.34 -3.20 (m, 2H), 3.20-3.00 (b, ÍH), 2.76 (dd, J = 14, 7Hz, ÍH), 2.43 (dd, J = 12, 7Hz, ÍH), (dd, J = 14, 7Hz, ÍH), 1.86-1.55 (m, 5H), 1.55-1.35 (m, 10H), 1.30-1.03 (m, 3H), 0.98-0.83 (m, 2H).
Example 3 (24) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4S) -3- t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.63 (methanol: chloroform = 1: 9); NMR (CDCI3): d 7.34-7.23 (m, 5H), 7.14 (d, J = 6.9Hz, ÍH), 6.58 (br.s, ÍH), 4.70 (dd, J = 6.3, 3.0Hz, ÍH), 4.63 (d, J = 9.3Hz, ÍH), 4.52-4.43 (m, 2H), 3.84-3.71 (m, ÍH), 3.49 (s, 2H), 3.35 (dd, J = 11.7, 3.0Hz, ÍH) , 3.26-3.04 (m, 2H), 2.84-2.70 (m, 3H), 2.49 (dd, J = 12.9, 6.6Hz, ÍH), 2.42 (dd, J = 12.9, 6.9Hz, ÍH), 2.17-2.07 (m, 2H), 1.94-1.37 (, 19H), 1.32-1.04 (m, 104 (, 3H), 1.00-0.84 (m, 2H) Example 3 (25) (2S) -N- (1-benzylpiperidine) -4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.46 (methanol: chloroform = 1: 9); NMR (CDC1: d 7.36-7.22 (m, 5H), 7.13 (d, J = 7.2Hz, ÍH), 6.58 (br.s, 1H), 4.70 (dd, J = 6.3, 3.0Hz, ÍH), 4.63 (d, J = 9.3Hz, 1H), 4.52-4.43 (m, 2H), 3.83-3.70 (m, ÍH), 3.49_ (s, 2H), 3.35 Cdd, J = 11.7, 3.0Hz, ÍH), 3.24-3.06? R-, 2H), 2.81-2.70 (m, 3H), 2.49 (dd, J = 12.9, 6.6Hz, ÍH), 2.42 (dd, J = 12.9, 6.9Hz, ÍH), 2.17-2.07 (m, 2H), 1. 93-1.37 (m, 19H), 1.3 -1.04 (m, 3H), 0.99-0.84 (m, 2H).
Example 3 (26) (2S) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4S) -3-t-butoxycarbonylazothiazol idin-4-ylcarbonylamino) propanamide _ TLC: Rf 0.38 (methanol: chloroform = 1:19); NMR (CDC13): d 7.34-7.21 (m, 5H), 7.15 (d, J = 6.9Hz, 1H), 6.78 (br.s, 1H), 4.67-4.44 (m, 4H), 3.82-3.68 (m , 1H), 3.50 (s, 2H), 3.32 (dd, J = 12.0, 3.9Hz, ÍH), 3.27 (dd, J = 12.0, 6.3Hz, ÍH), 3.19 (br.s, 1H), 2.82- 2.69 (m, 3H), 2.50-2.34 (m, 2H), 2.17-2.08 (m, 2HT ~, 1.93-1.36 (m, 19H), 1.31-1.04 (m, 3H), 0.99-0.82 (m, 2H) ).
E emplo 3 (27) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclopentylmethyl thio- 2- ((4R) -3- t-butoxycarbonyl aiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.48 (chloroform: methanol = 9: 1); NMR (CD3OD): d 7.32-7.22 (m, 5H), 4.64-4.43 (m, 4H), 3.70-3.58 (m, ÍH), 3.52 (s, 2H), 3.39-3".37 (m, ÍH), 3.14 (dd, J = 12.0, 4.8Hz, 1H), 2.95-2.69 (br, 4H), 2. 56 (d, J = 7.2Hz, 2H), 2.17-1.96 (m, 3H), 1.85-1.75 (m, 4H), 1.68-1.46 (m, 15H), 1.32-1.17 (m, 2H).
Example 3 (28) (2R) -N- (l-benzylpiperidin-4-yl) -3-cycloheptylmethyl t io-2- ((4R) -3-t-butoxycarbonylthiazolin-4-ylcarbonylamino) propanamide TLC: Rf 0.35 (chloroform: methanol = 19: 1); NMR (CD3OD): d 7.33-7.00 (m, 5H), 4.65-4.41 (m, 4H), 3.72-3.58 (m, ÍH), 3.52 (s, 2H), 3.37 (dd, J = 12.0, 7.6HA, 1HI, 3.14 (dd, J = 12.0, 4.8Hz, 1H), 2.95-2.67 ( br, 4H), 2.46 (d, J = 6.6Hz, 2H), 2.20-2.07 (m, 2E), 1.87-1.16 Cm, 26H) Example 3 (29) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl-5,5'-dimethylthiol azin idin 4- ilcarbonylamino) propanamide TLC: Rf 0.40 (methylene chloride: methanol = 93: 7); NMR (CD3OD): d 7.40-7.20 (m, 5H), 4.69-4.39 (m, 3H), 4.10 (s, 1H), 3.70-3.58 (m, ÍH), 3.52 (s, 2H), 2.96-2.65 (m, 4H), 2.50-2.40 (m, 2H), 2.19-2.04 (m, 2H). 1.91-1.08 (m, 28H), 1.03-0.87 (m, 2H).
Example 3 (30) _ (2R) -N- (2-acetoxyethyl) -N- (l-benzylpiperidin-4-yl) -3-cyclahexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-) ilcarboni lamino) propanamide TLC: Rf 0.50 (methanol: chloroform = 1:19); NMR (CDC13): d 7.36-6.80 (m, 6H), 5.14-5.04 (m, ÍH), 4.85-4.53 (m, 2H), 4.40-4.25 (m, ÍH), 4.22-4.10 (m, 2H) , 3.86-3.11 (m, 7H), 3.04-2.65 (m, 4H), 2.44-2.41 (m, 2H), 2.16-0.82 (m, 29H).
Example 3 (31) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-3-methyl-2- ((4R) -3- t -butoxycarbonyl thiazolidin-4-ylcarbonylamino) butanamide TLC: Rf 0.18 (methylene chloride: methanol = 19: 1); NMR (CDCl 3): d 7.40-7.20 (m, 6H), 6.80-6.63 (b, ÍH), 4.66 (dd, J = 8.3Hz, ÍH), 4.69-4.52 (m, 1H), 4.46 (d, J = 10Hz, ÍH), 4.35-4.20 (m, ÍH), 3.84-3.69 (m, 1 HOUR) , 3. 49 (s, 2H), 3.33 ~ (dd, J = 14, 3Hz, ÍH), 3.25 (dd, J = 14.8Hz, ÍH), 2.86-2.73 (m, 2H), 2.55-2.32 (m, 2H), 2. 20-2.05 (m, 2H), 1.96-1.60 (m, 9H), 1.60-T.33 (m, 13H), 1.33-1.05 (m, 6H), 1.03-0.85 (m, 2H).
Example 3 (32) (4R) -N- ((IR) -2-cyclohexylmethylthio-l- (4- (N '-benzyl-N' -trifluoroacetylamino) piperidin-1-ylcarbonyl) ethyl) -3-t- butoxicarbonyl thiazolidin-4-ylcarboxamide TLC: Rf 0.26 (ethyl acetate: hexane = 1: 2); NMR (CDClj): d 7.50-6.80 (m, 6H), 5.05-4.94 (m, ÍH), 4.77-4.56 (m, 5H), 4.38-4.35 (m, ÍH), 4.25-3.96 (, 2H), 3.39-2.96 (m, 3H), 2.91-2.35 (m, 5H), 1.94-0.80 (m, 24H).
Example 3 (33) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2RS, 4R) -3-t-butoxycarbonyl-2-methylthiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.42 (methylene chloride: methanol = 9: 1); NMR (CDCl 3): d 7.35-7.20 (m, 6H), 6.93-6.78 (b, 1H), 5.19 (q, J = 6Hz, ÍH), 4.68 (t, J = 6Hz, 1H), 4.54-4.42 ( m, ÍH), 3.83-3.68 (m, ÍH), 3.50 (s, 2H), 3.41-3.10 (m, 3H), 2.85-2.68 (m, 3H), 2.50-2.32 (m, 2H9, 2.18-2.07 (m, 2H), 1.93-1.33 (m, 22H), 1.33-1.03 (m, 3H), 0.98-0.80 (m, 2H).
Example 3 (34) (4R) -N- ((IR) -2-cyclohexylmethylthio-l- (4-N '-benzyl-N'-methylamino) piperidin-1-ylcarbonyl) ethyl) -3-t-butoxycarbonylthiazolidine -4-Icarboxamide TLC: Rf 0.76 (methanol: chloroform = 1: 9); NMR (CD3OD): d 7.58-7.46 (m, 5H), 5.08-4.95 (m, 1H), 4.78-4.04 (m, 7H), 3.74-3.57 (m, 1H), 3.45-3.06 (m, 3H) , 3.01-2.86 (m, ÍH), 2.82-2.64 (m, 5H), 2.50-2.43"(m, 2H), 2.30-2.10 (m, 2H), 2.06-0.86 (m, 24H) - Example 3 (35) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2RS) -3- t-butoxycarbonyl-lazolidin-2-ylcarbonylamino) propanamide TLC: Rf 0.36 (methylene chloride: methanol = 19: 1); NMR (CDCl 3): d 7.37-7.20 (m, 5H), 6.93-15.73 (b, 1H), 5.24 (b) and 5.19 (s) (ÍH), 4.48-4.35 (m, ÍH), 3.93- 3.70 ( m, 3H), 3.53-3.47 (m, 2H), 3.33-2.92 (m, 3H), 2. 85-2.63 (m, 3H), 2.56-2.38 (m, 2H), 2.21-2.07 (m, 2H), 1.95-1.35 (m, 19H), 1.33-1.03 (pT, 3H), 1.00-0.83 (m, 2H).
E j em lo 3 (36) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propanamide (The determination of the absolute configuration of * is not carried out, but the compound is only optically active isomer.) [A] D = +27.26 (c 0.50, CHC1; TLC: Rf 0.26 (methylene chloride: methanol = 19 :1); NMR (CDC1): d 7.37-7.20 (m, 5H), 6.90-6.76 (b, ÍH), 6.67-6.45 (b, ÍH), 5.20 (s, 1H), 4.48-4.35 (m, 1H), 3.93-3.70 (m, 3H), 3.49 (s, 2H), 3.34-2.94 (m, 3H), 2.84-2.63 (m, 3H), 2.56-2.41 (m, 2H), 2.20-2.06 (m, 2H), 1.94-1, 36 (m, 19H), 1.31-1.05"(m, 3H), 1.01- 0.84 (m, 2H).
Example 4 (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (((4R) -3-t-butoxycarbonylthiazolidin-4-ylmethyl) amino) propanamide The compound prepared in Reference Example 3 (600 mg) and N-methylmorpholine (131 mg) is dissolved in ethanol (5 ml). To this, (4R) -3-t-butoxycarbonyl-4-formyl thiazolidine (304 mg) and sodium cyanoborohydrate (124 mg) are added in successive manner. The reaction mixture is adjusted to a pH of 5.5 by the addition of acetic acid and stirred overnight at room temperature. To this same one, a saturated solution of sodium acid carbonate is added. The mixture is extracted with ethyl acetate. The extract is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel (chloroform: methanol = 40: 1) to obtain the compound (553 mg) of the present invention having the following physical data. TLC: Rf 0.48 (chloroform: methanol = 19: 1); NMR (CD3OD): d 7.33-7.20 (m, 5H), 4.55 (d, J = 9.3Hz, ÍH), 4.20 (d, J = 9.3Hz, H), 3.77-3.60 (m, "ÍH), 3.53 (s, 2H), 3.19 (dd, J = 7.5, 5.7Hz, ÍH), 3.121-2.57 (, 8H), 2.42 (d, J = 6.6Hz, 2H), 2.24-2.08 (m, 2H), 1.93-0.82 ( m, 15H), 1.47 (s, 9H).
Example 4 (1) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((3-t-butoxycarbonyl-aiazolidin-2-) imethyl) amino) propanamide By the same procedure as described in Example 4, which uses (+) - 3-t-butoxycarbonyl-2-formylthiazolidine instead of (4R) -3- t-butoxycarbonyl-4-formylthiazolidine in Example 4, obtains the compound of the present invention having the following physical data.
(The determination of the absolute configuration of * is not carried out, but the compound is only optically active isomer.) [] Z = -13.46 (c 0.50, CHC13); TLC: Rf 0.33 (methylene chloride: methanol = 19: 1); NMR (CDC1"): d 7.48 (d, J = 10Hz, ÍH), 7.35-7.20 (m, 5H), 5.18-5.05 (m, 1H), 4.10-3.88 (m, ÍH), 3.88-3.65 (m, 1H), 3.61-3.47 m, 3H), 3.19-2.71 (m, 8H), 2.58 (dd, J = 14, 9Hz, ÍH), 2.41 (dd, J = 12.6Hz, ÍH), 2.39 (dd, J = 12.6Hz, ÍH), 2.23-2.05 (m, 2H-), 1.98-1.30 ( m, 19H), 1.30-1.05 (m, 3H), 1.05-0.80 (m, 2H) Example 5 2 (2R) -N- (1-Benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide hydrochloride To a solution The compound prepared in Example 2 (615) is added in dioxane (5 ml), dioxane in HCl at 4N (6 ml). The mixture is stirred for 30 minutes at room temperature. The reaction mixture is concentrated to obtain the compound (590 mg) of the present invention having the following physical data.
TLC: Rf 0.49 (methanol: chloroform = 1: 9); NMR (CD3OD): 8.49-8.43 (1H, m), 7.58-7.46 (5H, m), 4.64 (% H, m), 4.64-4.52 (H, m), 4.48-4.38 (3H, m), 4. 11-3.84 (1H, m), 3.62-3.49 (4H, m), 3.40-3.22 (2H, m), 3.16-3.06 (2H, m), 2.98-2.74 (2H, m), 2.52-2.45 (2H, m), 2.18-2.03 (2H, m), 1.92-1.61 (7H, m), 1.52- 1.37 (1H, m), 1.32-1.08 (3H, m), 1.04-0.90 (2H, m) .
Example 5 (1) ~ Example 5 (11) ___ __ By the same procedure as described in Example 5, using the compounds prepared in Example 3 (2) ~ Example 3 (6), Example 3 (8) ~ Example 3 (10), Example 3 (19), Example 3 (29) and Example 3 (31), the following compounds of the present invention are obtained.
Example 5 (1) 2 (2R) -N- (l-benzylpiperidin-4-ylmethyl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-i-ylcarbonylamino) propanamide hydrochloride TLC: Rf 0.27 (methanol: chloroform = 1: 9); NMR (CD3OD): d 8.39 (ΔI, t, J = 12.0Hz), 7.57-7.46 (5H, ~ m), 4.60 (ΔI, t, J = 6.9Hz), 4.47-4.38 (4H, m), 4.30 (2H, s), 3.76-3.46 (6H, m), 3.28-2.88"(6H, m), 2.79 (1H, dd, J = 13.8, 7.8Hz), 2.47 (2H, d, J = 6.9Hz) , 2.06-1.60 (8H, m), 1.55-1.38 (3H, m), 1.33-1.09 _ (3H, m), 1.03-0.88 (2H, m).
Example 5 (2) 2 (2R) -N- (1- (4-methoxybenzyl) piperidin-4-ylmethyl) -3-cyclohexylmethylthio-2- ((4R) -thiazole idin-4-ylcarbonilamino) propanamide hydrochloride 2HCI TLC: Rf 0.31 (methanol: chloroform = 1: 9); NMR (CDcOD): d 8.39 (1H, t, J = 6.0Hz), 7.46-7.42 (2H, m), 7.02-6.98 (2H, m), 4.62-4.57 (ÍH, m), 4.47- 4.38 (3H , m), 4.23 (2H, s), 3.82 (3H, s), 3.62-3.55 (2H, m), 3.49-3.45 (2H, m), 3.28-3.04 (4H, m), 2.98- 2.77 (4H, m), 2.49-2.46 (2H, m), 2.06-0.86 (18H, m) .
Example 5 (3) 2 (2R) -N- (1- (4-methoxybenzyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide hydrochloride TLC: Rf 0.25 (methanol: chloroform = 1: 9); "NMR (CD3OD): d 8.44 (d, J = 6.9Hz, 1H), 7.48-7.43 (m, 2H), 7.04-6.99 (m, 2H), 4.64-4.54 (m, ÍH), 4.48-4.38 ( m, 3H), 4.24 (s, 2H), 4.10-3.84 (m, ÍH), 3.82 ~ (s, 3H), 3.68-3.47 (m, 3H), 3.36-3.22 (m, ÍH), 3.12-3.02 (m, 2H), 2.98-2.74 (m, 2H), 2.51-2.45 (m, 2H), 2.18-2.01 (m, 2H), 1.90-1.60 (, 7H), 1.52-1.37 (m, ÍH), 1.34-1.08 (m, 3H), 1.05-0.87 (m, 2H). "~ Example 5 (4) (2R) -N- (3-Hydroxy-4-methoxybenzyl) -3-cyclohexylmethylthio-2- hydrochloride ((4R-thiazolidin-4-ylcarbonylamino) propanamide TLC HCl: Rf 0.21 (hexane: ethyl acetate = 1: 1); NMR (OD CD): d 6.86-6.70 (m, 3H), 4.62-4.49 (m, 2H), 4.43 (d, J = 10.0Hz, 1H), 4.40 (d, J = 10.0Hz, ÍH), 4.26 (s, 2H), 3.82 (s ~, ~ 3H), 3.57 (dd, J = 12.0, 7.2Hz, 1H), 3.22 Cdd, J = 12.0, 7.2Hz, 1H), 2.92 (dd, J = 14.0, 6.6Hz, 1H), 2.78 (dd, J = 14.0, 8.2Hz, ÍH), 2.43 (d, J = 6.8Hz, 2H), 1.87-1.56 (m, 5H), 1.54-0.80 (m, 6H).
Example 5 (5) 2 (2R) -N-methyl-N- (l-benzylpyrrolidin-3-yl) -3-cyclohexylmethyl thio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide hydrochloride TLC: Rf 0.44 (chloroform: methanol: ammonia = 9: 1: 0.1); NMR (CD3OD): d 7.58-7.43 (m, 5H), 4.65-4.12 (m, 6H), 3.95-3.19 (m, 9H), 3.03-2.12 (m, 7H), 1.90-1.59 (m, 5H) , 1.57-0.80 (m, 6H).
Ex 5 (6) _ 2 (2S) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethoxy-2- ((4R) -thiazole idin-4-ylcarbonylamino) propanamide hydrochloride TLC: Rf 0.46 (methanol: methylene chloride = 1: 9); NMR (CD3OD): d 7.60-7.47 (m, 5H), 4.67-4.29 (m, 6H), 4.13-3.86 (m, ÍH), 3.79-3.45 (m, 6H), 3.40-3.20 (m, 2H), 3.18-3.04 (m, 2H), 2.18-2.00 (m, 2H), 1.93- 1.47 (m, 8H), 1.36-1.07 (m, 3H), 1.03-0.84 (m, 2H) .
Example 5 (7) 2 (2R) -N- (2-benzylaminoet-yl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide hydrochloride TLC: Rf 0.21 (chloroform: methanol: ammonia = 9: 1: 0.1); NMR (CD30D): d 7.55-7.43 (m, 5H), 4.62 (dd, J = 7.5, 6.9Hz, 1H), 4.47 (dd, J = 8.1, 6.0Hz, ÍH), 4.41 (s, 2H), 4.27 (s, 2H), 3.67-3.48 (m, 3H), 3.31 (dd, J = 12.0, 6.9Hz, ÍH), 3.22 (d, J = 6.0Hz, 2H), 2.97 (dd, J = 13.8, 6.0Hz, ÍH), 2.83 (dd, J = 13.8, 8.1Hz, 1H), 2.47 (d, J = 6.6Hz, 2H), 1.85-1.62 (m, 5H), 1.54-1.38 (m, ÍH), 1.33-d.0a_ (, 3H), 1.02-0.89 (m, 2H). Example 5 (8) _ 2 hydrochloride (4R) -N- ((IR) -2-cyclohexylmethylthio- 1- (4-benzylpiperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide TLC: Rf 0.32 (chloroform: methanol = 9: 1); NMR (CD3OD): d 12.20 -11.56 (br, 1H), 10.82-9.58 (br, ÍH), 9.37-9.14 (br, 1H), 7.65-7.62 (m, 2H), 7.44-7.42 (m, 2H) , 7.44-7.42 (m, 3H), 4.78 (dd, J = 14.1, 6.9Hz, ÍH), 4.51-4.22 (m, 5H), 4.15-3.04 (m, 10H), 2.83 (dd, J = 13.5, 6.9Hz, ÍH), 2.65 8dd, J = 13.5, 6.9Hz, ÍH), 2.40 (d, J = 6.6Hz, 2H), 1.75-1.57 (m, 5H), 1.44-1.29 (m, ÍH), 1.23 -1.00 (m, 3H), 0.92-0.80 (m, 2H).
Example 5 (9) 2 (4R) -N- ((IR) -2-cyclohexylmethyl thio-1- (4-phenylaminopiperidin-1-ylcarbonyl) ethyl) thiazolidin-4-yl carboxamide hydrochloride TLC: Rf 0.54 (chloroform: methanol = 9: 1); NMR (CD3OD): d 7.63-7.52 (m, 5H), 5.02 (t, J = 7.2Hz, ÍH), 4.65-4.38 (m, 4H), 4.27-4.14 (br, ÍH), 3.92-3.82 (m, 1H), 3.67-3.53 (m, 1H), 3.35-3.17 (m, 2H "T, 2.99-2.90 (m, 1H9, 2.79-2.69 (m, 2H), 2.50-2.43 (m, 2H) , 2.14-2.00 (m, 2H), 1.93-1.59 (m, 7H), 1.53-1.08 (m, 4H), 1.02-0.87 (m, 2H).
Example 5 (10) 2 (2R) -N- (l-benzylpiperidin- -i 1) -3-cyclohexylmethylthio-2- ((4R) -5,5-dimethyl thiazolidin-4-ylcarbonylamino) propanamide hydrochloride TLC: Rf 0.43 (methylene chloride: methanol = 9: 1); NMR (CD3OD): d 7.60-7.45 (m, 5H), 4.55-4.46 (m, 3H), 4.40 and 4.31 (s, 2H), 4.20 and 4.18 (s, ÍH), 4.10- 4.05 and 3.98-3.84 (m, 1H), 3.56-3.45 and 3.41-3.33 (m, 2H), 3.41-3.33 and 3.18-3.05 (m, 2H), 3.00-2.76 (m, 2H), 2. 52 and 2.48 (d, J = 7Hz, 2H), 2.19-2.00 (m, 2H), 1.95- 1.56 (m, 10H), 1.54-1.09 (m, 7H), 1.06-0.88 (m, 2H).
Example 5 (11) 2 (2R) -N- (l-Benzylpiperidin-4-yl) -3-cyclohexylmethylthio-3-methyl-2- ((4R) -thiazolidin-4-ylcarbonylamino) butanamide hydrochloride TLC: Rf 0.48 (methylene chloride: methanol = 9: 1); NMR (CD5OD): d 7.60-7.45 (m, 5H), 4.66-4.58 (m, ÍH), 4.51 and 4.31 (s, 2H), 4.48-4.37 Tm, 2H), A.13-4.06 and 3.98-3.85 (m, ÍH), 3.75-3.45 and 3.44-3.32 (m, 4H), 3.44-3.32 and 3.25-3.04 (m, 4H), 2.53 and 2.48 (d, J = 7Hz, 2H), 2.20-2.05 (m , 2H), 1.93-1.60 (m, 7H), 1.50-1.08 (m, 10H), 1.08-0.89 (m, 2H).
Example 6 (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4-benzylpTperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide The compound prepared in Example 5 (8) (566 mg) is dispersed in ethyl acetate. To this, a saturated solution of sodium hydrogen carbonate (20 ml) is added. The mixture is stirred for 5 minutes at ambient temperature. The extract is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue is dried under reduced pressure to obtain the compound (378 mg) of the present invention having the following physical data.
TLC: Rf 0.32 (chloroform: methanol = 9: 1); NMR (CD ^ OD): d 7.34-7.22 (m, 5H), 4.97 (t, J = 6.6Hz, ÍH), 4.18 (d, J = 9.3Hz, 1H), 4.13 (d, J = 9.3Hz, ÍH), 4.05 (dd, J = 7.5, 4.8Hz, ÍH), 3.69-3.53 (m, 6H), 3.15 (dd, J = 10.5, 4.8Hz, ÍH), 3.03 (dd, J = 10.5, 7.5Hz , ÍH), 2.90 (dd, J = 13.5, 6.6Hz, ÍH), 2.71 (dd, J = 13.5, 6.6Hz, 1H), 2.57-2.40 (m, 6H), 1.84-1.63 (m, 5H), 1.49-1.09 (m, 4H) 1.00-0.87 (m, 2H: ', Example 6 (1 (2R) -N- (2-benei laminoethyl) -3-cyclohexylmethyl thio -2- ((4RJ-thiazole idin- - ylcarbonylamino) propanamide By means of the same procedure as described in Example 6, which uses the compound prepared in Example 5 (7), the compound of the present invention having the following physical data is obtained.
TLC: Rf 0.26 (chloroform: methanol: ammonia = 9: 1: 0.1); NMR (CD3OD): d 7.36-7.21 (m, 5H), 4.40 (dd, J = 7.2, 6. 0Hz, ÍH), 4.21-4.40 (m, 3H), 3.76 (s, 2H), 3.39-3.34 (m, 2H), 3.21 (dd, J = 10.5, 4.5Hz, ÍH), 3.01 (dd, J = 10.5, 7.2Hz, 1H), 2.90 (dd, J = 13.5, 6.0Hz, 1H), 2.79 (dd, J = 13.5, 7.2Hz, ÍH), 2.74 (t, J = 6.3Hz, 2H), 2.40 (d, J = 6.9Hz, 2H), 1.83-1.62 (m, 5H), 1.48-1.08 (m, 4H), 0.98-0.85 (m, 2H).
Example 1 ~ Example 7 (11) By the same procedure as described in Example 5 - > Example 6 using the compounds prepared in Example 3 (7), Example (11) ~ Example 3 (16), Example 3 (18) ~ Example 3 (19), Example 3 (21), Example 3 (23) and Example 4, the following compounds of the present invention are obtained.
Ex emple 7 (2R) -N- (1- (4-methoxybenzoyl) piperidin- -yl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin- -ylcarbonylamino) propanamide TLC: Rf 0.54 (methanol: chloroform = 1: 9); NMR (CDC13): d 7.86 (d, J = 7.5Hz, ÍH), 7.39-7.35 (m, 2H), 6.93-6.89 (m, 2H), 6.65 (d, J = 7.5Hz, ÍH), 4.41- 4.33 (m, ÍH), 4.27 (d, J = 9.9Hz, ÍH), 4.21-4.17 (m, 1H), 4.06-3.95 (m, 2H), 3.83 (s, 3H) (dd, J = ll. l, 4.2Hz, 1H), 3.15-3.02 (m, 3H), 2.90 (dd, J = 13.5, 6.6Hz, 1H), 2.79 (dd, J = 13.5, 7.2Hz, 1H), 2.46 (d, J = 6.9Hz, 2H), 2.06-1.60 (m, 7H), 1.53-1.38 (m, 3H), 1.31-1.05 (m, 3H), 0.99-86 (m, 2H).
Example 7 (1) (4R) -N- ((IR) -2-cyclohexylmethylthio-l- (4-diphenylmethylpiperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide TLC: Rf 0.58 (methanol: chloroform = -1: 19); NMR (CDC1): d 7.82 (d, J = 8.7Hz, ÍH), 7.42-7.37 (m, 4H), 7.31-7.26 (m, 4H), 7.22-7.17 (m, 2H), 5.03-4.95 (m , ÍH), 4.27-4.21 (m, 2H), 4.14-4.10 (m, 1H), 4.06- (d, J = 9.9Hz, ÍH), 3.67-3.59 (m, 4H), 3.41 (dd, J = 10.8, 4.5Hz ", ÍH), 3.11 (dd, J = 10.8, 7.8Hz, ÍH), 2.85 (dd, J = 13-.5, 6.6Hz, 1H), 2.69 (dd, J = 13.5, 6.6Hz , 1H), 2.48-2.32 (m, 6H), 1.84-1.32 (m, 6H), 1.28-1.04 (m, 3H), 0.96-0.82 (m, 2H).
Example 7 (2) (2R) -N- (1- (4- f luorobenzoyl) pipepdin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.30 (methanol: chloroform = 1:19); NMR (CDClj): d 7.87 (d, J = 7.5Hz, ÍH), 7.44-7.37 (m, 2H), 7.14-7.06 (m, 2H), 6.63 (d, J = 7.2Hz, 1H), 4.64- 4.19 (m, 4H), 4.07-3.96 (m, 2H), 3.44 (dd, J = 10.5, 3.9Hz, ÍH), 3.20-3.00 (m, 3H), 2.90 (dd, J = 13.8, 6.6Hz, 1H), 2.79 (dd, J = 13.8, 7.5Hz, 1H), 2.46 (d, J = 6.9Hz, 2H), 2.06-1.62 (m, 5H), 1.52-1.38 (m, 3H), 1.31-1.06 (m, 3H), 1.00-0.85 (m, 2H).
Example 7 (3) (2R) -N- (1- (4-fluorobenzyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.52 (methanol: chloroform = 1: 9); NMR (CDC13): d 7.85 (d, J = 7.2Hz), ÍH), 7.32-7.24 (mA 2H), 7.04-6.97 (m, 2H), 6.44 (d, ~ J = 8.1Hz, ÍH), 4.39 -4.32 (m, 1H), 4.26 (d, "J = 9.6Hz, ÍH), 4.17 (dd, J = 7.8, 3.9Hz, 1H), 4.05 (d, J = 9.6Hz, ÍH), 3.8 6- 3.73 (m, 1H), 3.47 (s, 2H), 3.42 (dd, J = ll.l, 4.2Hz, ÍH), 3.12 (dd, J = ll.l, 7.8Hz, ÍH), 2.89 (dd, J = 13.5, 6.0Hz, ÍH), 2.83-2.72 (m, 3H), 2.47 (d, J = 6.6Hz, 2H), 2.15 (t, J = 10.8Hz, 2H), 1.96-1.37 (m, 10H) ), 1.32-1.05 (m, 3H), 0.99-0.84 (m, 2H).
Example 7 (4) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4- (4-methoxyphenyl) piperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide TLC: Rf 0.50 (methanol: chloroform = 1:19); NMR (CDC13): d 7.85 (d, J = 8.7Hz, ÍH), 6.92-6.83 (m, 4H), 5.11-5.04 (m, ÍH), 4.27 (d, J = 9.9Hz, 1H), 4.15 ( dd, J = 7.5, 4.2Hz, HH), 4.07 (d, J = 9.9Hz, HH), 3.89-3.70 (m, 7H), 344 (dd, J = 10.8, 4.2Hz, 1H), 3.18-3.01 (m, 5H), 2.90 (dd, J = 13.5, 6.9Hz, ÍH), 2.76 (dd, J = 13.5, 6.0Hz, ÍH), 2.42 (d, J = 6.9Hz, 2H), 1.85-1.58 ( m, 5H), 1.49-1.35 (m, 1H), 1.29-1.05 (m, 3H), 0.98-0.83 (m, 2H).
Example 7 (5) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4-pyridin-2-yl) piperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide TLC: Rf 0.38 (methanol: chloroform = 1:19); NMR (CDC13): d 8.22-8.19 (m, HH), 7.85 (d, J = 8.4Hz, HH), 7.55-7.49 (m, 1H), 6.71-6.64 (m, 2H), 5.12-5.04 (m , ÍH), 4.27 (d, J = 9.9Hz, ÍH), 4.15 (dd, J = 7.5, 4.2Hz, lH), 4.07 (d, J = 9.9Hz, 1H), 3.85-3.54 (m, 8H) , 3.44 (dd, J = 10.8, 4.2Hz, ÍH), 3.12 (dd, J = 10.8, 7.5Hz, ÍH), 2.91 (dd, J = 13.2, 6.9Hz, ÍH), 2.76 (dd, J = 13.2 , 6.3Hz, 1H), 2.42 (d, J = 6.9Hz, 2H), 1.86-1.59 (m, 6H), 1.50-135 (m, ÍH), 1.30-1.04 (, 1.04 (, 3H), 0.99- 0.84 (m, 2H).
Ex emplp_ 7 (.6) (4R) -N- ((IR) -2-cyclohexylmethylthio-l- (4- (pyridin-4-yl) piperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcaboxamide TLC: Rf 0.51 (methanol: chloroform = 2: 8); NMR (CDC13): d 8.32 (dd, J = 5.1, 1.8Hz, 2H), 7.83 (d, J = 8.7Hz, 1H), 6.67 (dd, J = 5.1, 1.8Hz, 2H), 5.09-5.01 ( m, 1H), 4.27 (d, J = 9.9Hz, ÍH), 4.19-4.14 (m, ÍH), 4.05 (d, J = 9.9Hz, 1H), 3.90-3.74 (m, 4H), 3.52-3.32 (m, 5H), 3.12"(dd, J = 10.8, 7.8Hz, 1H), 2.90 (dd, J = 13.2, 7.5Hz, ÍH), 2.77 (dd, J = 13.2, 6.3Hz, 1H), 2.42 (d, J = 6.9Hz, 2H), 2.02-1.60 (m, 6H), 1.50-1.34 8m, ÍH), 1.30-1.04 (m, 3H), 1.00-0.84 (m, 2H) Example 7j7j (2R) ) -N- (4-morpholin-4-ylmethyl) phenyl-3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.24 (methanol: chloroform = 1:19); NMR (CDCl 3): d 8.70 (br.s, 1H), 7.99 (d, J = 7.8Hz, 1H), 7.50-7.45 (m, 2H), 7.27 (d, J = 8.4Hz, 2H), 4.58 ( dd, J = 14.4, 7.2Hz, 1H), 4.31-4.23 (m, 2H), 4.08 (d, J = 9.9Hz, ÍH), 3.71-3.68 (m, 4H), 3.50-3.46 (m, 3H) , 3.14 (dd, J = 10.8, 7.8Hz, ÍH), 3.00 (dd, J = 13.8, 6.6Hz, 1H), 2.91 (dd, J = 13.8, 6.9Hz, ÍH), 2.49 (d, J = 6.9 , 2H), 2.44-2.41 (m, 4H), 1.87-1.59 (m, 5H), 1.54-1.38 (m, ÍH), 1.30-1.04 (m, 3H), 1.00-0.84 (m, 2H).
Example 7 (8) (4R) -N- ((IR) -2-Hexylmethylthio-1- (4-phenylaminopiperidin-1-ylcarbonyl) ethyl) thiazolidin-4-yl carboxamide TLC: Rf 0.46 (chloroform: methanol = 9: 1); NMR (CDCI3): d 7.85 (t, J = 7.5Hz, 1H), 7.21-7.16 (m, 2H), 6.73 (t, J = 7.2Hz, ÍH), 6.61 (d, J = 7.5Hz, 2H) , 5.11-5702 (m, 1H), 4.51-4.43 (m, ÍH), 4.27 (d, J09.9HZ, ÍH), 4.18-4.01 (m, 3H), 3.60-3.51 (m, 1H), 3.46- 3.40 (m, ÍH), 3.33-3.23 (m, ÍH), 3.13 (dd, J = 10.8, 7.5Hz, 1H), 3.01-2.85 (m, 2H), 2.78-2.69 (m, 1H), 2.44-2.40 (m, 2H), 2.22-2.07 (br, 2H), 1.82-1.06 (m, 11H), 0.98-0.86 ^ (m, 2H).
Example 7 (9) (2R) -N- (4- (N '-methyl-N' phenylamino) benzyl) -3-cyclohexylmethyl thio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.56 (methanol: chloroform = 1: 9); NMR (CDC13): d 7.88 (D, j = 7.6Hz, ÍH), 7.32-7.25 (m, 2H), 7.19-7.14 (m, 2H), 7.05-6.92 (m, 5H), 6.76 (t, J = 5.7Hz, 1H), 4.46 (dd, J = 14.7, 7.2Hz, 1H), 4.39-4.37 (m, 2H), 4.26 (d, J = 9.9Hz, 1H), 4.15 (dd, J = 7.2, 3.9Hz, ÍH), 4.05 (d, J = 9.9Hz, ÍH), 3.40 (dd, J = 10.8, 3.9Hz, 1H), 3.30 (s, 3H), 3.09 (dd, J = 10.8, 7.8Hz, ÍH), 2.92 (dd, J = 13.8, 6.3Hz, 1H), 2.83 (dd, J = 13.8, 7.2Hz, ÍH) ), 2.54-2.37 (m, 3H), 1.86-1.58 (m, 5H), 1.51-1.36 (m, A?,, 1.30-1.04 (m, 3H), 0.99-0.83 (m, 2H).
Example 7 (10), "" (2R) -N-amino-N-benzyl-3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) clothing TLC: Rf 0.22 (methylene chloride: methanol = 19: 1); NMR (CDC13): d 7.88 (bs, ÍH), 7.78 (d, J = 8Hz, ÍH), 7.39-7.25 (m, 5H), 5.00-4.65 (b, ÍH), 4.37 (q, J = 8Hz, ÍH), 4.25 (d, J = llHz, 1H), 4.12 (dd, J = 7, 4Hz, ÍH), 4. 02 (d, J = llHz, ÍH), 3.98 (s, 2H), 3.41 (dd, J = ll, 4Hz, ÍH), 3.09 (dd, J = ll, 8Hz, ÍH), 2.85 (dd, J = 14, 6Hz, 1Hz), 2.80 (dd, J = 14, 6Hz, ÍH), 2.53-2.25 (b, 1H), 2.42"(d, J = 7Hz, 2H), 1.85-1.50 (m, 5H), 1.50- 1.34 (m, 1H), 1.30-1.03 (m, 3H), 1.00-0.83 (m, 2H).
Example 7. (11) - - (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (((4R) -thiazolidin-4-ylmethyl) amine) propanamide TLC: Rf 0.47 (chloroform: methanol = 9: 1); NMR (CD3OD): d 7.33-7.20 (m, 5H), 4.14 (d, J = 9.4Hz, ÍH), 4.05 (d, J = 9.4Hz, ÍH), 3.77-3.52 (m, 2H), 3.52 (s, 2H), 3.18 (dd, J = 7.5, 5.7Hz, 1H), 2.97 (d, J = 10.2, 6. 2Hz, ÍH), 2.92-2.50 (m, 7H), 2.42 (d, J = 6.6Hz, 2H), 2. 23-2.07 (m, 2H), 1.90-0.80 (m, 15H).
Example 8 ... _ - (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butocarbonyl thiazole idin-4-yl carbonyl chloride lamino) propanamide To a solution of the compound prepared in Example 2 (1241 g) is added in ethyl acetate (10 ml), ethyl acetate in HCl at 0.1 N. The mixture is concentrated. The residue is recrystallized from ethyl acetate-hexane to obtain the compound (1.11 g) of the present invention having the following physical data.
TLC: Rf 0.60 (methanol: chloroform = 1: 9); NMR (DMSO-dfi): d 10.74 (br.s, ÍH), 8.39-8.14 (, 2H), 7.60-7.57 (m, 2H), 7.45-7.43 (m, 3H), 4.59-4.21 (m, 6H ), 3.80-3.66 (m, ÍH), 3.42-3.12 (m, 3H), 3.06-2.91 (m, 3H) 2.75-2.56 (m, 2H), 2.40 (d, J = 6.6Hz, 2H), 1.94 -1.52 (m, 9H), 1.45-1.00 (m, 13H), 0.95-0.79 (m, 2H) Example 9 - Example 9 (4) By the same procedure as described in Example - »Example 8, using the compound prepared in Reference Example 3 or the compounds prepared by the same procedure described in Reference Example 3 using the compound prepared in Example 1 (26), the following compounds of the present invention are obtained.
Eg emplo_ 9 - - (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-isopropyloxycarbonylthiazolidin-4-ylcarbonylamino) propanamide hydrochloride TLC: Rf 0.50 (methanol: chloroform = 1: 9); NMR (CD3OD): d 7.35-7.24 (m, 5H), 4.98-4.82 (m, ÍH), 4.66 (d, J = 9.0Hz, ÍH), 4.62 (dd, J = 7.2, 4.8Hz, 1H), 4.51 (d, J = 9.0Hz, 1H), 4.44 (dd, J = 7.5, 6.3Hz, 1H), 3.74-3.58 (m, 3H), 3.38 (dd, J = 12.0, 7.5Hz, 1H), 3. 15 (dd, J = 12.0, 4.5Hz, 1H), 2.98-2.69 (m, 4H), 2.44 (d, J = 6.9Hz, 2H), 2.30-2.20 (m, 2H), 1.93-1.78 (m, 4H), 1.76-1.36 (m, 6H), 1.34-1.08 (m, 9H), 1.02-0.86 (m, 2H).
E j emplp, 9. (1) (2R) -N- (l-benzylpiperidin-4-yl) -N-methyl-3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazole idin hydrochloride) -4-i 1 carboni lamino) propanamide TLC: Rf 0.38 (methanol: chloroform = 1:19); NMR (CD3OD): d 7.59-7.46 (m, 5H), 5.10-4.89 (m, 1H), 4.63-4.42 (m, 4H), 4.35 and 4.32 (s, 2H), 3.64-3.50 (m, 2H) , 3.42-3.28 (m, ÍH), 3.26-2.68 (m, 8H), 2.47-2.42 (m, 2H), 2.28-1.60 (m, 8H), 1.54-0.84 (m7 16H).
Example 9 (2) 2 (2R) -N- (1-benzylpiperidin-4-yl) -3-cycloCyhexylmethylthio-2- ((4R) -2,2-dimethylthiazolidin-4-ylcarbonyl amino) propanamide hydrochloride TLC: Rf 0.30 (methylene chloride: methanol = 93: 7); NMR (CD3OD): d 7.60-7.45 (m, 5H), 4.80-4.72 (, 1H), 4.63-4.57 and 4.50-4.43 (m, ÍH), 4.41 and 4.31 (s, 2H), 4.13-4.06 and 3.99-3.86 (m, ÍH), 3.80-3.68 (m, ÍH), 3.56-3.33 (m, 3H), 3.19-3.05 (m, 2H), 3.00-2.74 (m, 2H), 2.51 and 2.47 (d, J = 7Hz, 2H), 2.18-2.02 (m, 2H), 1. 95-1.60 (m, 13H), 1.52-1.37 (m, 1H), 1.37-1.08 (m, 3H), 1.05-0.88 (m, 2H).
Example 9 (3) (2R) -N- (l-Benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2S, 4S) -l-t-butoxycarbonyl-4-fluoro-pyrrolidin-2-ylcarbonylamino) propanamide hydrochloride TLC: Rf 0.72 (methanol: chloroform = 1: 9); NMR (CD3OD): d 8.27-7.82 (m, 2H), 7.54-7.48 (m, 5H), 5.24 (d, J = 52.5Hz, ÍH), 4.46-4.23 (m, 4H), 4.05- 3.67 (m, 2H), 3.60-3.03 (m, 5H), 2.99-2.68 (m, 2H) , 2.63 -2.30 (m, 4H), 2.22-0.86 (m, 24H).
Example 9 (4) (2R) -N- (1-benzylpiper? Din-4-i 1) -3-cyclohexylmethylthio-2- ((2S) -1- t -butoxycarbonyl-4-4-difluoropyrrolidin- hydrochloride. 2-ylcarboni lamino) propanamide T-LC: Rf 0.32 (methanol: chloroform = 3:97); NMR (CD30D): d 8.46-8.02 (m, 2H), 7.58-7.46 (m, 5H), 4.47-4.31 (m, 4H), 3.98-3.64 (m, 3H), 3.56-3.46 (m, 2H) , 3.44-3.04 (m, 5H), 2.94-2.64 (m, 3H), 2.54-2.30 (m, 3H), 2.18-2.00 (m, 2H), 1.90-0.86 (m, 24H).
Example 10 (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3- (2-methylpropoxycarbonyl) thiazolidin-4-ylcarbonylamino) propanamide To a solution of the compound prepared in Example 5 (352 g) is added in methylene chloride (6 ml), in cold ice and N-methylmorpholine (0.14 ml) and isobutyl chloroformate (0.85 ml) in a successive manner. The mixture is stirred overnight at room temperature. To the reaction mixture, saturated sodium carbonate solution (10 ml) is added. The mixture is extracted with methylene chloride (10 ml). The extract is washed with saturated sodium chloride solution (15 ml), dried over anhydrous sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel (methylene chloride: methanol = 19: 1) to obtain the compound (304 mg) of the present invention having the following physical data.
TLC: Rf 0.46 (chloroform: methanol = 9: 1); NMR (CD3OD): d 7.33-7.22 (m, 5H), 4.69 (d, J = 9.0Hz, 1H), 4.64 (dd, J = 7.2, 4.8Hz, ÍH), 4.53 (d, J = 9.0Hz) , 4.44 (dd, J = 7.8, 6.3, ÍH), 3.99-3.78 (br, 2H), 3.69-3.58 (m, 1H), 3.52 (s, 2H), 3.42-3.36 (m, 1H), 3.16 ( dd, J = 11.7, 4.8Hz, ÍH), 2.99-2.69 (br, 4H), 2.44 (d, J = 6.9Hz, 2H), 2.17-2.09 (m, 2H), 2.03-1.36 (m, 11H) , 1.33-1.09 (m, 3H), 1.01-0.88 (m, 8H).
Example 10 (1) - - (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-methoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide By means of the same procedure as described in Example 10 using the compound prepared in Example 5, the compound of the present invention having the following physical data is obtained.
TLC: Rf 0.36 (methanol: chloroform = 1:19); NMR (CDC13): d 7.34-7.22 (m, 5H), 7.10 (d, J = 7.8Hz, ÍH), 6.65 (br.s, ÍH), 4.76-4.62 (, 2H), 4.52-4.40 (m, 2H), 3.83-3.72 (m, 4H), 3.50 (s, 2H), 3.33 (dd, J = 12.0, 3.9Hz, 1H), 3.27 (dd, J = 12.0, 6.9Hz, ÍH), 3.16-3.02 (m, ÍH), 2.86-2.72 (m, 3H), 2.48 (dd, J = 12.3, 6.6Hz, ÍH), 2.43 (dd, J = 12.3, 6.9Hz, 1H), 2.17-2.08 (m, 2H ), 1.94-1.36 (m, 10H), 1.32-1.05 (m, 3H), 1.00-0.84 (m, 2H).
Example 11 ~ Example 11 __ (2_1 By the same procedure as described in Example 10 -> Example 8 using the compound prepared in Example 5, the following compounds of the present invention are obtained.
Example 11 (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-pivaloyl thiazolidin-4-ylcarbonylamino) propanamide hydrochloride TLC: Rf 0.49 (chloroform: methanol = 9: 1); NMR (DMSO-dβ, 100 ° C): d 10.94-10.63 (br, ÍH), 8.05-7.74 (br, 2H), 7.67-7.57 (m, 2H), 7.45-7.43 (m, 3H), 5.01 ( dd, J = 7.5, 4.5Hz, ÍH), 4.98 (d, J = 9.0Hz, ÍH), 4.53 (d, J = 9.0Hz, 1H), 4.44-4.33 (br, ÍH), 4.30-4.15 (br , 2H), 3.83-3.66 (br, ÍH), 3.38-3.20 (m, 3H), 3.09 (dd, J = 11.5, 4.5Hz, 1H), 3.06-2.92 (br, 2H), 2.85-2.72 (br , 2H), 2.43 (d, J = 6.5Hz, 2H), 2.12-1.84 (br, 4H), 1.77-1.58 (m, 5H), 1.46-1.38 (m, 1H), 1.27-1.09 (m, 12H ), 0.99-0.91 (m, 2H).
Example 11 (1). • (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3- (3-ethylbutyryl) thiazolidin-1-carbonylamino) propanamide hydrochloride TLC: Rf 0.51 (chloroform: methanol = 9: 1); NMR (DMSO-d6, 100 ° C): d 10.89-10.60 (br, 1H), 8.14-7.74 (br, 2H), 7.62-7.60 (m, 2H), 7.48-7.43 (m, 3H), 4.85 ( dd, J = 7.0, 4.5Hz, ÍH), 4.80 (d, J = 9.5Hz, 1H), 4.58-4.33 (br, 2H), 4.32-4.16 (br-2H), 3.82-3.66 (br, 1H) , 3.39-3.24 (br, 3H, 3.14-3.11 (m, 1H, 3.09-2.92 (br, 2H), 2.87-2.69 (br, 2H), 2.43 (d, J = 7.0Hz, 2H), 2.32-2.14 (br, 2H), 2.09-1.83 (, 5H), 177-1.57 (m, 5H), 1.47-1.38 (m, ÍH), 1.26-1.10 (m, 3H), 0.99-0.92 (m, 8H).
Example 11 (2) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3- (3-methylpropionyl) thiazolidin-4-i1carbonylamino) propanamide hydrochloride TLC: Rf 0.52 (chloroform: methanol = 9: 1); NMR (DMSO-db, 100 ° C): d 10.92-10.65 (br, 1H), 8.06-7.71 (br, 2H),, 7.62-7.60 (m, 2H), 7.45-7.43 8m, 3H), 4.88- 4.82 (m, 2H), 4.56-4.46 (br, 1H), 4.44-4.33 (br, 1H), 4.31-4.14 (br, 2H), 3.83-3.72 (br, ÍH), 3.40-3.26 (Br, 3h ), 3.16-3.12 (m, 1H), 3.10-2.92 (br, 2H) 2.87-2.69 (br, 2H), 2.87-2.69 (br, 2H), 2.51-2.48 (m, 1H), 2.43 (d, J = 6.5Hz, 2H), 2.00-1.83 (m, 9H), 1.46-1.38 (m, ÍH), 1.29-0.91 (m, 11H).
Ex emjpLo _12 (2R) -N- (2-hydroxyethyl) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonyl) lamino hydrochloride propanamide To a solution of the preparation in Example 3 (30) (160 mg), potassium carbonate (64 mg) is added in methanol (4 ml). The mixture is stirred for 30 minutes at room temperature. To the reaction mixture, water is added. The mixture is extracted with ethyl acetate. The extract is washed with water and saturated sodium chloride solution in successive manner, dried over anhydrous sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel (methanol: chloroform = 1: 40). By means of the same procedure as described in Example 8 using the purified compound, the compound (120 mg) of the present invention having the following physical data is obtained.
TLC: Rf 0.34 (methanol: chloroform = 1:19); NMR (CD3OD): d 7.49 (s, 5H), 5.19-4.93 (m, 1H), 4. 66-4.54 (m, 2H), 4.49-4.43 (m, ÍH), 4.34-3.98 (m, 3H), 3.84-3.27 (m, 8H), 3.22-2.87 (m, 4H), 2.78-2.64 (m, 1H), 2.47-2.28 (m, 3H), 2.13-1.60 (, 8H), 1.53- 1.09 (m, 12H), 1.01-0.85 (m, 3H).
Example 12 (1) _ - (4R) -N- (£ IR) -2-cyclohexylmethylthio-l- (4-benzylaminopiperidin-1-ylcarbonyl) ethyl) -3-t-butoxycarbonylthiazolidin-4-ylcarboxamide hydrochloride By means of the same procedure as described in Example 12 using the compound prepared in Example 3 (32), the compound of the present invention having the following physical data is obtained.
TLC: Rf 0.47 (methanol: chloroform = 1: 9); NMR (CD¿OD): d 7.54-7.44 (m, 5H), 5.04-4.94 (m, 1H), 4.70.5.42 (m, 3H), 4.48-4.43 (m, 1H), 4.38-4.16 (m, 3H), 3.56-2.88 (m, 1H), 2.80-2.67 (m, 2H), 2.49-2.44 (m, 2H), 2.36-2.18 (m, 2H), 1.90-0.85 (m, 22H).
EXAMPLE 13 2 (2R) -N- (l-benzylpiperidin-yl) -3-cyc-hexylmethylthio-2- (((4R) -3- (3-rathylbutyr yl) ti azol] hydrochloride 4-ilmet i 1) amino) propanamide By means of the same procedure as described in Example 4 - Example 8 using the compound prepared in Reference Example 3, the compounds of the present invention having the following physical data are obtained.
TLC: Rf 0.49 (methylene chloride: methanol = 99: 7); NMR (CD3OD): d 7.60-7.45 (m, 5H), 4.77-4.66 (m, 2H), 4.63-4.55 (m, 1H), 4.42 and 4.32 (s, 2H), 4.24-4.16 and 4.09-3.94 (m, 2H), 3.58-3.48 (m, 2H), 3.42-3.22 (m, 4H ), 3.20-2.73 (m, 4H), 2.622.50 (m, 2H), 2.38-2.32 (m, 2H), 2.25-2.03 (m, 3H), 1.98-1.62 (m, 7H), 1.58-1.42 (m, 1H), 1.38-1.10 (m, 3H), 1.08-0.90 (m, 8H).
Example 14. ~ Ex emplp __4_ (1) By means of the same procedure as described in Example 1 to react with the compound prepared in Reference Example 1, or the corresponding compounds with 4-amino-1-benzylpiperidine or the derivatives of amino acids in Example 1, the following compounds of the present invention are obtained.
Example 14 (2R) -N- (1- (4-methylbenzyl) piperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide TLC: Rf 0.26 (methanol: chloroform = 1:19); NMR (CD3OD): d 7.21-7.10 (m, 4H), 4.16-4.09 (m, ÍH), 3.73-3.58 (m, 1H), 3.47 (s, 2H), 2.89-2.77 (m, 3H), 2.66 (dd, J = 13.6, 7.8Hz, ÍH), 2.43 (d, J == 6.8Hz, 2H), 2.31 (s, 3H), 2.17-2.05 (m, 2H), 1.86-1.12 (, 22H), 1.03-0.84 (m, 2H).
Example 14 (1) (2RS) -N- (1-benzylpiperidin-4-yl) -2-t-butoxycarboni lamino-4-cyclohexyl thiobutanamide TLC: Rf 0.74 (methanol: chloroform = 1: 9); NMR (CDCl 3): d 7.40-7.20 (m, 5H), 6.20-6.05 (br, ÍH), 5.25-5.10 (br, ÍH), 4.25-4.10 (mHH), 3.90-3.68 (m, 1H), 3.49 (s, 2H), 2.86-2.46 (m, 5H), 2.21-1.15 (m, 18H), 1.44 (s, 9H).
E p e 15 (2R) -N- (l-benzylpiperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethyl sulfinylpropanamide The compound prepared in Example 1 (900 mg) is dissolved in methylene chloride (20 ml). After cooling the solution to -70 ° C, chlorobenzoic acid (344) is added to it. The reaction mixture is stirred for 3 and a half hours with heating from -70 ° C to -50 ° C. and this, saturated solution of sodium thiosulfate is added. The mixture is then stirred, and saturated sodium carbonate solution is added thereto. After separating the organic layer, the residue is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. The solvent is distilled from the mixture. The residue is purified with silica gel column chromatography (methanol: chloroform = 1:30 -> 1:10) to obtain the compound (714 mg) of the present invention having the following physical data.
TLC: Rf 0.58 (methanol: chloroform = 1: 9); NMR (CD3OD): d 7.33-7.22 (m, 5H), 4.49-4.39 (m, ÍH), 3.73-3.60 (m, 1H), 3.51 (s, 2H) 3.28-3.20 (m, 1H), 3.06- 2.73 (m, 4H), 2.62 (dd, J = 12.9, 9.0Hz, ÍH), 2.20-1.02 (m, 15H), 1.44 (s, 9H).
Example 16 ~ Example 16J20). ... By means of the same procedure as described in Reference Example - »Example 2 (in Example 2, (4) -3- t-butoxycarboml thiazolidin-4-ylcarboxylic acid or the corresponding derivatives are used) using the compound prepared in Example 1, Example 1 (1), Example 1 (2), Example 1 (12), Example 14, Example 14 (1) or Example 15 and subsequently, if necessary, by the same procedure as described in Example 8, the following compounds of the present invention are obtained.
Example 16 - --- (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2S) -1- t -butoxycarbonyl-1,2,3,6-tetrahydropyridine hydrochloride -2-Icarbonylamino) propanamide TLC: Rf 0.29 (methanol: chloroform = 1:19); NMR (CD3OD): d 8.33-8.16 (m, HH), 7.90-7.86 (m, HH), 7.55-7.44 (m, 5H), 5.80-5.60 (m, 2H), 4.46-4.23 (m, 3H), 4.16-3.46 (m, 3H), 3.58-3.00 (m, 4H), 2.91- 2.35 (m, 6H), 2.18 1.96 (m, 2H), 1.88-1.08 (m, 20H), 1. 02-0.85 (, 2H).
Example 1.6 (1) (2R) -N- (1-Benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2S) -1-t-butoxycarbonylpiperidin-2-licarbonylamino) propanamide hydrochloride TLC: Rf 0.34 (methanol: clproform = 1: 9); NMR (CD3OD): d 8.29 (br.s, ÍH), 7.79 (br.s, ÍH), 7. 56-7.45 (m, 5H), 4.68 (d, J = 3.0Hz, ÍH), 4.44 (dd, J = 14.4, 7.5Hz, 1H), 4.31 (s, 2H), 3.98-3.83 (m, 2H) , 3.60-3.00 (m, 5H), 2.89 (dd, J = 13.2, 6.0Hz, 1H), 2.80-2.72 (, 1H), 2.44 (d, J = 6.9Hz, 2H), 2.20-1.95 (m, 3H), 1.88-1.08 (, 24H), 1.02-0.85 (m, 2H).
Example 16 (2). = - (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4S) -3- t-butoxycarbonyloxazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.14 (methanol chloroform = 1:19); NMR (CDCI3): d 7.33-7.20 (m, 6H), 6.73 (br.s, 1H), 4.96 (br.s, 1H), 4.87 (d, J = 4.2Hz, ÍH), 4.49 (br.s) , ÍH), 4.36 (t, J = 6.0Hz, ÍH), 4.20 (d, J = 6.0Hz, 2H), 3.83-3.70 (m, ÍH), 3.50 (s, 2H), 3.13 (br.s, ÍH), 2.86-2.70 (m, 3H), 2.49-2.37 (m, 2H), 2.17-2.09 (m, 2H), 1.94-1.36 (m, 19H), 1.31-1.04 (m, 3H), 0.98- 0.82 (m, 2H).
Ej emp_lp_ 16 (3) -. -. (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2S) -1-t-butoxycarbonyl hydrochloride Ipyrrolidyl-2-ylcarboxylamino) propanamide TLC: Rf 0.56 (methanol: chloroform = 1: 9); NMR (CD3OD): d 8.44-7.89 (m, 2H), 7.54-7.46 (m, 5H), 4.46-4.30 (m, 3H), 4.24-4.12 (m, 1H), 4.04-3.82 (m, ÍH) , 6.30-3.02 (m, 6H), 2.94-2.66 (m, 2H), 2.48-2.38 (m, 2H), 2.32-0.82 (m, 28H).
Example L 6 (4) (2R) -N- £ l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2S, 4RS) -1- t-butoxycarbonyl-4-methyl-1-thiopyrrolidin-2- Icarbonylamino) propanamide TLC: Rf 0.57 (methanol: chloroform = 1: 9); NMR (CDC1A: d 7.34-7.02 (m, 7H), 4.62-4.52 (m, ÍH), 4.34-4.25 (m, ÍH), 3.90-3.66 (m, 2H), A. 4 9 (s, 2H) , 3.45-3.24 (m, 3H), 2.86-2.68 (m, 3H), 2.65-2.55 (m, 1H), 2.48-2.32 (m, 2H), 2.24-2.06 (m, 6H), 1.94-1.34 ( , 19H), 1.30-1.04 (m, 3H), 1.00-.082 (m, 2H).
Example 1j? (5) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((3S) -4-t-butoxycarbonylmorin-3-ylcarbonylamino) propanamide TLC: Rf 0.71 (methanol: chloroform = 1: 9); NMR (CDC13): d 7.32-7.22 (m, 5H), 6.96 (d, J = 7.2Hz, 1H) 9, 6.47 (d, J = 5.4Hz, ÍH), 4.48-4.42 (m, 3H), 3.88-3.72 (m, 3H), 3.58 (dd, J = 12.0, 3.9Hz, 1H), 3.53- 3.44 (m, 3H), 3.30-3.16 (m, 1H), 3.10-2.96 (m, ÍH), 2.84- 2.69 (m, 3H), 2.54-2.42 (m, 2H), 2.19-2.09 (m, 2H) , 1. 94-1.38 (m, 19H), 1.32-1.03 '(m, 3H), 1.01-0.85 (m, 2H).
Eg use.16 (6) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (2-phenoxybenzoi lamino) propanamide TLC: Rf 0.43 (methanol: chloroform = 1: 9); NMR (CDC1: d 8.53 (d, J = 7.2, ÍH), 8.18 (dd, J = 7.8 ~, 1.8Hz, 1H), 7.44-7.16 (m, 10H), 7.10-7.07 (m, 2H), 6.88 (d, J = 8.4Hz, ÍH), 6.44 (d, J = 8.1Hz, ÍH), 4.73-4.66 (m, 1H), 3.82-3.68 (m, 1H), 3.46 (s, 2H) ), 3. 06 (dd, J = 13.5, 4.8Hz, ÍH), 2.77-2.70 (m, 3H), 2.46 (dd, J = 12.3, 6.6Hz, 1H), 2.40 (dd, J = 12.3, 6.9Hz, 1H), 2. 16-2.05 (m, 2H), 1.90-1.58 (m, 7H), 1.50-1.30 (m, 3H), i.26-1.03 (m, 3H), 0.94-0.78 (m, 2H).
Example 16 (7) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (3-phenoxybenzoylamino) propanamide TIC: Rf 0.46 (methanol: chloroform = 1: 9); NMR (CDC13): d 7.51-7.10 (m, 13H), 7.04-6.98 (m, 2H), 6.55 (d, J = 7.8Hz, 1H), 4.59-4.52 (m, ÍH), 3.88- 3.75 (m, ÍH), 3.49 (s, 2H), 3.05 (dd, J = 13.8, 4.2Hz , ÍH), 2.80-2.72 (m, 3H), 2.58 (dd, J = 12.6, 6.9Hz, ÍH), 2.53"(dd, J = 12.6, 6.9H ?, 1H), 2.21-2.11 (m, 2H ), 1.98-1.40 (m, 10H), 1.31-1.05 (m, 3H), 1.01-0.86 (m, 2H).
Example 16 (8) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (4-phenoxybenzoylamino) propanamide TLC: Rf 0.37 (methanol: chloroform = 1:19); NMR (CDC13): d 7.83-7.76 (m, 2H), 7.44-7.14 (m, 9H), 7.08-6.97 (m, 4H), 6.60 (d, J = 7.8Hz, 1H), 4.64-4.54 (m , 1H), 3.92-3.74 (m, ÍH), 3.49 (s, 2H), 3.07 (dd, J = 13.6, 4.4Hz, 1H), 2.84-2.72 (m, 3H), 2.60 (dd, J = 12.8 , 6.6Hz, ÍH), 2.53 (dd, J = 12.8, 7.0Hz, 1H9, 2.23-2.08 (m, 2H9, 2.00-0.83 (m, 15H).
Example 16 (9) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethyl thio-2- (3-t-butoxy carbonyl lithium-1-Icarbonyl amino) propanamide TLC: Rf 0.47 (methanol: chloroform = 1:19); NMR (CDC1): d 8.87 (d, J = 7.8Hz, ÍH), 8.11 (d, J = 13.6Hz, 1H), 8.06 (d, J = 3.6Hz, ÍH), 7.30-7.20 (m, 5H), 7.01 (d, J = 8.1Hz, ÍH), 4.76-4.69 (m, ÍH), 3.88- 3.76 (m, 1H9, 3.48 (s, 2H), 3.12 (dd, J = 13.8, 6.0Hz, 1H), 2.95 (dd, J = 13.8, 6.3Hz, 1H), 2.81-2.76 (m, 2H), 2. 49 (dd, J = 12.6, 6.9Hz, ÍH), 2.44 (dd, J = 12.6, 6.6Hz, ÍH), 2.18-2.08 (m, 2H), 1.96-1.36 (m, 19H), 1.28-1.03 (m, 3H), 0.98-0.82 (m, 2H).
Example 16 (10) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (2-t-butoxycarbonylbenzoylamino) propanamide TLC: Rf 0.46 (methanol: chloroform = 1:19); NMR (CDC15): 6 7.93-7.90 (m, 1H9, 7.58-7.41 (m, 4H9, 7.33-7.20 (m, 5H), 6.53 (d, J = 7.8Hz, ÍH), 4.73 (dt, J = 7.8 , 5.7Hz, ÍH), 3.90-3.76 (m, ÍH), 3.54-3.45 (m, 2H), 3.27 (dd, J = 13.8, 5.7Hz, ÍH), 2.93 (dd, J = 13.8, 6.0Hz, ÍH), 2.86-2.81 (m, 2H), 2.54-2.41 (m, 2H), 2.16-2.05 (m, 2H), 1.99-1.38 (m, 19H), 1.30-1.04 (m, 3H), 0.99- 0.84 (m, 2H).
Example 16 (11) (2R) -N- (l-benzylpipepdin-4-yl) -3-cyclohexylmethylthio-2- (4-t-butoxycarbonylbenzoylamino) propanamide TLC: Rf 0.40 (methanol: chloroform = 1:19); NMR (CDC13): d 8.06-8.03 (m, 2H), 7.86-7.83 (m, 2H), 7.34-7.22 (m, 5H), 6.57 (d, J = 7.8Hz, 1H), 4.61-4.54 (m , 1H), 3.90-3.78 (m, 1H), 3.50 (s, 2H), 3.08 (dd, J = 14.1, 4.25Hz, 2H), 2.81-2.73 (m, 3H), 2.65-2.53 (m, 2H) ), 2.23-2.11 (m, 2H), 1.99-1.43 (m, 19H), 1.33-1.08 (m, 3H), 1.05-0.89 (m, 2H).
Example 16 (12) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (3-t-butoxycarbonylbenzoylamino) propanamide TLC: Rf 0.39 (methanol: chloroform = 1:19); NMR (CDC13): d 8.39 (t, J = 1.8Hz, ÍH), 8.17-8.12 (m, ÍH), 8.01-7.97 (m, 1H), 7.51 (t, J = 7.4Hz, ÍH), 7.34- 7.2A (m, 5H), 6.56 (d, J = 8.4Hz, 1H), 4.65-4.55 ~ (m, ÍH), 3.93-3.75 (m, ÍH), 3.49 (s, 2H), 3.08 (dd, J = 14.0, 4.8Hz, 1H), 2.85-2.72 (m, 3H), 2.66-2.49 (m, 2H), 2.25-2.09 (m, 2H9, 2.03-1.40 (m, 19H9, 1.35-0.85 (m, 5H).
Example 16 (13) __ (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (1-phenylcydohexylcarbonylamino) propanamide TLC: Rf 0.67 (methanol: chloroform = 1: 9); NMR (CDC13): d 7.45-7.22 (m, 10H), 6.29 (d, J = 7.0Hz, 1H), 6.18 (d, J = 8.0Hz, ÍH), 4.41-4.31 (m, ÍH), 3.78--3.57 (m, ÍH), 3.48 (s, 2H), 2.88 (dd, J = 14.0, . 4Hz, 1H), 2.76-2.69 (m, 2H), 2.60 (dd, J = 14.0, 7.2Hz, ÍH), 2.42-2.22 (m, 4H), 2.18-0.79 (m, 25H).
Example 16 (14) (2R) -N- (1- (4-methylbenzyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl thiazolidin-4-ylcarboni lamino) propanamide -JLLC: Rf 0.49 (methanol: chloroform = 1: 9) NMR (CD3OD): d 7.18 (d, J = 8.1Hz, 2H), 7.12 (d, J = 8.1Hz, 2H), 4.64-4.42 (m, 2H), 3.69-3.59 (m, ÍH), 3. 47 (s, 1H), 3.13 (dd, J = 12.0, 4.8Hz, ÍH), 2.91-2.68 (br, 4H), 2.44 (d, J = 6.9Hz, 2H), 2.31 (s, 3HT), 2.15 -2.07 (m, 2H), 1.88-1.77 (br, 4H), 1.76-1.36 Cm, 15H), 1.33-1.09 (m, 3H), 1.00-0.87 (m, 2H).
Example 16 (15) (2RS ") -N- (l-benzylpiperidin-4-yl) -4-cyclohexyl t io-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) butanamide TLC: Rf 0.50 (methanol: chloroform = 1: 9); NMR (CD3OD): d 7.40-7.20 (m, 5H9, 4.65-4.40 (m, 4H), 3.75-3.55 (m, ÍH), 3.55 and 3.54 (s, 2H), 3.45-3.28 (m, ÍH), 3.11 (dd, J = 12.0, 4.6Hz, ÍH), 2.95-2.80 (m, 2H), 2.73-2.40 (m, 3H), 2.25-1.20 (m, 27H).
Example 16 (16) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylsulfinyl-2- ((4R) -3-t-butoxycarbonyl thiazolidin-4-licarbonylamino) propanamide TLC: Rf 0.55 (methanol: chloroform = 1: 9); NMR (CD3OD): d 7.34-7.20 (m, 5H), 4.84-4.70 (m, ÍH), 4.65-4.45 (m, 3H), 3.74-3.56 (m, ÍH), 3.51 (s, 2H), ^ 3.44-3.00 (m, 4H), 2.20-1.00 (m, 17H), 1.49 (s, 9H).
Example 16 (17) (2S) -N- (1-benzylpiperidin-4-yl) -3-cyclohexyl-l-methoxy-2- ((4S) -3-t-butoxycarbonyloxazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.29 (methanol: chloroform = 1:19) "; NMR (CD 0D): d 7.32-7.22 (m, 5H), 4.90-4.86 (m, 2H), 4.51-4.43 (br, ÍH), 4.33 (dd, J = 7.5, 4.5Hz, 1H), 4.22 (t, J = 7.5Hz, ÍH), 4.07-3.96 (br, ÍH), 3.71-3.56 (m, 3H), 3.51 (s, 2H), 3.25 (dd, J = 9.0, 6.3Hz, ÍH), 3.23 (dd, J = 9.0, 6.6Hz, 1H), 2.89-2.80 (br, 2), 2.13 (dt, J = 11.7, 2.4Hz, 2H) 1.84-1.39 (m, 19H), 1.31-1.09 (m, 3H), 0.99-0.86 (m, 2H) Example 16 (18) (2R) -N- (2-benzylaminoethyl) -3-cyclchloride ? -hexylmethylthio-2- ((4R) -3-isopropyloxycarbonyl thiazole idin- 4 -i -carbonylamino) propanamide TLC: Rf 0.50 (methanol: chloroform = 1: 9); NMR (CD3OD): d 7.52-7.40 (m, 5H), 4.94-4.82 (m, lh), 4.67-4.64 (m, 2H), 4.48 (d, J = 9.0Hz, ITT), 4.53-4.28 (br , ÍH), 4.22 (d, J = 13.2Hz, ÍH), 4.19 (d, J = 13.2Hz, 1H), 3.67-3.34 (m, 3H), 3.23-3.09 (m, 3H), 3.01-2.77 ( m, 2H), 2.45 (d, J = 7.2Hz, 2H), 1.86-1.63 (m, 5H), 1.52-1.09 (m, 10H), 1.01-0.88 (m, 2H).
Example 16 (19) (2R) -N- (2-benzyl aminoeti 1) -3-cyclohexylmethylthio-2- (J4R) -3- (3-methylbutyryl) ti azol idin-4-ylcarboni lamino) propanamide hydrochloride TLC: Rf 0.46 (methanol: chloroform = 1: 9); NMR (DMSO-de): d 9.40-9.00 (br, 2H9, 8.25-7.90 (br, 2H) 7.43-7.40 (m, 3H), 4.88-4.80 (m, 2H), 4.47-4.36 (m, 2H) , 4.16 (s, 2H), 3.53-3.41 (m, 2H), 3.37-3.27 (br, 1H), 3.20-3.14 (m, 1H), 3.05-2.94 (m, 2H), 2.91 (dd, J = 13.5, 6.0Hz, ÍH), 2.78 (dd, J) 13.5, 7.5Hz,? H), 2.44 (d, J = 7.0Hz, 2H), 2.30-2.15 (br, 2H), 2.09-2.01 (m, 1H), 1.78-1.58 (m, 5H), 1.47-1.39 (m, ÍH), 1.26-1.09 (m, 3H), 0.99-0.90 (m, 8H).
Example 16 (20) (2R) -N- (1- (4-hydroxybenzyl) piperidin- -yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl-thiazolidin-4-ylcarbonylamino) propanamide TLC: Rf 0.31 (methanol: chloroform = 1: 9); NMR (CD3OD): d 7.12 (d, J = 8.4Hz, 2H), 6.73 (d, J = 8.4Hz, 2H), 4.64-4.53 (m, 2H), 4.48-4.42 (m, 2H), 3.69- 3.61 (m, 1H), 3.43-3.33 (m, 3H), 3.14 (dd, J = 12.0, 4.8Hz, ÍH), 2.90-2.71 (br, 4H), 2.44 (d, J = 6.9Hz, 2H) , 2.15-2.08 (m, 2H), 1.89-1.77 (br, 4H), 1.75-1.37 (m, 15-H), 1.33-1.09 (m, 3H), 1.00-.088 (m, 2H).
Example 17 (4R) -N- ((IR) -2-cyclohexylmethyl thio-1- (4-benzylaminopiperidin-1-ylcarbonyl) ethyl) -3- (3-methylbutyryl) thiazolidm-4-ylcarboxamide hydrochloride - By the same procedure as described in Example 5 - Example 10 (in Example 10, isovaleryl chloride was used instead of isobutyl chloroformate) - > Example 12 using the compound prepared in Example 3 (32), the compound of the present invention having the following physical data is obtained.
TLC: Rf 0.32 (methanol: methylene chloride = 7:93); NMR (CD3OD): d 7.55-7.43 (m, 5H), 5.07-4.93 (m, ÍH), 4.90-4.72 (m, 2H), 4.70-4.50 (m, 2H), 4.42-4.10 (m, 3H) , 3.56-3.08 (m, 4H), 3.00-2.87 _ (m, ÍH), 2.82-2.66 (m, 2H), 2.50-2.00 (m, 7H), 1.90-1.60 (m, 2H), 1.36-1.09 (m, 3H), 1.04-0.88 (m, 8H).
Example 18 (4R) -N- ((IR) -2-cyclohexylmethyl thio-1-4-benzylaminopiperidin-1-ylcarbonyl) ethyl) -3-isopropyloxy carbonyl thiazole-4-ylcarboxamide hydrochloride By means of the same procedure as described in Reference Example 3 - > - Example 2 (in Example 2, (4R) -3-isopropyloxycarbonyl thiazolidin-4-ylcarboxylic acid is used in place of (4R) -3-t-butoxycarbonyl thiazolidin-4-ylcarboxylic acid) - »Example 12 using the compound prepared in Example 1 (29), the compound of the present invention having the following physical data is obtained.
TLC: Rf 0.38 (methanol: methylene chloride = 7:93); NMR (CD3OD): d 7.58-7.40 (m, 5H), 5.05-4.94 (m, ÍH), 4.93-4.80 (M, ÍH), 4.73-4.57 (m, 3H), 4.48 (d, J = 9Hz, 1H), 4.36-4.16 (m, 3H), 3.56-3.05 (m, 4H), 3.01-2.87 (m, ÍH), 2.80-2.66 (m, 2H), 2.50-2.42 (m, 2H), 2.34- 2.17 (m, 2H), 1.90-1.61 (m, 6H), 1.61-1.37 (m, 2H), 1.36-1.10 (m, 9H), 1.03-0.88 (m, 2H).
Example 19 (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -2,2-dimet i 1-3- (3-methylbutyryl) thiazolidin-4-hydrochloride ilcarbonylamino) propanamide By means of the same procedure as described in Example 2 (in Example 2, hydrochloride • (4R) -2,2-dimethylthiazolidin-4-ylcarboxylic acid is used instead of (4R) -3- t-butoxycarbonyl thiazolidin acid -4-ylcarboxylic acid) - »Example 10 (in Example 10, isovaryl chloride is used instead of isobutyl chloroformate) - > Example 8 using the compound prepared in Reference Example 3, the compound of the present invention having the following physical data is obtained. "* TLC: Rf O.26 (methanol: methylene chloride = 7.93); NMR (CD3OD): d 7.58-7.43 (m, 5H) 4.95-4.88 and 4.50-4.28 (m, 1H), 4.50-4.28 (m, 3H), 4.10-3.83 (m, ÍH), 3.56-3.33 (m , 3H), 3.20-3.05 (m, 3H), 2.95-2.70 (m, 2H), 2.50-2.38 (m, 2H), 2.27-1.98 (m, 5H), 1.90-1.60 (m, 10H), 1.53 -1.35 (m, ÍH), 1.35-1.08 (m, 3H), 1.05-0.85).
Example 20 ~ Example 20 (2) By means of the same procedure as described in Example 8 using the compound prepared in Example 3 (8), Example 3 (9) or Example 3 (27), the following compounds are obtained of the present invention.
EXAMPLE 20 (2S) -N- (1-Benzylpiperidin-4-yl) -3-cycloiaoxymethoxy-2- ((4R) -3- t-butoxycarbonyl-aiazolidin-4-ylcarbonylamino) propanamide hydrochloride TLC: Rf O.39 (methanol: methylene chloride = 1.19); NMR (CD3OD): d 7.60-7.43 (m, 5H), 4.65-4.52 (m, 2H), 4.52-4.37 (m, 2H), 4.31 (s, 2H), 4.02-3.85 (m, 1H), 3.79-3.05 (m, 10H), 2.18-2.03 (m, 2H), 1.96-1.62 (m, 7H), 1.60-1.36 Cm, 10H), 1.33-1.10 (m, 3H), 1.02- 0.83 (m, 2H).
EXAMPLE 20 (1) (2R) -N- (2-Benzylaminoethyl) -3-cyclahexylmethylthio-2- ((4R) -3-t-butoxycarbonyl-l-thiazolidin-4-ylcarbonyl) propanamide hydrochloride TLC: Rf 0.50 (methanol: chloroform = 1: 9); NMR (CD3OD): d 7.53-7.43 (m, 5H), 4.63-4.59 (m, 2H), 4.45 (d, J = 9.3Hz, 1H), 4.39-4.28 (br, ÍH), 4.27 (d, J = 12.9Hz, 1H), 4.23 (d, J = 12.9Hz, 1H), 3.74-3.32 (br, 3H), 3.25-3.11 (m, 3H), 2.99-2.74 (br, 2H), 2.45 (d, J = 6.9Hz, 2H), 1.85-1.63 (m, 5H), 1.47-1.37 (m, 10H), 1.34-1.09 (m, 3H), 1.02-0.89 (m, 2H).
Example 20 (2) (2R) -N- (1-Benzylpiperidin-4-yl) -3-cyclopentylmethyl-thio-2- ((4R) -3-t-butoxycarbonylthiazole idin-4-ylcarbonylamino) propanamide hydrochloride TLC: Rf 0.39 (methanol: methylene chloride = 1.19); NMR (CD3OD): d 7.60-7.43 (m, 5H), 4.65-4.52 (m, 2H), 4.51-4.39 (m, 2H), 4.31 (s, 2H), 4.02-3.84 (m, ÍH), 3.58-3.02 (m, 10H), 2.98-2.72 (m, 2? F), 2.57 ( d, J = 8Hz, 2H) 2.20-1.95 (m, 3H), 1.90-1.71 (m, 3H), 1.71- 1.35 (m, 14H), 1.33-1.13 (m, 2H).
Example 21 ~ 21 (5) By converting the compounds prepared in Example 2, Example 3 (8) or Example 3 (9) to the corresponding salts according to a known method, the following compounds of the present invention are obtained.
* 'X. ~ _TLC: Rf 0.45 (methanol: chloroform = 1: 9); _RMN (DMSO-d: 8.51-8.14 '(br, 2H) 7.48-7.38 (m, ? L), 4.59-4.45 (m, 2H), 4.36-4.30 (m, 2H), .4.13 (s, 2H), 3.41-3.24 (m, 3H), 3.03-2.86 (m, 3H), 2.79-2.55 (m ,. ~ 2H), 2.38 (d, J = 6.9Hz, 2H), 1.75-1.56 (m, 5H), 1. 41-1.24 (m, 10), _ 1.23-1.03 (m, 3H), 0.92-0.80 (m, 2? _- Example 21 (3) __ Fumaric acid salt of (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolin-4-ylcarboni lamino) propanamide TLC: Rf 0.69 (methanol: chloroform = 1:14); - MN (CD ^ OD): d 7.50-7.42 (m, 5H), 6.70 ~ (s, 2H), 4.62j ((d, J = 9.2, ÍH), 4.57 (dd, J = 7.1, 4.7Hz, 1H), 4.47 (d, -T = 9.2Hz, 1H), 4.40-4.39 (m, ÍH), 4.15 (s, 2H) 3.92-3.81 (m, ÍH), 3.42-3.30 (m, 3H), 3.15-3.10 (m, ÍH), 3.01-2.73 (m, 4H), 2.44 (d, J = 6.9Hz, 2H), 2.10-2.00 (m , s, 4- da 4- 9- 0, 0- 3- da OLLC: Rf 0.46 (methanol: chloroform = 1: 9); NMR (CDC1): d 8.39-8.00 (br, 1H9, 7.62-7.32 (m, 6H), 4.64 (t, J = 5.0Hz, ÍH), 4.55 (d, J = 9.2Hz-, ÍH), (4.39Cd, J = 9.2Hz, lH), 4.32-4.26 (, ÍH), 4.19 (d, J = 13.2Hz, ÍH), 4.13 (d, J = 13.2Hz, ÍH), 3.71-3.38 (br, 2H), 3.30-3.10 (m, 6H), 2.98-2.86 (, 2H), 2.38 (d, J = 6. 9Hz, 2H), 1.82-1.60 (m, 5H), 1.54-1.35 (m, 10H), 1.28-.05.05 (m, 3H), 0.94-0.83 (, 2H).
Reference Example 4 (4R) -thiazolidin-4-ylcarboxylic acid 20 To a solution of L-cysteine (100.22 g) is added in water (180 ml), 35% formic acid solution (85.0 ml) dropwise on cold ice. The mixture is stirred for 1 hour. The precipitated crystal is collected. The resulting crystal UW5 is washed with ethanol and dried under reduced pressure to obtain the title compound (105.4 g) having the following physical data.
TLC: Rf 0.30 (ethyl acetate: acetic acid: water = / -3: 1: 1); NMR (D20) d 4.32 (ΔI, d, J = 10.2Hz, 4.30 (lH, dd, J = 7.5, 5.7Hz), 4.20 (1H, d, J = 10.2Hz), 3.28 (lH, d, dd, J = 12.0, 7.5Hz), 3.18 (lH, d, dd, J = 12.0, 5.7Hz) 15 Reference Example 5 (4R) -3-t-Butoxycarbonyl-alkylazidin-4-ylcarboxylic acid To a solution of the compound prepared in Reference Example 4 (122 g) is added in ethanol (500 ml), an aqueous solution of 2N NaOH (460 ml) at room temperature. To the obtained solution, di-t-butyl dicarbonate (230 ml) is added dropwise in cold ice. The reaction mixture is stirred for 1 hour, concentrated under reduced pressure and centrifuged with 2 N HCl. The mixture is extracted with ethyl acetate, the organic layer is washed with saturated sodium chloride solution, dried by means of anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (214 g) having the following physical data: TLC: Rf 0.29 (methanol: chloroform = 1: 9); NMR (CD3OD): d 4.80-4.62 (HH, m), 4.56 (HH, d, J = 8.7Hz), 4.43-4.28 (1H, m), 3.44-3.32 (HH, m), 3.25-3.14 (1H, m), 1.47 and 1.43 (9H, m).
Reference Example 6 Acid (2R) -2- t-butoxycarbs- nylamino-3-cyclohexylmethyl thiopropane, co- To a solution of L-cysteine (4.24 g), an aqueous solution of 2N NaOH (35 ml) is added in ethanol (35 ml). After refluxing the solution thereto is added (bromomethyl) cyclohexane (5.4 ml). "The reaction mixture is stirred for 4 hours, and di-t-butyl dicarbonate (8.8 ml) is added dropwise thereto. The mixture is stirred for 2 hours.The ethanol is distilled from the solution.The mixture is acidified by the addition of 2N HCl in cold ice. The reaction mixture is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried by means of anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (10.5 g) having the following physical data. The title compound thus obtained is the same as that prepared in Reference Example 1.
Example 22 (2R) * - N- (1-benzylpiperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide To a solution of the compound prepared in Reference Example 6 (316 g) is added in dimethylformamide (950 ml), on ice cold, 1-hydroxybenzotriazole (153 g), 4-amino-1-benzylpiperidine (204 ml) and l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (230 g) in a successive manner. The mixture is stirred for 2 and a half hours. The reaction mixture is poured onto trio ice and extracted with ethyl acetate. The organic layer is washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. column in silica gel (methanol: methylene chloride = 1:19) to obtain the compound (425 g) of the present invention The title compound thus obtained is the same as that prepared in Example 1.
Reference example __ _ 2 (2R) -N- (1-benzylpiperidin-4-i 1) -2-amino-3-cycloheptylmethylthiopropanamide hydrochloride To the compound prepared in Example 22 (423 g) is added a dioxane solution of HCl at 4N (1600 ml) at room temperature. The mixture is stirred for 3 hours and concentrated under reduced pressure. The resulting solid is washed with ether to obtain the title compound (427 g) having the following physical data. The title compound thus obtained is the same as that prepared in Reference Example 3.
TLC: Rf 0.49 (methanol: chloroform = 1: 9); ~ NMR (CD3OD): d 7.61-7.47 (m, 5H), 4.42 and 4.30 (s, 2H). 4.25-4.14 and 4.02-3.91 (m, 2H), 3.57-3.46 (m, 2H), 3.38-3.32y 3.12-2.84 (m, 4H), 2.65-2.45 (m, 2H), 2.19-1.83"(m , 6H), 1.74-1.63 (m, 3H) 1.58-1.41 (, 1H), 1.36-1.09 (m, 3H), 1.05-0.90 M (, 2H).
Example 23 (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide To a solution of the compound prepared in Reference Example 7 (426 g) is added in dimethylformamide (1000 ml), on ice cold, N-methylmorpholine (190 ml), 1-hydroxybenzotriazole (132 g), the compound prepared in the Reference Example 5 (202 g) and l-ethyl-3- (3-dimethylaminopropyl-carboiimide hydrochloride (199) in successive form.) The reaction mixture is stirred for 3 hours and poured into cold ice (4000 ml) and ethyl acetate ( 1000 ml) The reaction mixture is extracted with ethyl acetate.The organic layer is washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution in a successive manner, dried with anhydrous magnesium sulfate and Concentrate under reduced pressure The resulting solid is recrystallized from ethanol and water to obtain the compound (42-0 g) of the present invention The title compound thus obtained is the same as that prepared in the Reference Example 2.
Reference Example 8 2,5-dioxopyrrolidin-1-yl ester of (4R) -3-t-butoxycarbonyl-thiazolidin-4-yl carboxylic acid To a solution of the compound prepared in Reference Example 5 (233) g) is added N-hydroxysucmimide (126.5) in dimethylformamide (100 ml), l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (210 g) ) on cold ice. The reaction mixture is stirred for 3 hours and poured into cold water (3000 ml). The precipitated crystal is filtered under reduced pressure. The precipitate is washed with cold water and dried under reduced pressure. The residue is recrystallized from isopropyl alcohol to obtain the title compound (322.2 g) having the following physical data.
TLC: Rf 0.70 (ethyl acetate); NMR (CDCI3): d 5.25-5.10 and 5.00-4 ¡5 (, ÍH), 4.75-4.40 (M, 2H), 3.60-3.35 (m, 2H9, 2 ¡5 (s, 4H), 1.49 (S, 9H).
Reference Example 9 _ __ Acid (2R) -2- ((4R) -3-t-Butoxycarbonylthiazolidin-4-ylcarbonylamino) -3-cyclohexylmethylthiopropanoic acid To a suspension of L-cysteine (30.3 g) is added an aqueous solution of 2N NaOH (250 ml). To this solution, (bromomethyl) cyclohexane (40.1 ml) is added. The reaction mixture is refluxed for 2 hours. After the mixture is cooled to room temperature, the compound prepared in Reference Example 8 (82.6 g) and dimethylformamide (50 ml) is added thereto. The reaction mixture is stirred for 3 hours and then concentrated. The residue is acidified by the addition of 2N HCl and ice and extracted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride solution successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (109.2 g) having the following physical data. .
TLC: Rf 0.37 (methanol: chloroform = 1:10); KMN (CDC13): d 4.83-4.57 (m, 3H), 4.48-4.37 (mHI), 3.47-3.14 (m, 2H), 2.99 (d, J = 6Hz, 2H), 2.43 (d, J = 7Hz) , 2H), 1.86-1.56 (m, 5H), 1.56-1.370 (n, 10H), 1.34-1.05 (, 3H), 1.05-0.80 (m, 2H).
Eg emplo_24_ (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3- t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide To a solution of the compound prepared in Reference Example 9 (108.2 g) is added in acetonitrile (1200 ml), on cold ice, N-methylmorpholine (27.5 ml) and isobutylchloroformate (32.4) dropwise in a successive manner. The reaction mixture is stirred for 30 minutes on cold ice, to which is added a solution of 4-amino-1-benzylpiperidine (47.6 g) in acetonitrile (500 ml) dropwise. The reaction mixture is stirred for 30 minutes and poured into water (7000 ml). The precipitate is collected. The precipitate that was collected is washed with water. The residue is recrystallized by addition of isopropyl alcohol (100 ml) to obtain the compound (98.3 g) of the present invention. The title compound thus obtained is the same as that prepared in Reference Example 2 and Example 23.
Formulation of Example 1 The following compounds are mixed by conventional method and minced to obtain 100 tablets, each containing 50 mg of active ingredient. • (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxy carbonylthiazolidin-4-ylcarbonylamino) propanamide •• - - 5.0 g • Sodium carboxymethylcellulose (disintegrating agent) __-_ * ______-__ 0 * 2 g • Magnesium stearate (lubricating agent) 0.1 g • Microcrystalline cellulose 4.7 g Formulation of Example 2 ~ The following compounds are mixed by conventional method and the solution is sterilized by conventional method, 5 ml portions are placed in ampoules and cold-dried by a conventional method to obtain 100 ampoules, each containing 20 mg of active ingredient. • (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethyl thio-2- ((4R) -3-t-butoxy carbonylthiazolidin-4-ylcarbonylamino) propanamide .. 2.0 g • mannitol .... 20 g • distilled water _.500 ml It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.
Having described the invention as above, the content of the following claims is claimed as property: Claims 1. An amino acid derivative of the formula (I - [characterized in that, R1 is, D to which Cl-15, 2) alkoxy Cl-8, 3) phenyl, 4) C3-8 cycloalkyl, 5) heterocyclic ring, 6) Cl-4 alkyl substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring, 7) Cl-4 alkoxy substituted with phenyl, C3-8 cycloalkyl or heterocyclic ring or 8) C2-4 alkenyl substituted with phenyl, cycloalkyl C3-8 or heterocyclic ring, wherein all phenyl, C3-8 cycloalkyl and heterocyclic ring in R1 may be substituted with 1 ~ 3 substituent (s) selected from the group consisting of the following (i) - (ix): (i) alkyl Cl-4, (ii) alkoxy Cl-4, (iii) phenyl, (iv) phenoxy, (v) benzyloxy, (vi) -SR5 (in which Rs is hydrogen or alkyl Cl-4), (vii) acyl C2-5, (viii) halogen, (ix) alkoxycarbonyl Cl-4, (x) itro and (xi) -NR6R7 (in which R6 and R7 are independently, hydrogen, alkyl Cl-4 or alkoxycarbonyl Cl -4, or R6 and R7 are taken together with the nitrogen atom, to which these are attached represents the 5-7 membered saturated heterocyclic ring which necessarily contains a nitrogen atom and optionally also contains a nitrogen atom or an atom of oxygen), A is a single bond, -CO- or -S02-, R2 is hydrogen or alkyl Cl-4, which can be substituted with a phenyl, D is alkylene Cl-4 or alkenylene C2-4, E is 1 ) -COO-, 2) -OCO-, -C0NR8- (wherein R8 is hydrogen or Cl-4 alkyl), 4) -NR9CO- (wherein R9 is hydrogen or C1-4 alkyl), 5) -O-, 6) -S-, 7) -SO-, 8) -SC-2-, 9) -NR10- (wherein R10 is hydrogen or C1-4 alkyl), 10) -CO-11) -S02NRX- (wherein R > n is hydrogen or C1- or 12-alkyl) -NRi¿S02- (in which that R is hydrogen or Cl-4 alkyl), R3 is 1) carbocyclic ring, 2) heterocyclic ring or 3) Cl-4 alkyl substituted with carbocyclic ring or heterocyclic ring, wherein all carbocyclic ring and heterocyclic ring in R3 can be substituted with 1 ~ 3 selected substituent (s) from the group consisting of the following (i) - (ix): (i) - (ix): (i) alkyl Cl-4, (ii) alkoxy Cl-4, (iii) phenyl, (iv) phenoxy, ( v) benzyloxy, (vi) -SR13 (wherein R13 is hydrogen or C1-4 alkyl), C2-5 (vii) acyl, (viii) halogen, (ix) C1-4 alkoxycarbonyl, (x) nitro y ( xi) -NR14R1S (in which R14 and R1S are independently, hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R14 and R15 are taken together with the nitrogen atom, to which these are linked represents the 5-7 membered saturated heterocyclic ring which necessarily contains a nitrogen atom and additionally optionally contains a nitrogen atom or an oxygen atom), J is J1 or J2, J1 is D-0- or 2) -NR16- ( where R16 is hydrogen or Cl-4 alkyl), J2 is 1) -NR17- (wherein R17 is Cl-4 alkyl substituted with a phenyl, NR18R19 (in which R18 and R19 are independently, hydrogen or Cl-4 alkyl), hydroxy , Cl-4 alkoxy, - (Cl-4 alkylene) -OH, - (Cl-4 alkylene) -O- (Cl-4 alkyl) - (Cl -4 alkylene) -O- (C2-5 acyl) 2) -NR ^ -NR "- (in which R, 2 * 0w and R, 241- are independently, hydrogen or Cl-4 alkyl, which can be substituted with a phenyl), 3) -NR22- (Cl-4 alkylene) -NR23- (wherein R22 and R23 are independently, hydrogen or Cl-4 alkyl, which can be substituted with a phenyl), 4) -NR24- (Cl-4 alkylene) -0- (wherein R24 is hydrogen or Cl-4 alkyl, which can be substituted with a phenyl) or ) -NR2S- (alkylene Cl-4) -S- (in which R2S is hydrogen or alkyl Cl-4, which can be substituted with a phenyl), R4 is R4_1, R4"2 or R4-3, R4" 1 is Dalchyl Cl-8, 2) carbocyclic ring, 3) heterocyclic ring or 4) Cl-8 alkyl substituted with 1 ~ 3 substituent (s) selected from the group consisting of the following (i) - (v) );

Claims (28)

(i) carbocyclic ring, (ii) heterocyclic ring, (iii) COOR26 (wherein R26 is hydrogen or Cl-4 alkyl substituted with a phenyl (wherein the phenyl can be substituted with Cl-4 alkoxy), (iv) SR27 (wherein R27 is hydrogen or Cl-4 alkyl) and (v) 0R28 (wherein R28 is hydrogen or Cl-4 alkyl), with the proviso that when J is -NR17-, -NR20-NR2X- -NR-22 alkylene Cl-4) -NR-, each of R 4-1 and R > 17 R4- xy R21 and R4"1 and R23 are taken together with the nitrogen atom to which these link represent the heterocyclic ring, wherein all carbocyclic ring and heterocyclic ring in R4-1 and heterocyclic ring represented by each R4" 1 and R17, R4-1 and R21 and R4"1 and R23 are taken together with the nitrogen atom to which they are bound and can be substituted with 1 ~ 3 substituent (s) selected from the group consisting of following (i) - (xi): (i) alkyl Cl-4, (ii) alkoxy Cl-4, (iii) phenyl, (iv) phenoxy, (v) benzyloxy, (vi) -SR29 (wherein R29 is hydrogen or Cl-4 alkyl), (vii) C2-5 acyl, (viii) halogen, (ix) alkoxycarbonyl Cl-4, (x) nitro and (xi) -NR30R31 (wherein R30 and R31 are independently, hydrogen, Cl-4 alkyl or Cl-4 alkoxycarbonyl, or R30 and R is taken together with the nitrogen atom, which these link represents the 5-7 membered saturated heterocyclic ring which necessarily contains a nitrogen atom and optionally also contains a nitrogen atom or an oxygen atom), R4-2 is 1) carbocyclic ring, 2) heterocyclic ring or 3) Cl-8 alkyl substituted with 1 ~ 3 substituents selected from the group consisting of the following (i) - (v): (i) carbocyclic ring, (ii) heterocyclic ring, (iii) COOR32 (wherein R32 is hydrogen or Cl-4 alkyl substituted with a phenyl (wherein the phenyl can be substituted with alkoxy Cl-4), (iv) SR33 (wherein R33 is hydrogen or Cl-4 alkyl) and (v) 0R34 (wherein R34 is hydrogen or Cl-4 alkyl), with the proviso that when J is - NR16-, -NR17-, NR20-NR21- or -NR22- (alkylene Cl-4) -NR23-, each of R4"2 and R16, R4" 2 and R16, R4-2 and R17, R4"2 and R21, and R4"2 and R23 are taken together with the nitrogen atom to which these link represent the heterocyclic ring, wherein at least one ring of all carbocyclic ring and heterocyclic ring in R4" 2 and heterocyclic ring represented by each R4"2 and R16, R4" 2 and R17, R4"2 and R21, and Y4-2 and R23 are taken together with the nitrogen atom to which these are bonded is substituted with a hydroxy or an -O- (alkylene) Cl-4) -0- (Cl-4 alkyl) and can be further substituted with 1 ~ 2 substituents selected from group consisting of the following i) - (xiii): (i) alkyl Cl-4, ii) alkoxy Cl-4, iii) phenyl, iv) phenoxy, v) benzyloxy, (vi) -SR35 (wherein R3S is hydrogen or alkyl Cl-4), vii) C2-5 acyl, viii) halogen, ix) alkoxycarbonyl Cl-4, x) nitro and x?) - NR (where R and R 'are independently, hydrogen, alkyl Cl -4 or alkoxycarbonyl Cl-4, or R, 36 and R37 are taken together with the nitrogen atom, to which these are attached represents the 5-7 membered saturated heterocyclic ring which necessarily contains a nitrogen atom and optionally contains a nitrogen atom or an oxygen atom), (xii ) hydroxy and (xiii) -O- (alkyleneCl-4) -O- (alkylCl-4), R4"3 is LM, -L- is 1) - (carbocyclic ring, which can be substituted with 1 ~ 3 substituent (S)) -, 2)) - (heterocyclic ring, which can be substituted with 1 ~ 3 substituent (S)) - or 3) - (C 1-4 alkylene) - (carbocyclic ring or heterocyclic ring , which can be substituted with 1 ~ 3 its (s) -substituent), with the proviso that when J is -NR16-, -NR17-, -NR20-NR21- or -NR22- (alkylene Cl-4) -NR23 -, each L and R16, L and R17, L and R21 and L and R23 are taken together with the nitrogen atom to which they are attached represents - (heterocyclic ring, which can be substituted with
1 ~ 3 substituent (s)), M is 1) carbocyclic ring or heterocyclic ring, which can be substituted with 1 ~ 3 its thi s (s) (with the proviso that when the carbocyclic ring is phenyl, such ring is substitute with at least one substituent (s), and that when the heterocyclic ring is 5-7 membered saturated heterocyclic ring, in which the nitrogen atom in the heterocyclic ring is linked to the L group as shown G- and in which a nitrogen atom or an oxygen atom may additionally contain, subsequently such a ring is substituted with at least one substituent or substituents,
2) Cl-4 alkyl substituted with 1 ~ 2 its selected donor (s) from the group consisting of the following (i) - (ii); (i) carbocyclic ring, which can be substituted with 1 ~ 3 substituent (s), (ii) heterocyclic ring, which can be substituted with 1 ~ 3 substituent (s), 3) -O- (carbocyclic ring or heterocyclic ring, which can be substituted with 1 ~ 3 its constituent (s)) (with the proviso that when the carbocyclic ring is phenyl, such ring is replaced with at least one substituent or substituents, 4) -S- (carbocyclic ring or heterocyclic ring, which can be substituted with 1 ~ 3 substituent (s)), 5) -NR38- (carbocyclic ring or heterocyclic ring, which can be substituted with 1 ~ 3 their constituent (s) (in which R38 is hydrogen or Cl-4 alkyl which can be substituted with a phenyl), 6) -O-CH;; - (carbocyclic ring, which can be substituted with 1 ~ 3 its constituent (s)) (with the proviso that when the carbocyclic ring is phenyl, such a ring is substituted with at least one or more substituent (s)), 7) -O- (C2-4 alkylene) - (carbocyclic ring, which can be substituted with 1 ~ 3 its constituent (s)), 8) -O- (Cl-4 alkylene) - (heterocyclic ring, which can be substituted by 1 ~ 3 its (s)), (9) -S- (Cl-4 alkylene) - (carbocyclic ring or ring heterocyclic, which can be substituted with 1 ~ 3 substituent (s)), 10) -NR39- (Cl-4 alkylene) - (carbocyclic ring- or heterocyclic ring, which can be substituted with 1 ~ 3 substituent (s)) (wherein R39 is hydrogen, Cl-4 alkyl which can be substituted with a phenyl or C2-5 acyl which can be substituted with 1 ~ 3 of halogen) or 11) -CO- (carbocyclic ring or heterocyclic ring, which can be substituted with 1 ~ 3 its ti tiyente (s)), where the sutituyente (s) carbocyclic ring and heterocyclic ring in L and M, and the heterocyclic ring represented by L and R16, L and R17, L and -R21, and L and R23 are taken together with the nitrogen atom to which these are linked is selected from the following (i) - (xiv): (i) alkyl Cl-4, (ii) C2-4 alkenyl, (iii) hydroxy, (iv) alkoxy Cl-4, (v) - (alkylene Cl-4) -OH, (vii) halogen,; viii) NR4,0UtR-, 41 (in which R40 R41 are independently, hydrogen, Cl-4 alkyl or Cl-4 alkoxycarbonyl, or R40 and R41 are taken together with the nitrogen atom to which these link represent the saturated heterocyclic ring of 5 ~ 7 members which necessarily contains a nitrogen atom, and in addition additionally contains a nitrogen atom or an oxygen atom), (ix) SR42 (wherein R42 is hydrogen or Cl-4 alkyl), (x) nitro , (xi) trifluoromethyl, (xii) alkoxycarbonyl Cl-4, (xiii) oxo and (xiv) C2-5 acyl, with the proviso that when J is J1, R4 does not represent R4-1] or non-toxic salts thereof , or hydrates thereof, 2. A compound according to claim 1, characterized in that R1 is Cl-15 alkyl or Cl-8 alkoxy. 3. A compound according to claim 1, characterized in that R1 is 1) phenyl, 2) C 3-8 cycloalkyl, 3) C 1-4 alkyl substituted with phenyl or C 3-8 cycloalkyl, 4) C 1-4 alkoxy substituted with phenyl or C 3-8 cycloalkyl or 5) C 2-4 alkenyl substituted with phenyl or C3-8 cycloalkyl (all phenyl, C3-8 cycloalkyl) can be substituted. 4. A compound according to claim 1, characterized in that R1 is 1) heterocyclic ring, 2) Cl-4 alkyl substituted with heterocyclic ring,
3) Cl-4 alkoxy substituted with heterocyclic ring or
4) C 2-4 alkenyl substituted with heterocyclic ring (Any heterocyclic ring can be substituted). 5. A compound according to claim 1 or 4, characterized in that R1 is 1) 5 ~ 15 membered mono- or bi-heterocyclic ring containing 1 ~ 2 atom (s) of nitrogen and 1 ~ 2 atom (s) of oxygen or a sulfur atom, 2) Cl-4 alkyl substituted with 5 ~ 15 membered mono- or bi-heterocyclic ring containing 1 ~ 2 atom (s) of nitrogen and 1 ~ 2 atom (s) of oxygen or a sulfur atom, 3) Cl-4 alkoxy substituted with 5-1-membered mono- or bi-heterocyclic ring containing 1 ~ 2 nitrogen atom (s) and 1 ~ 2 oxygen atom (s) or a sulfur atom, 4) C2- alkenyl 4 substituted with 5 ~ 15 membered mono- or bi-heterocyclic ring containing 1 ~ 2 atom (s) of nitrogen and 1 ~ 2 atom (s) of oxygen or a sulfur atom, 6. A compound according to claim 1 or 5, characterized in that E is -COO-, -O-, -S-, -SO- or -SO; 7. A compound according to any one of claims 1 to 5, characterized in that E is -O- or -S-. 8. A compound according to any one of claims 1 to 7, characterized in that R3 is Cl-4 alkyl substituted with carbocyclic ring or heterocyclic ring (all carbocyclic ring can be substituted). 9. A compound according to any of claims 1 to 7, characterized in that R3 is C3-10 cycloalkyl or C1-4 alkyl substituted with C3-10 cycloalkyl (all cycloalkyl can be substituted). 10. A compound according to any of claims 1 to 7, characterized in that RJ is heterocyclic ring or. alkyl substituted with heterocyclic ring (all heterocyclic ring can be substituted). 11. A compound according to claim 1 or 2, characterized in that it is (1) (2R) -N- (1-benzylpiperidin-4-yl) -2-t-butoxycarbonyl amino-3-cyclohexyl-lime-thiopropanamide, (2) (2R) -N- (4-hydroxybenzyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (3) (2S) -N- (1-benzylpiperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexymethyl thiopropanamide, (4) (2R) -N- (1-benzylpiperidin-4-ylmethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (
5) (2R) -N- (3-methoxymethoxy-4-methoxybenzyl) - 2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (
6) (2R) -N- (1- (4-methoxybenzyl) piperidin-4-ylmethyl) -2-t-butoxycarboni lamino-3-cyclohexylmethyl thiopropanamide, (
7) (2R) -N-methyl-N- (1-benzylpyrrolidin-3-yl) -2-t-butoxycarbonilamino-3-cyclohexymethylthiopropanamide, (
8) (2R) -N- (1- (4-methoxybenzyl) piperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexymethyl thiopropanamide, (
9) (2R) -N- (1- (4-methoxybenzoyl) piperidin-4-yl) -2-t-buto-icarboni-lamino-3-cyclohexylmethoxypropanamide, (
10) (2R) -N- (1- (4-fluorobenzyl) piperidin-4-yl) -2-t-butoxycarboni lamino-3-cyclohexylmethylthiopropanamide, (
11) N - ((lR) -2-cyclohexylmethylthio-1- (4-benzylpiperazin-1-ylcarbonyl) ethyl) carbamic acid t-butyl ester, (
12) N - ((lR) -2-cyclohexylmethylthio-1- (4-diphenylmethylpiperazin-1-ylearbonyl) ethyl) carbamic acid t-butyl ester, (
13) ((2R) -N- (2 - benzylaminoethyl) -2-t-butoxycarbonylamino-3-cyclohexylmethyl thiopropanamide, (
14) N- ((lR) -2-Hexhexylmethyl-1- (4- (4-methoxy phenyl) piperazin-1-ylearbonyl) ethyl) carbamic acid t-butyl ester, (
15) (2R) -N- (1- (4-fluorobjencil) piperidin-4-yl) -2-t-butoxycarboni lamino-3-cyclohexylthiopropanamide, (
16) (2R) -N- (1- (4-fluorobenzoyl) piperidin-4-yl) -2-t-butoxycarbonilamino-3-cyclohexylmethyl thiopropanamide, (
17) N - ((lR) -2-cyclohexylmethyl thio-1- (4- (pyridin-2-yl) piperazin-1-ylcarbonyl) ethyl) carbamic acid t-butyl ester, (
18) N - ((LR) -2-cyclohexylmethylthio-1- (4- (pyridin-4-yl) piperazin-1-ylearbonyl) ethyl) carbamic acid t-butyl ester, (
19) (2R) -N- (4- (morpholin-4-ylmethyl) phenyl) -2-t-butoxycarboni lamino-3-cyclohexymethylthiopropanamide, (N- ((IR) -2-skyhexylmethyl thio-1- (4- phenyl aminopiperidin-1-ylcarbonyl) ethylcarbamic acid t-butyl ester, (21) (2R) -N- (4- (N '-methyl-N' -phenylamino) benzyl) -2-t-butoxycarbomlamino-3-cyclohexylmethyl thiopropanamide, (22) (2R) -N- ((4-methoxyphenyl) amino) -2-t-butoxy carbonylamino-3-cyclohexylmethylthiopropanamide, (23) (2R) -N-amino-N-benzyl-2-t-butoxycarbonylamino-3-cyclohexylmethyl thiopropanamide, (24) (2S) -N- (1-benzylpiperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexy-1-methylthiopropanamide, (25) (2R) -N- (1-benzylpiperidin-4-yl) -2-t-buto i carboni lamino-3-cyclopentylmethylthiopropanamide, (26) - (2R) -N- (1-benzylpiperidin-4-yl) -2-t-butoxycarboni lamino-3-cycloheptylmethylthiopropanamide, (27) (2R) -N- (1-benzylpiperidin-4-yl) -N-meth i 1-2- 1 -butoxycarbonylamino-3-cyclohexy -methylthiopropanamide, (28) (2R) -N- (2-acetoxyethyl) -N- (1-benzylpiperidin-4-yl) -2- t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide, (29) (2R) -N- (1-benzylpiperidin-4-yl) -2-t-butoxycarbonylamino-3-cyclohexylmethylthio-3-methylbutanamide, (30) N- ((IR) -2-cyclohexylmethylthio-1- (4- (N '-benzyl-N' -trifluoroacetylamino) piperidin-1-ylcarbonyl) ethyl) carbamic acid t-butyl ester or (31) N- ((IR) -2-cyclohexylmethyl-ol- (4 - (N '-benzyl-N' -methyl) amino) -peridyl-1-ethylcarbonyl) ethyl) -carbamic acid t-butyl ester, or a non-toxic salt thereof or a hydrate thereof. 12. A compound according to claim 1 or 2, characterized in that it is (1) (2R) -N- (1- (4-methylbenzyl) piperidin-4-yl) -2-t-butoxycarbonylamino-3-hydrohexylmethyl thiopropanamide, (2) 2RS) -N- (1-benzylpiperidin-4-yl) -2-t-butoxy carbonylamino-4-cyclohexylthiobutanamide or (3) (2R) -N- (1-beneylpiperidin-4-yl) -2-t-butoxycarbonyl-3-cyclohexylmethylsulfinylpropanamide, or a non-toxic salt thereof or a hydrate thereof. 13. A compound according to claim 1 or 3, characterized in that it is (1) "(2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (2-phenoxybenzoylamino) propanamide, (2) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (3-phenoxybenzoylamino) propanamide, (3) (2R) -N- (benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (4-phenoxybenzoylamino) propanamide, (4) (2R) -N- (benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (2-t-butoxycarbonylbenzoylamino) propanamide ^ (5) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethyl thio-2- (4-l-butoxycarbonylbenzoylamino) propanamide, (6) (2R) -N- £ l-benzylpiperidin-J-yl) -3-cyclohexylmethylthio-2- (3-t-butoxycarbonylbenzoylamino) propanamide or (7) (2R) -N- (l-benzylpiperidin-4-yl) -3-ciclohexilmetiltio-2- (1-feniIciclohexi Icarbonil amino) propanamide, or a nontoxic salt thereof or a hydrate thereof. 14. A compound according to claim 1 or 4, characterized in that it is (1) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonyl amino) propanamide, (2) (2R) -N- (4-hydroxybenzyl) -3-cyclohexylmethylthio-2- ((2RS) -3- t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propanamide, (3) (2R) -N- (4-hydroxybenzyl) -3-cyclohexylmethyl-2 • ((4R) -3-t-butoxycarbonylthiazolidin-4-hydrocarbonylamino) propanamide, (4) (2R) -N- (l-benzylpiperidin-4-ylmethyl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (5) (2R) -N- (3-hydroxy-4-methoxybenzyl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonyllamino) propanamide, (6) (2R) -N- (1- (4-methoxybenzyl) piperidin-4-ilm_etil) -3-ciclohexilmetiltio-2- ((4R) -3-t-butoxicarboniItiazolidin-4 -i Icarbonil amino) propanamide, (7) (2R) -N-methyl-N- (l-benzylpyrrolidin-3-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl-thiazolidin-4-licarbonylamino) propanamide, (8) (2R) -N- (1- (4-methoxybenzyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonyl amino) propanamide, (9) (2R) -N- (1- (4-methoxybenzoyl) piperidin-4-yl) -3-ciclohexilmetiltio-2- ((4R) -3-t-butoxicarboniltiazolidin-4-ilcarboni lamino) propanamide, (10 ) (2S) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethoxy-2- ((4R) -3- t -butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (11) (2R) -N- (2-benzylaminoethyl) -3-cyclohexylmethylthio-2- ((4R) -3- t -butoxycarbonyl thiazolidin-4-ylcarbonylamino) propanamide, (12) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4-benzylpiperazin-1-ylcarbonyl) ethyl) -3-t-butoxycarbonyl thiazole idinyl-carboxamide, (13) (4R) -N - ((1R) -2-ciclohexilmetiltio-l- (4-di-1-fer lmetilpiperazin i Icarbonil) ethyl?) -3-t-butoxycarbonyl t iazolidin- 4 -ilcarboxamida, (14) (4R) -N- ((IR) -2-ciclohexilmetiltio-l- (4- (4-etoxlfenil) piperazin-1-ylcarbonyl) ethyl) -3-t-4-ylcarboxamide butoxicarboniltiazolidin-, (15) (2R) -N- (1- (4-fluorobenzyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl-thiazolidin-4-ylcarbonyl amino) propanamide, (16; (2R) -N- (1- (4-fluorobenzoyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (17) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4- (pyridin-2-yl) piperazin-1-ylcarbonyl) ethyl) 3-t-butoxy carbonylthiazole idin-4-ylcarboxamide, (18) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4- (pyridin-1-yl) piperazin-1-ylcarbonyl) ethyl) 3-t-butoxycarbonyl thiazole idin-4-ylcarboxamide, (19) (2R) -N- (l-benzylpiperidin-4-yl-3-cyclohexylmethyl thio-2- ((3RS) -4-t-butoxycarbonylthiomorpholin-3-ylcarbonylamino) propanamide, (
20) (2R) -N- (4- (morpholin-4-ylmethyl) phenyl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (
21) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4-phenylaminopiperidin-1-ylcarbonyl) ethyl) -3-t-butoxycarboni Itiazolidin-4-ylcarboxamide, (
22) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4RS) -3-t-butoxycarbonyl-1,3-perhydrothiazin-4-ylcarbonylamino) propanamide, (
23) (2R) -N- (4- (N '-methyl-N' -phenylamino) benzyl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxy carbonylthiazolidin-4-ylcarbonylamino) propanamide, (
24) (2R) -N- ((4-methoxyphenyl) amino) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl-thiazolidin-4-ylcarbonylamino) propanamide, (
25) (2R) -N-amino-N-benzyl-3-cyclohexylmethylthio-2- (4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (
26) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclahexylmethylthio-2- ((4S) -3-t-butoxycarbonylthiazo lidin-4-ylearbonyl amino) propanamide, (
27) (2S) -N- (l-benzylpiperin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (
28) "(2S) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4S) -3-t-butoxycarbonylthiazolidin-4-ylcarbonyl amino) propanamide, (29") (2R) -N- (1-benzylpiper idin-4-yl) -3-cyclopentylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (30) (2R) -N- (1-benzylpiperidin-yl) -3-cycloheptylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (31) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl-5,5-dimethylthiazolidin-4-ylcarbonylamino) propanamide, (32) (2R) -N- (2-acetoxyethyl) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonyl-thiazolidin-4-ylearyl amino) propanamide , (33) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-3-methyl-2- ((4R) -3-t-butoxycarbonyl thiazole idin-4-ylcarboni lamino) butanamide, (34) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4- (N '-benzyl-N' -trifluoroacetylamino) piperidin-1-ylearbonyl) ethyl) -3-t-butoxycarbonyl thiazolidin- 4-Carboxamide, (35) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2RS, 4R) -3-t-butoxycarbonyl-2-methyl ti azo lidin- 4 -carboni lamino) propanamide, (36) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4- (N '-benzyl-N' -methylamino) piperidin-1-yl carbonyl) ethyl) -3-t-butoxycarbonyl iazolidin-4-ylcarboxamide, (37) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (2RS) -3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino) propanamide, (38) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (3-t-butoxycarbonylthi azsl idin-2-ylcarbonylamino) propanamide, (39) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (((4R-3-t-butoxycarbonylthiazolidin-4-ylmethyl) amino) propanamide, (40) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((3-t-butoxycarbonylthiazolidin-2-ylmethyl) amino) propanamide, (41) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethyl thio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (42) (2R) -N- (1-benzylpiperidin-4-methyl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (43) (2R) -N- (1- (4-methoxybenzyl) piperidin-4-ylmethyl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcabonbonyl) propanamide, (44) (2R) -N- (1- (4-methoxybenzyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (45) (2R) -N- (3-hydroxy-4-methoxybenzyl) -3-cyclohexylmethylthio-2- ((4R) -thiazole idin-4-ylcarbonylamino) propanamide, (46) (2R) -N-methyl-N- (l-benzylpyrrolidin-3-yl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (47) (2S) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethoxy-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (48) (2R) -N- (2-benzylaminoethyl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide (49) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4-benzylpiperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide, (50) (4R) -N- ((IR) -2-cyclohexylmethylthio- 1- (4-phenylaminopiperidin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide, (51) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -5,5-dimethylthiazolidin-4-ylcarbonylamino) propanamide, (52) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-3-methyl-2- ((4R) -thiazolinyl-4-ylcarbonylamino) butanamide, (53) (2R) -N- (1- (4-methoxybenzoyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (54) (4R) - N- ((IR) -2-cyclohexylmethylthio-1- (4-diphenylmethylpiperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide, (55) (2R) -N- (1- (4-f-uorobenzoyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (56) (2R) -N- (1- (4-fluorobenzyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (57) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4- (4-methoxy phenyl) piperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide, (58) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4- (pyridin-2-yl) piperazin-1-ylcarbonyl) ethyl) thiazolidin-4-ylcarboxamide, (59). (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4- (pyridin-4-yl) piperazin-1-ylcarbonyl) ethyl) thiazolidin-4-yl carboxamide, (60) (2R) -N- (4- (morpholin-4-ylmethyl) phenyl) -3-cyclohexylmethyl thio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (61) (2R) -N- (4- (N '-methyl-N' -phenylamino) benzyl) -3-cyclohexylmethylthio-2- ((4R) -thiazolidin-4-ylcarbonylamino) propanamide, (62) (2R) -N-amino-n-benzyl-3-cyclohexylmethylthio-2- ((4R) -thiazole idin-4-ylcarbonylamino) propanamide, (63) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (((4R) -thiazolidin-4-ylmethyl) amino) propanamide, X (64) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-isopropyloxycarbonyl thiazole idin-4-alkylcarbonylamino) propanamide, (65) (2R) -N- (1-benzylpiperidin-4-yl) -N-methyl-3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonyl amino) propanamide, (66) (2R) -N- (1-benzylpiperi din-4-yl) -3-cyclohexylmethylthio-2- ((4R) -2,2-dimethylthiazolidin-4-ylcarbonylamino) propanamide, (67) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2S, 4S) -1-t-butoxycarbonyl-4-fluoropyrrolidin-2-ylcarbonylamino) propanamide, (68) (2R) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethyl-2- ((2S) -l-t-butoxycarbonyl-4, 4-difluoropyridine lidin-2-licarbonylamino) propanamide, (69) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3- (2-methylpropoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (70) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethyl thio-2- ((4R) -3-methoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (71) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R-3-pivaloyl thiazolidin-4-ylcarbonylamino) propanamide, (72) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3- (3-methylbutyryl) ti azo lidin-4-ylcarboni lamino) propanamide, (73) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3- (2-methopropionyl) thiazolidin-4-ylcarbonylamino) propanamide, (74) (2R) -N- (2-hydroxyethyl) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (75) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4-benzylaminopiperidin-1-ylcarbonyl) ethyl) -3-butoxycarbonylthiazolidin-4-ylcarboxamide or (76) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (((4R) -3- (3-methylbuturyl) thiazolidin-methyl) -amino) propanamide, or a non-toxic salt thereof or a hydrate thereof. 15. A compound according to claim 1 or 4, characterized in that it is (1) 2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (2S) -lt-butoxycarbonyl-1,2,3,6-tet ahydropyridin din-2-licarbonylamino propanamide, (2) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2S) -1-t-butoxycarbonylpiperidin-2-ylcarbonyl amino) propanamide, (3) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4S) -3-t-butoxycarbonyloxazolidin-4-ylcarbonylamino) propanamide, (4) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2S) -1-t-butoxycarbonylpyrrolidin-2-ylcarbonylamino) propanamide, (5) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((2S, 4RS) -l-t-butoxycarbonyl-4-methyltiopyrrolidin-2-ylcarbonyllamino) propanamide, (6) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethyl thio-2- ((3S) -4- t-butoxycarbonylmorpholin-3-ylcarbonylamino) propanamide, (7) __ (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- (3-t-butoxycarbonyl thio-4-ylcarbonylamino) propanamide, (8) (2R) -N- (1- (4-methylbenzyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) propanamide (9) (2RS) -N- (1-beneylpiperidin-4-yl) -4-cyclohexylthio-2- ((4R) -3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino) butanamide, (10) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylsulphinyl-2- ((4R) -3-t-butoxycarbonylthiazo lidin-4-ylcarbonyl amino) propanamide, (11) (2S) -N- (l-benzylpiperidin-4-yl) -3-cyclohexylmethoxy-2- ((4S) -3- t -butoxycarbonylloxazolidin-4-ylearbonyl amino) propanamide, (12) (2R) -N- (2-benzylaminoethyl) -3-cyclohexylmethylthio-2- ((4R) -3-isopropyloxycarbonylthiazolidin-4-ylcarbonylamino) propanamide, (13) (2R) -N- (2-benzylaminoethyl) -3-cycloh-exylmethylthio-2- ((4R) -3- (3-methylbutyryl) thiazolidin-4-ylcarbonylamino) propanamide, (14) (2R) -N- (1- (4-hydroxybenzyl) piperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -3-t-butsxycarbonylthiazolidin-4-ylcarbonyl amino) propanamide, (15) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4-benzylaminopiperidin-1-ylcarbonyl) ethyl) -3- (3-methylbutyryl) ti azol idin- -lcarboxamide, (16) (4R) -N- ((IR) -2-cyclohexylmethylthio-1- (4-benzylaminopiperidin-1-ylcarbonyl-9-ethyl) -3-isopropyloxycarbonyl thiazole idin-4-l-carboxcarboxamide or (17) (2R) -N- (1-benzylpiperidin-4-yl) -3-cyclohexylmethylthio-2- ((4R) -2,2-dimethyl-3- (3-methylbutyryl) thiazolidin-4-ylcarbonylamino) propanamide, or a non-toxic salt thereof or a hydrate thereof. 16. A pharmaceutical composition characterized in that it comprises, as an active ingredient, a derivative of the formula (I) described in claim 1, a non-toxic salt thereof or a hydrate thereof. 17. An N-type calcium channel inhibitor characterized in that it comprises, as an active ingredient, an amino acid derivative of the formula (I) described in claim 1, a non-toxic salt thereof or a hydrate thereof. 18. A pharmaceutical composition, characterized in that it prevents and treats cerebral infarction, transient ischemic attack, encephalomyelitis after cardiac surgery, spinal angiopathy, hypertension with stress, neurosis, epilepsy, asthma and pollakiuria, which comprises as an active ingredient, an amino acid derivative of the formula (I) described in claim 1, a non-toxic salt thereof or a hydrate thereof. 19. A pharmaceutical composition, characterized in that it treats pain, comprising as an active ingredient an amino acid derivative of the formula (I) described in claim 1, a non-toxic salt thereof or a hydrate thereof.
MXPA/A/2000/012599A 1998-06-26 2000-12-15 Amino acid derivatives and drugs containing the same as the active ingredient MXPA00012599A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP10/195125 1998-06-26

Publications (1)

Publication Number Publication Date
MXPA00012599A true MXPA00012599A (en) 2001-07-31

Family

ID=

Similar Documents

Publication Publication Date Title
AU759488B2 (en) Amino acid derivatives and drugs containing the same as the active ingredient
RU2607045C2 (en) Benzylamine derivatives as inhibitors of plasma kallikrein
DE69833858T2 (en) AMINO ACID DERIVATIVES
EP0445796B1 (en) Derivatives of acetic acid containing peptide bonds
US7820673B2 (en) Urea derivative, process for producing the same, and use
KR100662309B1 (en) Melanocortin Receptor Ligand
JPH02223543A (en) New benzoic acid derivative, phenylacetic acid deriative, preparation of them, and pharmaceutical formulation containing them
KR20040084945A (en) Cell adhesion inhibitors
MXPA05004378A (en) 2 - alkyl - (2 - amino - 3 - aryl - propionyl) - piperazine derivatives and related compounds as melanocortin receptor ligands for the treatment of obesity.
HU222498B1 (en) N-Acyl alpha-amino acid derivatives, pharmaceutical compositions containing them, process for their preparation and intermediates
JP2004513063A (en) Cell adhesion inhibiting anti-inflammatory and immunosuppressive compounds
JPWO2000000470A1 (en) Amino acid derivatives and drugs containing them as active ingredients
CA2157792C (en) N-(3-piperidinyl-carbonyl)-beta-alanine derivatives as paf antagonists
EP0858262B1 (en) Thrombin inhibitors
KR100633349B1 (en) Amino acid derivatives and drugs containing them as active ingredients
MXPA00012599A (en) Amino acid derivatives and drugs containing the same as the active ingredient
JP4214524B2 (en) Amino acid derivatives and drugs containing them as active ingredients
KR100522012B1 (en) Amino acid derivatives
JPWO2000004005A1 (en) Amino acid derivatives and drugs containing them as active ingredients