JP2001089498A - Prodrug of thrombin inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a prodrug comprising an inhibitor of a trypsin-like serine protease such as thrombin especially for the treatment of symptom necessitating the inhibition of thrombin (e.g. thrombosis). SOLUTION: The objective prodrug is composed of a compound of formula R1O(O)C-CH2-(R)CgI-Aze-Pab-R2 [R1 is R3, A1C(O)N(R4)R5 or A1C(O)OR4; A1 is a 1-5C alkylene; R2 (substituting with one hydrogen atom of amidino unit of Pab-H) is OH, OC(O)R6, C(O)OR7 or C(O)OCH(R8)OC(O)R9; R3 is H, a 1-10C alkyl or the like; R4 and R5 are each independently H, a 1-6C alkyl, phenyl or 2-naphthyl; R6 is a 1-17C alkyl, phenyl or 2-naphthyl which may have substituents; R7 is 2-naphthyl, phenyl, a 1-3C alkylphenyl or the like which may have substituents; R8 is H or a 1-4C alkyl; R9 is 2-naphthyl, phenyl, a 1-6C alkoxy or the like] or its pharmacologically permissible salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to the use of pharmaceutically useful prodrugs of pharmaceutically active compounds whose active compounds are in particular antagonists of trypsin-like serine proteases, especially thrombin, the use of prodrugs as medicaments, The present invention relates to a pharmaceutical composition containing them, and a method for producing them.

[0002]

BACKGROUND OF THE INVENTION Blood clotting is a major implicated in hemostasis (i.e., prevention of blood loss from damaged blood vessels) and thrombosis (i.e., formation of blood clots in blood vessels, sometimes resulting in occlusion of blood vessels). Process. Coagulation results from a complex series of enzymatic reactions. One of the basic steps in this series of reactions is the conversion of the proenzyme prothrombin to the active enzyme thrombin. Thrombin is known to play a central role in coagulation. It activates platelets resulting in platelet aggregation, spontaneously polymerizes fibrinogen to fibrin monomers to become fibrin polymers, and activates factor XIII, which crosslinks the polymer to produce insoluble fibrin. In addition, thrombin activates factor V and factor VIII, resulting in "positive feedback" production of thrombin from prothrombin. By inhibiting platelet aggregation and fibrin formation and crosslinking, effective inhibitors of thrombin are expected to exhibit antithrombotic activity. In addition, antithrombotic activity is expected to be enhanced by effectively inhibiting the positive feedback mechanism.

[0003]

BACKGROUND OF THE INVENTION The development of low molecular weight thrombin inhibitors has
Claesson's "Blood Clotting Fibrin", 5, 411 (1994
Year). Blomback et al., J. Clin. Lab. In
vest. 24 , Suppl. 107, 59 (1969) discloses a thrombin inhibitor based on an amino acid sequence located near the cleavage site of fibrinogen Aα chain. These authors suggested that the tripeptide sequence Phe-Val-Ar
g suggests that it is the most effective inhibitor.

[0004] Low molecular weight peptide-based thrombin inhibitors are subsequently disclosed, for example, in US Patent No. 4,346,078;
O 93/11152, WO 94/29336, WO 93/18060 and WO
95/01168; and European patent applications 648 780, 468 231, 559
046, 641 779, 185 390, 526 877, 542 525, 195 21
2, 362 002, 364 344, 530 167, 293 881, 686 642 and 601 459.

More recently, thrombin inhibitors based on peptide derivatives have been disclosed in European Patent Application 0 669 317, International Patent Application WO
95/23609, WO 95/35309, WO 96/25426 and WO 94 /
29336. In particular, the latter application discloses the peptide derivative R ^a OOC-CH _2- (R) Cgl-Aze-Pab-H, where R ^a is H, benzyl or C _1-6 alkyl.

[0006] Although these active compounds are known to exhibit significant antithrombin activity, it is beneficial to improve their pharmacokinetic properties after oral and parenteral administration. Examples of pharmacokinetic properties that are desired to be improved include the following: (a) gastrointestinal for the purpose of reducing internal and / or reciprocal, individual variability with respect to the bioavailability of the active compound; (B) plasma concentration time to reduce the risk of being out of treatment and side effects (eg, bleeding) caused by too high a peak concentration and side effects (eg, thrombus formation) caused by too low a peak concentration; Flatten the profile (ie, reduce the peak / min ratio of plasma concentration during the administration period); and (c) increase the duration of action of the active compound.

[0007] In addition, oral and parenteral administration of active thrombin inhibitors at high local concentrations (eg, in the intestinal lumen or subcutaneously) cause undesirable local bleeding.

Finally, active orally administered thrombin inhibitors, which also inhibit trypsin and other serine proteases in the gastrointestinal tract, are useful for inhibiting digestive disorders (eg, when trypsin is inhibited in the intestinal lumen). Shows other side effects.

Certain N-benzyloxycarbonyl derivatives of the above active compounds are disclosed as thrombin inhibitors in International Patent Application WO 94/29336, but it is stated that these derivatives are useful as prodrugs. Absent. In fact, WO 94/29336 makes no mention of suitable prodrugs of the active compounds.

The inventors have found that the above-mentioned problems are solved by administering the compounds according to the invention. The compounds of the present invention are inert per se and are metabolized in the body by oral and / or parenteral administration to produce active thrombin inhibitors, such as the compounds described above.

[0011]

DISCLOSURE OF THE INVENTION According to the present invention, a compound of the formula I R¹O (O) C-CH_Two-(R) Cgl-Aze-Pab-R^Two (I) [wherein, R¹Is -R^Three, -A¹C (O) N (R^Four) R^FiveOr -A¹C (O) OR^Fourso
Yes; A¹Is C_1-5R is alkylene;^Two(Amidino unit of Pab-H
OH, OC (O) R⁶, C (O) OR⁷
Or C (O) OCH (R⁸) OC (O) R⁹And R^ThreeIs H, C_1-10Al
Kill or C_1-3Alkylphenyl (the latter group may be
C _1-6Alkyl, C_1-6Alkoxy, nitro or halogen
R)^FourAnd R^FiveIndependently
H, C_1-6Alkyl, phenyl and 2-naphthyl;
Or R¹But -A¹C (O) N (R^Four) R^FiveIf they are joined
Pyrrolidinyl or pipette together with the nitrogen atom
Represents lysinyl; R⁶Is C_1-17Alkyl, phenyl or
2-naphthyl (these are all optionally C_1-6Alkyl
Or substituted by halogen); R⁷Is 2-na
Futyl, phenyl, C_1-3Alkylphenyl (the latter three
Is optionally C_1-6Alkyl, C_1-6Alkoxy, Nito
B) or C)_1-12A
Lequil (the latter group may be C_1-6Alkoxy, C_1-6A
Substituted by siloxy or halogen);
R⁸Is H or C_1-4Alkyl; and R⁹Is 2-naph
Chill, phenyl, C_1-6Alkoxy or C_1-8Alkyl
(The latter group may optionally be halogen, C_1-6Alkoxy or
Is C_1-6Substituted by acyloxy). However,
R¹Is R^ThreeAnd R^ThreeIs benzyl, methyl, ethyl, n-butyl
Tyl or n-hexyl; and R^TwoIs C (O) OR⁷so
If so, R⁷Is not benzyl. ] Or the compound
Pharmaceutically acceptable salts (hereinafter referred to as "the compound of the present invention")
Are provided.

The compounds of the present invention may exhibit tautomerism. All tautomers and mixtures thereof are included in the scope of the present invention.

The compounds of the present invention may also contain one or more asymmetric carbon atoms and exhibit optical and / or diastereoisomerism. All diastereomers can be separated by conventional methods, for example, chromatography or fractional crystallization. The various stereoisomers can be isolated by separating the racemic or other mixtures of the present compounds by conventional means, for example by fractional crystallization or HPLC. Alternatively, the desired optical isomer can be prepared by reacting the appropriate optically active starting material under conditions that do not racemize or epimerize, or can be derivatized, for example, with a homochiral acid, to give the diastereomeric derivative. (For example, HPLC, chromatography on silica).
All stereoisomers are included in the scope of the present invention.

According to another aspect of the present invention there is provided the use of a compound of formula I as defined above, except for proviso, as a prodrug.

The alkyl groups represented by R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁹ are straight-chain or branched when there is a sufficient number of carbon atoms, cyclic or partially cyclic. Cyclic, saturated or unsaturated, interrupted by oxygen, and / or substituted or terminated by OH, provided that the OH group is SP ²
Does not bond to a carbon atom adjacent to a carbon atom or an oxygen atom. “Partially cyclic alkyl group” means a group such as CH ₂ Ch.

The alkyl group represented by R ⁸ , R ³ , R ⁶ and R ⁷ are substituted, straight-chain or branched if there is a sufficient number of carbon atoms, saturated or unsaturated, and // interrupted by oxygen. The alkyl part of the alkylphenyl group represented by R ³ and R ⁷ is straight-chain or branched if there is a sufficient number of carbon atoms, and / or is saturated or unsaturated. The alkylene group represented by A ¹ is linear or branched when there is a sufficient number of carbon atoms,
And / or saturated or unsaturated. The alkoxy group denoted by R ⁹ , R ³ , R ⁷ and R ⁹ are substituted, straight-chain or branched if there is a sufficient number of carbon atoms, and / or saturated or unsaturated. The acyloxy group represented by R ⁷ and R ⁹ is substituted, straight-chain or branched if there is a sufficient number of carbon atoms, and / or saturated or unsaturated. Abbreviations are described at the end of the specification.

According to another aspect of the invention, (a) R ¹ is not —A ¹ C (O) OR ⁴ ; (b) R ⁴ and R ⁵ are not independently H; (c) When R ² is OC (O) R ⁶ , R ⁶ is not C _1-17 alkyl; Formula I as defined above with the additional proviso that
Are provided.

According to another aspect of the invention: (a) R ¹ is —A ¹ C (O) OR ⁴ ; (b) R ⁴ and R ⁵ are independently H; (c) When R ² is OC (O) R ⁶ , there is provided a compound of formula I, wherein R ⁶ is C _1-17 alkyl.

[0019] When R ¹ is ^{-A 1 C (O) N (} R 4) R 5, preferred compounds of the present invention is an A ¹ is C _1-3 alkylene; R ⁴ is H
Or C _1-6 alkyl; R ⁵ is C _1-6 alkyl or C
_A compound that is _4-6 cycloalkyl, or R ⁴ and R ⁵
Are together pyrrolidinyl.
When R ¹ is —A ¹ C (O) OR ⁴ , preferred compounds of the present invention include those wherein A ¹ is C _1-5 alkylene; and R ⁴ is C _1-6 alkyl. When R ¹ is R ³ , preferred compounds of the invention include those wherein R ³ is H, C _1-10 alkyl (the latter group is straight-chain or branched if there is a sufficient number of carbon atoms. And / or partially cyclic or cyclic), or C _1-3 alkylphenyl (the latter group is optionally substituted and straight-chain or branched when there is a sufficient number of carbon atoms) ) Is included.

In preferred compounds of the present invention, R ² is OH, OC
(O) R ⁶ (in the latter group, R ⁶ is optionally substituted phenyl or C _1-17 alkyl (the latter group is straight-chain or branched if there is a sufficient number of carbon atoms, , Cyclic or partially cyclic and / or saturated or unsaturated), C (O) OR ^7, wherein R ⁷ is optionally substituted phenyl, C _1-12 alkyl ( The latter group is optionally substituted, straight-chain or branched if there is a sufficient number of carbon atoms, cyclic or partially cyclic, and / or saturated or unsaturated),
Or C _1-3 alkylphenyl (the latter group is optionally substituted and is straight-chain or branched if there is a sufficient number of carbon atoms), or C (O) OCH (R ⁸ ) OC (O) R
⁹ (where R ⁸ is H or methyl, and R ⁹ is phenyl or C _1-8 alkyl (the latter group is optionally substituted and may be substituted if straight chain or with a sufficient number of carbon atoms) Which are branched and / or cyclic or partially cyclic).

The compounds of the more preferred the present invention [0021], R ¹ is H, linear C _1-10 alkyl, branched C _{3- 10} alkyl, partially cyclic C _4-10 alkyl, C _4-10 Cycloalkyl, optionally substituted linear C _1-3 alkylphenyl, optionally substituted branched C ₃ alkylphenyl, -A ¹ C (O) N (R
⁴ ) R ⁵ wherein A ¹ is C _1-3 alkylene, R ⁴ is H or C _1-3 alkyl, and R ⁵ is C _2-6 alkyl or
C _5-6 cycloalkyl, or R ⁴ and R ^{5 taken} together are pyrrolidinyl), or —A ¹ C (O) OR ^4, wherein A ¹ is C _1-5 alkylene; And R ⁴ is C _1-4 alkyl); R ² is OH, OC (O) R ⁶ (in the latter group, R ⁶ is optionally substituted phenyl, linear C _1-4
Alkyl, branched C _3-4 alkyl or cis-oleyl), C (O) OR ^7, wherein R ⁷ is optionally substituted,
And / or optionally unsaturated linear C _1-4 alkyl; optionally substituted and / or optionally unsaturated branched C _3-4 alkyl; optionally substituted phenyl, optionally substituted A linear C _1-3 alkylphenyl, or an optionally substituted branched C ₃ alkylphenyl), or C (O) OCH (R ⁸ ) OC (O) R ^9, wherein R ⁸
Is H or methyl, and R ⁹ is phenyl, C _5-7 cycloalkyl, linear C _1-6 alkyl, branched C _3-6 alkyl or partially cyclic C _7-8 alkyl ) Is included.

Particularly preferred compounds of the invention are those wherein R ¹ is linear C _1-6 alkyl, C _6-10 cycloalkyl, or optionally substituted linear C _1-3 alkylphenyl;
R ² is OH, OC (O) R ⁶ (in the latter group, R ⁶ is a linear C _1-3
Alkyl or branched C ₃ alkyl), C (O) OR
⁷ (wherein, R ⁷ linear C _{1 -3} alkyl substituted phenyl branched C _3-4 alkyl optionally substituted, optionally linear C _1-4 alkyl substituted optionally by case Or branched C ₃ alkylphenyl), or C (O) OCH (R ⁸ ) O
C (O) R ⁹ (wherein, R ⁸ is H, and R ⁹ is C _5-7 cycloalkyl, linear C _{1 -6} alkyl or partially cyclic C
_7-8 alkyl). R ¹ is R ³
Where R ³ is optionally substituted C _1-3 alkylphenyl, preferred optional substituents are C _1-6 alkyl
(Especially methyl). When R ² is C (O) OR ⁷ and R ⁷ is optionally substituted C _1-12 alkyl, preferred optional substituents are halogen (especially chloro) and C _1-6 alkoxy (especially methoxy) ) Is included. When R ² is C (O) OR ⁷ and R ⁷ is optionally substituted phenyl,
Preferred optional substituents include C _1-6 alkyl (especially methyl), C _1-6 alkoxy (especially methoxy) and halogen (especially chloro). When R ² is C (O) OR ⁷ and R ⁷ is optionally substituted C _1-3 alkylphenyl, preferred optional substituents include nitro.

Preferred compounds of the invention include Examples 1-6
8 compounds. More preferred compounds of the invention include EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ ; nPrOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ ; tBuOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ ; EtOOCCH _2- (R) Cgl-Aze-Pab-COOEt; EtOOCCH _2- (R) Cgl-Aze-Pab-COO-nBu; PrlC (O) CH ₂ CH ₂ CH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z; ChNHC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z; (nPr) ₂ NC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOCC (C
_{H 3) 3; EtOOCCH 2 -} (R) Cgl-Aze-Pab-COOCH 2 OOCC (CH 3) 3; EtOOCCH 2 - (R) Cgl-Aze-Pab-COOCH (CH 3) OOCCH 3; MeOOCCH 2 - ( R) Cgl-Aze-Pab-OOCPh; MeOOCCH _2- (R) Cgl-Aze-Pab-OH; EtOOCCH _2- (R) Cgl-Aze-Pab-OH; BnOOCCH _2- (R) Cgl-Aze-Pab- OH; nPrOOCCH _2- (R) Cgl-Aze-Pab-Z; nPrOOCCH _2- (R) Cgl-Aze-Pab-OH; iPrOOCCH _2- (R) Cgl-Aze-Pab-OH; tBuOOCCH _2- (R) (NPr) ₂ NCOCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-OH; ChNHCOCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-OH; EtOOCCH _2- (R) Cgl-Aze-Pab-OAc; HOOCCH _2- (R) Cgl-Aze-Pab-OH; HOOCCH _2- (R) Cgl-Aze-Pab-O-cis-oleyl; Cyclooctyl-OOCCH _2- (R) Cgl -Aze-Pab-Z; tBuCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z; (2-Me) BnOOCCH _2- (R) Cgl-Aze-Pab-Z; ChCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z; ChOOCCH 2 - (R) Cgl-Aze-Pab-Z; PhC (Me) 2 OOCCH 2 - (R) Cgl-Aze-Pab-Z; (Me) 2 CHC (Me) 2 OOCCH _2- (R) Cgl-Aze-Pab-Z; BnOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-OMe); ChCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-COOPh (4 -OMe); (2-Me) BnOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-OMe); EtOOCCH ₂ -(R) Cgl-Aze-Pab-COOPh (4-Me); BnOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-Me); BnOOCCH _2- (R) Cgl-Aze-Pab-COO- nBu; iPrOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ ; EtOOCCH _2- (R) Cgl-Aze-Pab-COO-iBu; BnOOCCH _2- (R) Cgl-Aze-Pab-COO _{-nPr; EtOOCCH 2 - (R)} Cgl-Aze-Pab-COOCH 2 OOCCh; EtOOCCH 2 - (R) Cgl-Aze-Pab-COOCH 2 OOCCH 2 Ch; EtOOCCH 2 - (R) Cgl-Aze-Pab-COOCH (Me) OOCPh; EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOCPh; BnOOCCH _2- (R) Cgl-Aze-Pab-COOCH (Me) OAc; EtOOCCH _2- (R) Cgl-Aze-Pab -COOCH ₂ OAc; tBuOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OAc; MeOOC-C (= CHEt) CH ₂ -OOCCH _2- (R) Cgl-Aze-Pab-Z; Men-OOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-OMe); and EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CCl ₃ .

Particularly preferred compounds of the present invention include: EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CCl ₃ ; BnOOCCH _2- (R) Cgl-Aze-Pab-COOnBu; nPrOOCCH _2- (R) Cgl -Aze-Pab-Z; cyclooctyl-OOCCH _2- (R) Cgl-Aze-Pab-Z; EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOCCh; MeOOCCH _2- (R) Cgl-Aze- Pab-OH; EtOOCCH _2- (R) Cgl-Aze-Pab-OH; nPrOOCCH _2- (R) Cgl-Aze-Pab-OH; iPrOOCCH _2- (R) Cgl-Aze-Pab-OH; BnOOCCH _2- ( R) Cgl-Aze-Pab- OH; and EtOOCCH ₂ - (R) include Cgl-Aze-Pab-OAc.

[Production] According to the present invention, (a) R ² is
(O) a R ^6, and the presence of the corresponding compound of formula I R ⁶ is as defined above with an alkoxide base (eg an alkali metal alkoxide), for example a suitable organic solvent (e.g. THF), R ² is O by reaction at room temperature
Preparation of a compound of formula I is H, (b) R ² is C (O) OR ^7, and the compound of formula I the corresponding R ⁷ is as defined above or a hydroxyl acid addition salt thereof R ² is reacted with an amine at room temperature, for example, in the presence of a suitable base (eg, potassium carbonate or triethylamine) and a suitable organic solvent (eg, THF or EtOH).
(C) the corresponding compound of formula II H- (R) Cgl-Aze-Pab-R ² (II), wherein R ² is as defined above. Having the formula III R ¹ O (O) C—CH ₂ —L ¹ (III), wherein L ¹ is a leaving group, such as a halide (eg, bromide) or an alkylsulfonate (eg, trifluoromethylsulfonate); And R ¹ is as defined above) and a suitable base (eg, potassium carbonate) and a suitable organic solvent (eg, THF, D
MF or acetonitrile) to produce a compound of formula I by reacting at room temperature to an elevated temperature (eg, 40 ° C.)
(d) The corresponding compound of formula I wherein R ¹ is C _1-10 alkyl or C _1-3 alkylphenyl and R ² is OH or C (O) OR ⁷ is converted to a suitable base (eg, an alkali metal alkoxide). Or hydroxide, for example, by reaction at room temperature in the presence of a suitable organic solvent (eg, water or MeOH), wherein R ¹ is H, R ² is OH or C (O) OR ⁷ , and R
Preparation of a compound of formula I wherein ⁷ is as defined above,
(e) converting a corresponding compound of formula I wherein R ² is OH to a compound of formula IV R ⁶ C (O) —OC (O) R ⁶ (IV), wherein R ⁶ is as defined above. Or a compound of formula VR ⁶ C (O) Hal (V), wherein Hal is Cl or Br and R ⁶ is as defined above, for example with a suitable base (eg, triethylamine in the presence of pyridine or DMAP) and an appropriate organic solvent (e.g. methylene or THF chloride), R ² is OC (O) R ⁶ by reacting at room temperature,
And preparation of a compound of formula I wherein R ⁶ is as defined above; (f) the corresponding formula VI P ¹ O (O) C-CH _2- (R) Cgl-Aze-Pab-R ² Wherein P ¹ is an acid-labile ester protecting group (eg, tBu
Or Bn) wherein R ² is OC (O) R ⁶ and R ⁶ is as defined above) with a suitable acid (eg, TFA), eg, a suitable organic solvent (eg, Preparation of a compound of formula I wherein R ¹ is H, R ² is OC (O) R ⁶ and R ⁶ is as defined above by reacting at room temperature in the presence of methylene chloride) , (G) the corresponding formula VII R ^1a O (O) C-CH _2- (R) Cgl-Aze-Pab-R ² (VII) (wherein R ^1a is a C _1-10 alkyl other than that to be formed) Or
A C _1-3 alkylphenyl group, and R ² is as defined above or is an labile alkyl substituent) under the conditions well known to those skilled in the art. R ¹ is R ³ , R ³ is C _1-10 alkyl or C _1-3 alkylphenyl, R ² is OH or C (O) OR ⁷ and R ⁷ is defined above There is also provided a process for the preparation of a compound of Formula I, comprising the preparation of a compound of Formula I as described.

Compounds of formula II are well known to those skilled in the art for compounds of formula VIII Boc- (R) Cgl-Aze-Pab-R ² (VIII), wherein R ² is as defined above. It can be produced by deprotection under the conditions specified.

Compounds of formulas VI and VII are those wherein R ¹ is R ³ ;
It can then be prepared analogously to the method described above for the preparation of compounds of formula I wherein R ³ is C _1-10 alkyl or C _1-3 alkylphenyl.

The compound of formula VIII is a compound of formula IX H-Pab-R ² (IX), wherein R ² is as defined above.
It is prepared by reacting with Boc-Cgl-Aze-OH at room temperature, for example, in the presence of a suitable coupling agent (eg, EDC), a suitable base (eg, DMAP) and a suitable organic solvent (eg, dichloromethane or acetonitrile). be able to.

Compounds of formula VIII where R ² is OH are of the corresponding formula
VIII wherein R ² is C (O) OR ⁷ or C (O) OCH (R ⁸ ) OC (O) R ⁹ or an acid addition salt thereof with hydroxylamine, such as a suitable base ( For example, it can be produced by reacting at room temperature in the presence of potassium carbonate or triethylamine) and a suitable organic solvent (for example, THF or EtOH).

Compounds of formula VIII wherein R ² is C (O) OR ⁷ or C (O) OCH (R ⁸ ) OC (O) R ⁹ are obtained by converting Boc- (R) Cgl-Aze-Pab-H to a compound of formula X L ² C (O) OR ^2a (X) wherein L ² is a leaving group (eg, halogen or phenolate) and R ^2a is R ⁷ or —CH (R ⁸ ) OC (O) R ⁹ And R ⁷ , R ⁸ and R ⁹ are as defined above) and a temperature below room temperature, for example, in the presence of a suitable base (eg, NaOH) and a suitable organic solvent (eg, THF). To produce the compound.

Alternatively, a compound of formula VIII wherein R ² is OC (O) R ⁶ may be substituted by a corresponding compound of formula VIII wherein R ² is OH or a compound of formula IV as defined above or It can be prepared by reacting with a compound of formula V as defined, for example, at room temperature in the presence of a suitable base (eg triethylamine, pyridine or DMAP) and a suitable organic solvent (eg methylene chloride or THF). .

Alternatively, compounds of formula VIII where R ² is OC (O) R ⁶ can be obtained by converting Boc- (R) Cgl-Aze-Pab-H to formula XI R ⁶ C (O) -OOC (O) R ⁶ (XI) (wherein R ⁶ is as defined above), for example, by reaction at room temperature in the presence of a suitable organic solvent (eg, THF).

Compounds of formula VIII where R ² is OH are of the corresponding formula
A compound of formula VIII wherein R ² is OC (O) R ⁶ and R ⁶ is as defined above, is reacted with a suitable base (eg, an alkali metal alkoxide), for example, in a suitable solvent (eg, (THF) at room temperature.

Compounds of formula IX are well known in the literature,
Further, it can be manufactured in the same manner as in the above method. For example, R ² is C (O) OR ⁷ or C (O) OCH (R ⁸ ) OC (O) R ⁹ ,
And a formula wherein R ⁷ , R ⁸ and R ⁹ are as defined above
The compound of IX may be prepared by combining H-Pab-H or a protected derivative thereof with a compound of formula X as defined above, for example, in the presence of a suitable base (eg, NaOH) and a suitable organic solvent (eg, THF) at room temperature or below. By reacting at a temperature of

Boc- (R) Cgl-Aze-Pab-H is prepared by reacting H-Pab-H or a protected derivative thereof with Boc-Cgl-Aze-OH, for example as described above for compounds of formula VIII. can do.

Alternatively, Boc- (R) Cgl-Aze-Pab-H has the formula XI
Deprotect the compound of I Boc- (R) Cgl-Aze-Pab-P ² (XII), wherein P ² is a protecting group orthogonal to Boc, under conditions well known to those skilled in the art. It can be manufactured by the following.

The compounds of formulas III, IV, V, X, XI and XII are all commercially available and well known in the literature,
Further, it can be produced using a known method (for example, a method described later). The compounds of the present invention can be isolated from their reaction mixtures using conventional methods.

Those skilled in the art will understand that in the above method, the functional group of the intermediate compound must be protected by a protecting group. Functional groups that are desirable to protect include hydroxy, amino, amidino and carboxylic acids. Suitable hydroxy protecting groups include trialkylsilyl and diarylsilyl groups (eg, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), and tetrahydropyranyl. Suitable carboxylic acid protecting groups include C _1-6 alkyl or benzyl esters. Suitable amino and amidino protecting groups include t-butyloxycarbonyl or benzoyloxycarbonyl. The amidino nitrogen can be mono- or di-protected.

Protecting groups can be prepared by methods well known to those skilled in the art,
For example, it can be removed according to the method described below. The use of protecting groups is described in detail in "Protecting Groups for Organic Chemistry", edited by JWFMcOmie, Plenum Press (1973) and "Protecting Groups for Organic Synthesis", 2nd Edition, TWGreene & PGMWutz, Willie Interscience (1991). ing.

[Medical and Pharmaceutical Uses] The compounds of the present invention are useful because they are metabolized in the body to produce compounds having pharmacological activity. Thus, they are suitable as drugs, especially as prodrugs. In particular, the compounds of the invention are inactive to thrombin itself, but metabolize in the body to produce potent thrombin inhibitors, as demonstrated, for example, by the tests described below.

By "the compounds of the invention are inert to thrombin itself" it is meant that they show a value of more than 1 μM with respect to the IC ₅₀ TT as determined in test A below. Therefore, the compounds of the present invention are expected to be useful in conditions requiring inhibition of thrombin. Accordingly, the compounds of the present invention find application in the therapeutic and / or prophylactic treatment of thrombosis and hypercoagulability in the blood and tissues of animals, including humans.

It is known that hypercoagulability leads to thromboembolism. Examples of thromboembolism include activated protein C resistance, such as factor V-mutation (factor V Leiden) and antithrombin III, protein C,
Genetic or acquired deficiency of protein S, heparin cofactor II. Other conditions known to be associated with hypercoagulability and thromboembolism include circulating antiphospholipid antibodies (anticoagulant lupus), homocysteinemia, heparin-induced thrombocytopenia and fibrinolysis. Includes defects. Accordingly, the compounds of the present invention find application in the therapeutic and / or prophylactic treatment of these conditions.

In addition, the compounds of the present invention have application in the treatment of conditions in neurodegenerative diseases such as Alzheimer's disease, where there is an undesirable excess of thrombin without signs of hypercoagulability.

Examples of specific disease applications include venous thrombosis, pulmonary embolism, arterial thrombosis (eg in myocardial infarction, unstable angina, thrombosis-based stroke and peripheral arterial thrombosis). And the therapeutic and / or prophylactic treatment of systemic embolism of the left ventricle after atrial or transmural myocardial infarction, usually during atrial fibrillation.

In addition, the compounds of the present invention may be used to prevent reocclusion after thrombolysis (ie, thrombosis), percutaneous transluminal angioplasty (PTA) and coronary artery bypass surgery; microsurgery; It is expected to be useful in preventing rethrombosis.

Other applications include therapeutic and / or prophylactic treatment of sporadic intravascular coagulation caused by bacteria, multiple trauma, poisoning or other mechanisms; blood is used in the body for vascular grafts, vascular stents, vascular catheters. Anticoagulant treatment when in contact with foreign surfaces, such as mechanical and biological prosthetic valves or other pharmaceutical devices; and during extracorporeal blood, for example during cardiovascular surgery using cardiopulmonary machinery or hemodialysis And anti-coagulation treatment when in contact with a therapeutic device.

In addition to its action in the coagulation process, thrombin is known to activate many cells, such as neutrophils, fibroblasts, endothelial cells and smooth muscle cells. Accordingly, the compounds of the present invention may also be used for idiopathic and adult respiratory distress syndrome; pulmonary fibrosis after radiation therapy or chemotherapy, septic shock, sepsis, inflammatory response, such as, but not limited to, edema, acute or chronic atheroma In the therapeutic and / or prophylactic treatment of atherosclerosis, such as coronary artery disease, cerebral artery disease, peripheral artery disease, reperfusion injury, and restenosis after percutaneous transluminal angioplasty (PTA) Useful.

The compounds of the present invention that inhibit trypsin and / or thrombin are also useful in treating pancreatitis. According to another aspect of the present invention, there is provided a method of treating a condition requiring inhibition of thrombin. The method comprises administering to a human suffering from or susceptible to such a condition a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as defined above. Become.

The compounds of the invention are generally administered orally in pharmaceutically acceptable dosage forms and in pharmaceutical preparations containing the prodrug as a free base or as a pharmaceutically acceptable non-toxic organic or inorganic acid addition salt. It is administered topically, buccally, enterally, transdermally, nasally, tracheally, bronchially, by other parenteral routes, or by inhalation. The composition can be administered in various dosages depending on the disease to be treated, the patient, and the route of administration.

The compounds of the present invention can also be used as antithrombotic agents having different mechanisms of action, such as the antiplatelet agents acetylsalicylic acid, ticlopidine, clopidogrel, thromboxane receptor and / or synthetase inhibitors, fibrinogen receptor antagonists, prostacyclin Mimetics, phosphodiesterase inhibitors and ADP-receptors (P
It can be combined with ₂ T) antagonists and / or may be co-administered.

Furthermore, the compounds of the present invention are useful for treating thrombotic diseases,
Especially in the treatment of myocardial infarction, tissue plasminogen activator (natural or recombinant), streptokinase,
Urokinase, prourokinase, anisoleated streptokinase plasminogen activator complex (ASPA
C), which can be combined with and / or co-administered with a thrombolytic substance such as an animal salivary gland plasminogen activator.

According to another aspect of the present invention, a compound of formula I or a pharmaceutically acceptable salt thereof as defined above is admixed with a pharmaceutically acceptable adjuvant, diluent or excipient. An agent containing the mixture is provided.

For therapeutic treatment in humans, a suitable daily dose of a compound of the invention is from about 0.001 to 100 mg for oral administration.
/ Kg body weight, 0.001 to 50 mg / k for parenteral administration
g weight.

The compounds of the present invention are compounds of the formula R ^a O (O) C-CH _2- (R) Cgl-Aze-Pab-H, wherein R ^a is as defined above, especially R ^It has the advantage of having improved pharmacokinetic properties as confirmed above after oral and parenteral administration when compared to compounds where ^a is H.

The compounds of the present invention are inactive against thrombin, trypsin and other serine proteases.
Thus, the compound remains inactive in the gastrointestinal tract, thereby avoiding possible complications when the active anticoagulant itself is administered orally, such as bleeding and digestive disorders due to inhibition of trypsin. it can. In addition, local bleeding following parenteral administration of an active thrombin inhibitor can be avoided by using the compounds of the present invention.

The compounds of the present invention are also more efficacious, less toxic, long acting, have a broad spectrum of activity, have fewer side effects, are readily absorbed than previously known compounds,
Or it has the advantage of having other useful pharmacological properties.

[Biological test] Test A Measurement of thrombin clotting time (TT) Human thrombin (T 6769, Sigma Chemical Co .; final concentration 1.4)
NIH units / ml) buffer (pH 7.4, 100 μl) and inhibitor solution (100 μl) were incubated for 1 minute. next,
Pooled citrated normal human plasma (100 μl) was added and the clotting time was measured with an automatic device (KC 10, Amelung). Clotting time (sec) was plotted against inhibitor concentration and IC ₅₀ TT was determined by interpolation. IC ₅₀ TT is the inhibitor concentration that doubles the thrombin clotting time in human plasma.

Test B Determination of Thrombin Clotting Time in Plasma In Vitro Thrombin Inhibition Following Oral or Parenteral Administration of Compounds of the Invention Catheter to Collect Blood from the Carotid Artery One or Two Days Before the Experiment Tested in conscious rats equipped with On the day of the experiment, a compound dissolved in ethanol: Solutol (registered trademark): water (5: 5: 90) was administered, a blood sample was collected at a predetermined time, and one part of a sodium citrate solution (0.13 mol / L) was collected. ) And 9 parts of blood. Thrombin clotting time was measured using plasma as described below. Dilute citrated rat plasma (100 μl) with saline (0.9%, 100 μl)
Buffer for human thrombin (T 6769, Sigma Chemical)
7.4, 100 μl) was added to initiate plasma clotting. The coagulation time was measured with an automatic device (KC 10, Amelung). Active thrombin inhibitor HO (O) C-CH in rat plasma
₂ (R) Cgl-Aze-Pab-H (see International Patent Application WO 94/29336)
Was estimated by using a standard curve of thrombin clotting time in pooled citrated rat plasma against known concentrations of the above active thrombin inhibitor dissolved in saline. Based on the estimated plasma concentration of the active thrombin inhibitor HO (O) C-CH ₂ (R) Cgl-Aze-Pab-H (assuming that the thrombin clotting time is longer with the compound) in rats, oral prodrugs The area under the curve after targeted and / or parenteral administration was calculated by trapezoidal rule and extrapolation of the data to infinity (AUCpd). Orally or parenterally administered after the active thrombin inhibitor _{HO (O) C-CH 2} (R) in vivo efficacy rate of Cgl-Aze-Pab-H in the prodrug was calculated according to the following formula: [(AUCpd / Dose) / (AUC activity, iv / dose)] × 100 (where AUC activity, iv is HO (O) C—CH ₂ (R) Cgl-A
Obtained by intravenously administering ze-Pab-H to conscious rats
AUC).

Test C Thrombin clotting time in urine ex vivo
Determination of ethanol: Solutol®: water (5: 5: 90)
Active thrombin inhibitor HO excreted in urine after oral or parenteral administration of a compound of the invention dissolved in
The amount of (O) C-CH ₂ (R) Cgl-Aze-Pab-H was estimated by measuring the thrombin clotting time in urine in vitro (assuming that the thrombin clotting time is longer with the compound).
Conscious rats were placed in metabolic cages capable of separate collection of urine and feces for 24 hours and administered compounds of the present invention orally. Thrombin clotting time in the collected urine was measured as described below. Pooled citrated normal human plasma (100 μl) was incubated with concentrated rat urine or its diluted saline solution for 1 minute. Next, a human thrombin (T 6769, Sigma Chemical Co.) buffer (pH 7.4; 1
00 μl) to initiate plasma clotting. The coagulation time was measured with an automatic device (KC 10; Amelung). Active thrombin inhibitor HO in rats urine _{(O) C-CH 2 (} R) Cgl-A
The concentration of ze-Pab-H is based on a standard curve of thrombin clotting time in pooled citrated normal human plasma against known concentrations of the above active thrombin inhibitors dissolved in concentrated rat urine (or its saline dilutions). Was estimated. By multiplying the total amount of rat urine released over 24 hours by the estimated mean urinary concentration of the active inhibitor, the amount of active inhibitor excreted in urine (AM
OUNTpd) can be calculated. Active thrombin inhibitor HO after oral or parenteral administration of prodrug
The in vivo efficacy of (O) C-CH ₂ (R) Cgl-Aze-Pab-H was calculated according to the following formula: [(AMOUNTpd / dose) / (AMOUNT activity, iv / dose)] × 1
00 (where AMOUNT activity, iv is HO (O) C-CH ₂ (R) Cg
After intravenous administration of l-Aze-Pab-H to conscious rats,
Means the amount excreted in urine).

Test D Determination of HO (O) C-CH _2- (R) Cgl-Aze-Pab-H in urine by LC-MS Ethanol: Solutol® : water (5: 5: 90)
Active thrombin inhibitor HO excreted in urine after oral or parenteral administration of a compound of the invention dissolved in
The amount of (O) C-CH _2- (R) Cgl-Aze-Pab-H is LC-
Measured by MS analysis. Animal experiments were performed as described in Method C above. Collect urine sample, -20 ℃ before analysis
And frozen. Urine samples were analyzed for their HO (O) C-CH _2- (R) Cgl-Aze-
The Pab-H content was analyzed according to the following method: the dissolved urine samples were mixed and spun on a centrifuge if necessary. Insert the solid phase extraction tube (Analytichem Bond Elut. No. 1210-2059)
Activated with 1.0 ml of methanol and conditioned with 1.0 ml of acetonitrile: water (50:50), then with 1.0 ml of 0.1% formic acid. 50 μl of working internal standard (20 μmol / L) was added to each extraction tube. 50 μl of the standard solution was added to the urine standard solution. For 200 μl of sample or urine standard, blank urine was added to each tube and then pulled down by gravity or gentle vacuum. The residual urine was washed off with 1.0 ml ammonium acetate (2 mmol / L) and 1.0 ml acetonitrile: ammonium acetate (2 mmol / L)
(35:65). The collected eluate was transferred to an autosampler vial. 30 μl of the extract is applied to an LC column (Hyp
ersil BDS-C18; 3 μm; 75 mm × 4.0 mm inner diameter; Hewlett-Packard No. 79926 03-354) and 0.75 ml / l with ammonium acetate buffer (1.3 mmol / L) containing 40% acetonitrile and 0.1% formic acid. Eluted in minutes. The effluent at 30 μl / min was separated to enter the electrospray ion source of the PE Sciex API-3 mass spectrometer. HO
(O) C-CH _2- (R) Cgl-Aze-Pab-H and HO (O) C-CH _2- (R) Cgl
The retention time of -Pro-Pab-H (internal standard) is around 1.5 minutes. These molecular ions ((M + H) ⁺ ) were observed by unit mass resolution at 430.2 and 444.2 m / z, respectively. In order to calibrate based on the peak area ratio of HO (O) C-CH _2- (R) Cgl-Aze-Pab-H with respect to the internal standard, there are two concentrations of the urine standard solution, which are the limits of quantification. It was used. 0.05 linearity of this method
Check was performed in the range of 0 to 20 μmol / L. Coefficient of variation is 1
1-2% at 2020 μmol / L and 7% at 0.50 μmol / L
%Met. The limit of quantification was 0.050 μmol / L. twenty four
HO on the total amount of urine that is released over time _{(O) C-CH 2 -} (R) Cg
By multiplying the measured urine concentration of l-Aze-Pab-H,
The amount of active inhibitor excreted in urine (AMOUNTpd) can be calculated. Next, the in vivo efficacy of the active thrombin inhibitor was calculated as described in Method C above. The following examples illustrate the invention in detail.

[0061]

EXAMPLES General Experimental Method Finnigan with Electrospray Interface
Mass spectra were recorded on a MAT TSQ 700 triple quadrupole mass spectrometer. ¹ H NMR and ¹³ C NMR measurements are available on BRUKER ACP 30
Performed on a 0, Varian UNITY 400 and 500 spectrometer. When the operating frequency is ¹ H, 300.13, 399.96 and 499 respectively.
82 MHz, and at ¹³ C, 75.46, 100.5 respectively
8 and 125.69 MHz. Chemical shifts are given in δ units.

Preparation of Starting Materials Boc- (R) Cgl-Aze-Pab-H, Boc- (R) Cgl-Aze-Pab × HCl, H-
(R) Aze-Pab-Z, H- (R) Aze-Pab-Z × HCl, Bn-OOCCH _2- (R) Cg
l-Aze-Pab-Z, Boc- (R) Cgl-Aze-Pab-Z, Boc- (R) Cgl-Aze-
OH and Pab-Z × HCl were prepared according to the method described in International Patent Application WO 94/29336.

Example 1 EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ (i) Boc- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ THF at 0 ° C. (125 ml) and 2M NaOH (70 ml; 140 mmol)
To a solution of Boc- (R) Cgl-Aze-Pab-H (6.1 g; 13 mmol) in water was added allyl chloroformate (1.7 g; 14 mmol) dropwise. After stirring at 0 ° C. for 1 hour, the reaction mixture was concentrated, water (100 ml) was added, and the resulting aqueous phase was extracted with methylene chloride (3 × 100 ml). The combined organic phases were concentrated to give 6.4 g of crude product, which was used as eluent for EtOAc:
Purified by flash chromatography using THF: Et3N (68: 29: 3). Concentration provided 5.8 g (81%) of the subtitle compound as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.19 (bt, 1H), 7.78 (d, 2
H), 7.26 (d, 2H), 6.02-5.92 (m, 1H), 5.32 (d, J = 17Hz,
1H), 5.18 (d, J = 10Hz, 1H), 5.06 (d, J = 7Hz, 1H), 4.8
2 (bs, 1H), 4.61 (d, J = 6Hz, 2H), 4.58-4.48 (m, 1H),
4.38-4.27 (m, 2H), 4.14-4.03 (m, 1H), 3.77-3.68 (m, 1
H), 2.60-0.90 (m, 24H). ¹³ C NMR (125 MHz, CDCl ₃ ) carbonyl and amidine signals: δ 172.70, 170.74, 168.02, 164.54, 155.9
8.

(Ii) H- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ × 2
TFA Boc- (R) Cgl-Aze-P in methylene chloride (15 ml) at 0 ° C
ab-COOCH ₂ CH = CH ₂ (2.03 g; 3.65 mmol; above step)
TFA (15 ml) was added to the solution from (i)). The reaction mixture was stirred at ambient temperature for 3 hours, then concentrated to give 2.8 g of the subtitle compound as a white solid. ¹ H NMR (500 MHz, MeOH (d4)): δ 7.80 (d, 2H), 7.57 (d,
2H), 6.02 (m, 1H), 5.45 (d, J = 17Hz, 1H), 5.33 (d, J =
10Hz, 1H), 5.91-4.80 (m, 3H), 4.56 (s, 2H), 4.38 (bq,
J = 8Hz, 1H), 3.71 (d, J = 7Hz, 1H), 2.76-2.60 (m, 1H),
2.35-2.20 (m, 1H), 1.9-1.0 (m, 11H).

(Iii) EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ C
H = CH ₂ H- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ × 2TFA (649 mg; 0.95 mmol; from step (ii) above), K ₂ CO ₃ (656 mg, 4.8 mmol), water ( A mixture of 0.1 ml) and THF (10 ml) was stirred at 40 ° C. for 2 hours and ethyl bromoacetate (190 ml) in THF (1 ml).
mg; 1.14 mmol). After stirring at 40 ° C. for 4 hours and at ambient temperature for 14 hours, the reaction mixture was filtered, concentrated and purified by flash chromatography using EtOAc: THF: Et ₃ N (68: 29: 3) as eluent. 244mg (47
%) Of the title compound as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.46 (bt, 1H), 7.81 (d,
2H), 7.35 (d, 2H), 6.08-5.94 (m, 1H), 5.35 (d, J = 18H
z, 1H), 5.23 (d, J = 11Hz, 1H), 4.93 (dd, J = 6 and 9H
z, 1H), 4.66 (d, 2H), 4.62-4.38 (AB part of ABX spectrum), 4.16-4.04 (m, 4H), 3.20 (d, 2H), 2.86 (d, 1H),
2.64-2.45 (m, 2H), 2.0-1.0 (m, 17H). ¹³ C NMR (100 MHz, CDCl ₃ ) carbonyl and amidine signals: δ 175.33, 172.24, 170.72, 168.19, 164.3
Five.

Example 2 nPrOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH _{2 The} title compound was converted to H- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ × 2TFA
03 mg; 0.74 mmol; see Example 1 (ii) above) and n-propylbromoacetate (160 mg; 0.88 mmol), prepared according to the method described in Example 1 (iii).
77 mg (68%) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.48 (bt, 1H), 7.83 (d,
2H), 7.35 (d, 2H), 6.76 (wide, 1H), 6.02 (m, 1H),
5.37 (dd, 1H), 5.24 (dd, 1H), 4.94 (t, 1H), 4.67 (dd,
2H), 4.49 (AB part of ABX spectrum, 2H), 4.12 (m, 2H),
3.98 (t, 2H), 3.24 (AB-system, 2H), 2.87 (d, 1H), 2.52
(m, 2H), 1.99 (bd, 2H), 1.80-1.50 (m, 7H), 1.61 (q, 2
H), 1.30-1.10 (m, 2H), 1.00 (qd, 2H), 0.90 (t, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) amidine and carbonyl signals: δ 175.4, 172.3, 170.7, 167.9, 164.5.

Example 3 tBuOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH _{2 The} title compound was converted to H- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ × 2TFA
85 mg; 0.42 mmol; see Example 1 (ii) above) and t-butyl bromoacetate (96 mg; 0.50 mmol), 93 mg (39) prepared according to the method described in Example 1 (iii).
%) As a white solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.50 (bt, 1H), 7.81 (d,
2H), 7.36 (d, 2H), 6.07-5.97 (m, 1H), 5.36 (d, J = 16H
z, 1H), 5.22 (d, J = 10Hz, 1H), 4.93 (dd, J = 9 and 6Hz,
1H), 4.76 (d, J = 6Hz, 2H), 4.57-4.46 (m, 2H), 4.18-
4.04 (m, 2H), 3.19-3.08 ( _AB -spectrum, J _AB = 20Hz, 2
H), 2.86 (d, J = 8Hz, 1H), 2.72-2.53 (m, 2H), 2.0-0.9
(m, 23H). ¹³ C NMR (100 MHz, CDCl ₃ ) amidine and carbonyl signals: δ 175.28, 171.53, 170.76, 167.81, 164.1.

Example 4 EtOOCCH _2- (R) Cgl-Aze-Pab-COOEt (i) Boc- (R) Cgl-Aze-Pab-COOEt The subtitle compound was Boc- (R) Cgl-Aze-Pab-COOEt. Prepared from H (600 mg; 1.3 mmol) and ethyl chloroformate (150 mg; 1.4 mmol) according to the method described in Example 1 (i).
0 mg (34%) was obtained as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.37 (bs, 1H), 8.16 (bs,
1H), 7.72 (d, 2H), 7.18 (d, 2H), 5.17 (d, 1H), 4.73
(t, 1H), 4.47 (dd, 1H), 4.27 (m, 2H), 4.06 (q, 2H), 3.
66 (t, 1H), 2.48 (m, 1H), 2.37 (m, 1H), 1.4-1.8 (m, 7
H), 1.22 (s, 9H), 1.3-0.8 (m, 7H). ¹³ C NMR (75 MHz, CDCl ₃ ) carbonyl and amidine signals: δ 172.6, 170.7, 167.9, 164.8, 156.0.

(Ii) H- (R) Cgl-Aze-Pab-COOEt × 2HCl Boc- (R) Cgl-Aze-Pab-COOEt (20 ml) in EtOAc (20 ml)
mg; 0.44 mmol; from step (i) above) at 0 ° C. over 5 min. Reaction mixture at 0 ° C
For 1 hour and then concentrated to give 225 mg (100%) as a white solid. ¹ H NMR (300 MHz, D ₂ O): δ 7.85 (d, 2H), 7.61 (d, 2
H), 4.98 (dd, 1H), 4.60 (s, 1H), 4.44 (p, 5H), 3.90 (d,
1H), 2.73 (m, 1H), 2.37 (m, 1H), 2.0-1.65 (m, 9H), 1.
39 (t, 3H), 1.4-1.1 (m, 7H), 0.98 (m, 1H). ¹³ C NMR (75 MHz, D ₂ O) amidine and carbonyl signals: δ 172.7, 169.4, 166.8, 154.3.

(Iii) EtOOCCH _2- (R) Cgl-Aze-Pab-COOEt The title compound was converted to H- (R) Cgl-Aze-Pab-COOEt × 2HCl (160 mg;
0.31 mmol; from step (ii) above) and ethyl bromoacetate (52.5 mg; 0.31 mmol) from Example 1 (ii
Prepared according to the method described under i) to obtain 100 mg (61%) as a light yellow powder. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.48 (bt, 1H), 7.81 (d,
2H), 7.38 (d, 2H), 4.51 (AB part of ABX spectrum, 2H),
4.21 (q, 2H), 4.15-4.05 (m, 4H), 3.21 (AB-spectrum, 2H), 2.86 (d, 1H), 2.68 (m, 1H), 2.53 (m, 1H), 1.
96 (bd, 2H), 1.90-1.70 (m, 12H), 1.35 (t, 3H), 1.22
(t, 6H), 1.30-0.95 (m, 2H). ¹³ C NMR (75 MHz, CDCl ₃ ) carbonyl and amidine signals: δ 175.5, 172.2, 170.7, 167.6, 164.9.

Example 5 EtOOCCH _2- (R) Cgl-Aze-Pab-COO-nPr (i) Boc- (R) Cgl-Aze-Pab-COO-nPr Boc- (R) Cgl-Aze-Pab -H (6.0 g; 13 mmol) and n-
The subtitle compound was prepared according to the procedure described in Example 1 (i) above using propyl chloroformate (1.57 ml; 14 mmol). Yield 5.4 g (76%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.25 (bt, 1H), 7.82 (d,
2H), 7.31 (d, 2H), 5.09 (bd, 1H), 4.87 (dd, 1H), 4.58
(dd, 1H), 4.39 (dd, 2H), 4.14 (q, 1H), 4,10 (t, 2H),
3.79 (t, 1H), 2.54 (dm, 2H), 2.21 (s, 1H), 1.87-1.55
(m, 8H), 1.33 (s, 9H), 1.45-1.0 (m, 4H), 0.99 (t, 3
H). ¹³ C NMR (100 MHz, CDCl ₃ ) amidine and carbonyl signals: δ 172.7, 170.6, 167.8, 165.0, 155.9.

(Ii) H- (R) Cgl-Aze-Pab-COO-nPr × 2 TFA 2.1 g (3.7 mmol) of Boc- (R) Cgl-Aze-Pab-COO-nPr (from step (i) above) ) To give the subtitle compound according to the method described in Example 1 (ii). Yield 3.7 g. ¹ H NMR (400 MHz, MeOH-d ₄ ): δ 7.77 (d, 2H), 7.60 (d,
1H), 4.86 (dd, 1H), 4.56 (AB part of ABX spectrum, 2
H), 4.33 (m, 4H), 3.72 (d, 1H), 3.30 (m, 1H), 2.68 (m,
1H), 2.28 (m, 1H), 1.9-1.7 (m, 9H), 1.4-1.1 (m, 6H),
1.02 (t, 3H). ¹³ C NMR (100 MHz, MeOH-d ₄ ) carbonyl and amidine signals: δ 172.7, 169.3, 168.0, 161.4.

(Iii) EtOOCCH _2- (R) Cgl-Aze-Pab-COO-nPr The title compound was converted to H- (R) Cgl-Aze-Pab-COO-nPr × 2TFA (472 m
g; 0.69 mmol; from step (ii) above) and ethyl bromoacetate (138 mg; 0.83 mmol) from Example 1.
Prepared according to the method described in (iii) to give 0.22 mg (58%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.46 (bt, 1H), 7.82 (d,
2H), 7.32 (d, 2H), 4.92 (dd, 1H), 4.49 (AB part of ABX spectrum, 2H), 4.10 (m, 6H), 3.23 (AB spectrum, 2
H), 2.80 (dm, 2H), 1.98 (bd, 2H), 1.74 (q, 2H), 1.63
(dd, 2H), 1.52 (m, 1), 1.21 (t, 3H), 1.20-1.10 (m, 2
H), 0.98 (t, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) carbonyl and amidine signals: δ 175.3, 172.2, 170.7, 167.6, 164.8.

Example 6 MeOOCCH _2- (R) Cgl-Aze-Pab-COO-nPr The title compound was converted to H- (R) Cgl-Aze-Pab-COO-nPr × 2TFA (365 m
g; 0.53 mmol; see Example 5 (ii) above) and methyl bromoacetate (98 mg; 0.64 mmol), prepared according to the method described in Example 1 (iii) to give 114 mg (41%) as a white solid. Obtained. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.44 (bt, 1H), 7.82 (d,
2H), 7.32 (d, 2H), 7.04 (wide, 1H), 4.92 (dd, 1H),
4.49 (AB part of ABX spectrum), 4.12 (m, 2H), 4.10 (t, 2
H), 3.63 (s, 3H), 3.24 (s, 2H), 2.87 (d, 1H), 2.65 (m,
1H), 2.52 (m, 1H), 2.01 (wide, 1H), 1.96 (bd, 2H),
1.75 (q, 4H), 1.63 (bdd, 1H), 1.53 (m, 1H), 1.3-1.1 (m,
5H), 0.99 (t, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) carbonyl and amidine signals: δ 175.3, 172.5, 170.7, 167.7, 165.0.

Example 7 EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH ₂ OMe (i) Boc- (R) Cgl-Aze-Pab-COOCH ₂ CH ₂ OMe Boc- (R) Cgl -Aze-Pab-H (6.0 g; 13 mmol) and 2
The subtitle compound was prepared according to the procedure described in Example 1 (i) above using -methoxyethyl chloroformate (1.94 g; 14 mmol). Yield 3.9 g (52%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.24 (bt, 1H), 7.83 (d,
2H), 7.31 (d, 2H), 5.08 (bd, 1H), 4.87 (dd, 1H), 4.58
(dd, 1H), 4.39 (dd, 2H), 4.30 (t, 2H), 4.15 (m, 1H),
3.79 (bt, 1H), 3.68 (t, 2H), 3.40 (s, 3H), 2.65-2.45
(m, 2H), 2.20 (wide, 1H), 1.9-1.55 (m, 6H), 1.34
(s, 9H), 1.3-0.95 (m, 6H). ¹³ C NMR (100 MHz, CDCl ₃ ) carbonyl and amidine signals: δ 172.7, 170.7, 167.8, 164.6, 155.9.

(Ii) H- (R) Cgl-Aze-Pab-COOCH ₂ CH ₂ OMe × 2
1.71 g of TFA in Boc- (R) Cgl-Aze-Pab-COOCH ₂ CH ₂ OMe
(from (i)) to give the subtitle compound according to the method described in Example 1 (ii) above. Yield 1.89 g (88%). ¹ H NMR (400 MHz, MeOH-d ₄ ): δ 7.77 (d, 2H), 7.59 (d,
2H), 4.85 (dd, 1H), 4.56 (d, 2H), 4.49 (m, 2H), 4.37
(m, 1H), 4.28 (m, 1H), 3.70 (m, 3H), 3.37 (s, 3H), 2.6
8 (m, 1H), 2.28 (m, 1H), 1.9-1.7 (m, 7H), 1.4-1.1 (m,
6H). ¹³ C NMR (100 MHz, MeOH-d ₄ ) carbonyl and amidine signals: δ 172.7, 169.3, 168.0, 154.6.

(Iii) EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ C
H ₂ OMe The title compound was H- (R) Cgl-Aze-Pab-COOCH ₂ CH ₂ OMe × 2TFA (4
87 mg; 0.69 mmol; from step (ii) above) and ethyl bromoacetate (138 mg; 0.83 mmol), prepared according to the method described in Example 1 (iii) above to give the crude product, which is used as eluent in THF : Purification by flash chromatography using methylene chloride (3: 1). 0.13 mg (34%) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.46 (bt, 1H), 7.83 (d,
2H), 7.32 (d, 2H), 7.21 (wide, 1H), 4.92 (dd, 1H),
4.49 (AB part of ABX spectrum, 2H), 4.30 (t, 2H), 4.12
(q, 2H), 4.07 (q, 2H), 3.68 (t, 1H), 3.40 (s, 3H), 3.
24 (s, 2H), 2.62 (m, 1H), 2.52 (m, 1H), 2.07 (wide,
1H), 1.97 (bd, 1H), 1.8-1.5 (m, 5H), 1.3-1.1 (m, 6H),
1.05-0.95 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) carbonyl and amidine signals: δ 175.3, 172.2, 170.7, 167.8, 164.6.

Example 8 MeOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH ₂ OMe The title compound was converted to H- (R) Cgl-Aze-Pab-COOCH ₂ CH ₂ OMe × 2TFA (4
90 mg; 0.7 mmol; see Example 7 (ii) above) and methyl bromoacetate (128 mg; 0.84 mmol), prepared according to the method described in Example 1 (iii) above to give the crude product, which is eluted THF: methylene chloride (3:
Purified by flash chromatography using 1). 155 mg (41%) was obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.44 (t, 1 H), 7.83 (d, 2
H), 7.31 (d, 2H), 4.92 (dd, 1H), 4.49 (AB part of ABX spectrum, 2H), 4.30 (t, 2H), 4.13 (m, 2H), 3.68 (t, 2
H), 3.63 (s, 3H), 3.39 (s, 3H), 3.25 (s, 2H), 2.87 (d,
1H), 2.62 (m, 1H), 2.52 (m, 1H), 1.96 (bd, 1H), 1.8-
1.5 (m, 6H), 1.3-1.1 (m, 5H), 1.00 (q, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) carbonyl and amidine signals: δ 175.2, 172.6, 170.7, 167.8, 164.5.

Example 9 EtOOCCH _2- (R) Cgl-Aze-Pab-COO-nBu (i) Boc- (R) Cgl-Aze-Pab-COO-nBu The subtitle compound was Boc- (R) Cgl- Aze-Pab-H (1.01 g; 2.1 mmol) and n-butyl chloroformate (0.32 g; 2.
4 mmol) according to the method described in Example 1 (i). After stirring at ambient temperature for 1.5 hours, the reaction mixture was concentrated and extracted three times with methylene chloride. The combined organic phases were washed with water, dried over Na ₂ SO ₄ and concentrated to 1.0 g (83 g).
%) To give the subtitle compound as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.81-9.31 (bs, 1H), 8.3
6-8.20 (m, 1H), 7.35 (d, 2H), 7.84 (d, 2H), 6.78-6.43
(bs, 1H), 5.05-4.82 (m, 2H), 4.69-4.15 (m, 3H), 4.15
-4.08 (m, 3H), 3.86-3.70 (m.1H), 2.68-2.42 (m, 2H),
1.92-0.88 (m, 25H). ¹³ C NMR (125 MHz, CDCl ₃ ) amidine and carbonyl signals: δ 172.5, 170.7, 167.9, 164.9, 156.0. FAB-MS: (m + 1) = 572 (m / z)

(Ii) H- (R) Cgl-Aze-Pab-COO-nBu × 2HCl The subtitle compound was converted to Boc- (R) Cgl-Aze-Pab-COO-nBu (2.5 g; 4.4 g
Mmol (from step (i) above), prepared according to the method described in Example 4 (ii) to give 2.4 g (100%) as a white solid. ¹ H NMR (300 MHz, MeOH-d ₄ ): δ 7.78-7.60 (m, 2H), 4.
66-4.49 (m, 2H), 0.98 (t, 2H), 4.49-4.35 (m, 3H), 4.3
5-4.22 (m, 1H), 3.75 (d, 1H), 1.92-1.67 (m, 8H), 1.56
-1.07 (m, 8H). One signal of the protons is partially obscured by the CD ₃ OH signal. ¹³ C NMR (100 MHz, MeOH-d ₄ ) amidine and carbonyl signals: δ 172.7, 169.3, 167.9, 154.7. MS (m + 1) = 472 (m / z)

(Iii) EtOOCCH _2- (R) Cgl-Aze-Pab-COO-nBu The title compound was converted to H- (R) Cgl-Aze-Pab-COO-nBu × 2HCl (400 m
g; 0.74 mmol) and ethyl bromoacetate (147
mg; 0.88 mmol) in the same manner as described in Example 1 (iii). The product is purified by flash chromatography using methylene chloride and EtOH (gradient 0.1% => 12.8%) as eluents, 290 mg
(70%) was obtained as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.70-9.36 (bs, 1H), 8.4
7 (t, 1H), 7.81 (d, 2H), 7.32 (d, 2H), 7.07-6.73 (bs,
1H), 4.97-4.87 (dd, 1H), 4.62-4.35 (m, 2H), 4.20-3.98
(m, 6H), 3.27-3.12 (m, 2H), 2.84 (s, 1H), 2.70-2.40
(m, 2H), 2.03-0.85 (m, 22H). ¹³ C NMR (75 MHz, CDCl ₃ ) amidine and carbonyl signals: δ 175.3, 172.3, 170.8, 167.9, 165.0. FAB-MS: (m + 1) = 558

Example 10 PrlC (O) CH ₂ CH ₂ CH ₂ OOCCH ₂ — (R) Cgl-Aze-Pab-Z (i) PrlC (O) CH ₂ CH ₂ CH ₂ OH γ-butyrolactone (4.0 g; 46.5 mmol) and pyrrolidine (6.6 g; 92.8 mmol) at room temperature for 2.5
Stirred for hours. The product was concentrated under vacuum to 14.5 g (100
%) Of the product as a yellow oil. ¹ H NMR (300 MHz, MeOH-d ₄ ): δ 3.58 (t, 2H), 3.50 (t,
2H), 3.40 (t, 2H), 2.42 (t, 2H), 2.06-1.75 (m, 6H).

(Ii) PrlC (O) CH ₂ CH ₂ CH ₂ OOCCH ₂ Br PrlC (O) CH ₂ CH ₂ CH ₂ OH (7.
2g; 45.8 mmol; from step (i) above) and DMAP
(5.6 g; 45.8 mmol) was added dropwise to bromoacetyl bromide (4.0 ml; 45.8 mmol). After stirring at room temperature for 1.5 hours, bromoacetyl bromide (1.0 ml, 11.4
Mmol) and DMAP (1.4 g, 11.4 mmol) were added and the reaction mixture was refluxed for 1.5 hours. Water was added and extracted three times with methylene chloride. The organic phase was dried over Na ₂ SO ₄ and concentrated to give 10.3 g (81%) of the product as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 4.15 (t, 2H), 3.75 (s, 2
H), 3.40-3.31 (m, 4H), 2.30 (t, 2H), 1.98-1.83 (m, 4
H), 1.81-1.73 (m, 2H).

(Iii) PrlC (O) CH_TwoCH_TwoCH_TwoOOCCH_Two-(R) Cgl-A
ze-Pab (Z) The title compound was converted to H- (R) Cgl-Aze-Pab-Z (6 g; 10.4 mmol).
And PrlC (O) CH_TwoCH _TwoCH_TwoOOCCH_TwoBr (3.5g; 12.4mi
Lmol; from step (ii) above) to Example 1 (iii)
It was manufactured according to the method. Hep as crude eluent
Uses tan: EtOAc: isopropanol (1: 2: 2)
4.2 Purification by flash chromatography
g of 0.1M NH as eluent_Four44% Ase in OAc
Purify using preparative RPLC using tonitrile 2.
64 g (36%) of the product were obtained as a white solid.¹ H NMR (500MHz, CDCl_Three): Δ 9.80-9.22 (b s, 1H), 8.3
6 (t, 1H), 7.96-7.58 (m, 3H), 7.45 (d, 2H), 7.37-7.22
(m, 5H), 5.20 (s, 2H), 4.95-4.88 (dd, 1H), 4.72-4.29
(m, 2H), 4.15-4.04 (m, 2H), 4.04-3.88 (m, 2H), 3.40
(t, 2H), 3.34 (t, 2H), 3.28-3.17 (m, 2H), 2.85 (d, 1
H), 2.67-2.48 (m, 1H), 2.23 (t, 2H), 2.14-0.93 (m, 18
H).¹³ C NMR (125MHz, CDCl_Three) Amidine and carbonyl
Gunnar: δ 175.3, 172.4, 170.9, 170.4, 168.2, 164.
6. FAB-MS: (m + 1) = 703

Example 11 ChNHC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z (i) ChNHC (O) CH ₂ OH cyclohexylamine (9.9 g; 99.8 mmol) and
A mixture of 2,5-dioxo-1,4-dioxane (3.0 g, 25.9 mmol) was stirred at 100 ° C. for 2.5 hours. The product was concentrated to give 8.1 g (100%) of the product as a brown solid. ¹ H NMR (500 MHz, MeOH-d ₄ ): δ 3.92 (s, 2H), 3.75-3.6
5 (m, 1H), 1.90-1.58 (m, 5H), 1.43-1.07 (m, 5H). Two signals of the protons are obscured by CD ₃ OH signal. ¹³ C NMR (125 MHz, MeOH-d ₄ ) amidine and carbonyl signals: δ 174.0, 62.5, 33.7, 26.5, 26.1, 26.0. The signal for one of the carbons is obscured by the CD ₃ OD signal.

(Ii) ChNHC (O) CH ₂ OOCCH ₂ Br ChNHC (O) CH ₂ OH in methylene chloride (80 ml) at 0 ° C.
(8.0 g; 50.9 mmol; from step (i) above) and DMA
To a mixture of P (6.2 g; 50.9 mmol) was added dropwise bromoacetyl bromide (4.0 ml; 45.8 mmol). After stirring at room temperature for 1.5 hours, bromoacetyl bromide (1.0 ml, 11.4
Mmol) and DMAP (1.4 g, 11.4 mmol) were added and the reaction mixture was refluxed for 1.5 hours. Water was added and the aqueous phase was extracted three times with methylene chloride. The organic phase is washed with water and Na
Dried over ₂ SO ₄ and concentrated to give 10.3 g (73%) of the product as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.12-6.00 (bs, 1H), 4.6
2 (s, 2H), 3.90 (s, 2H), 3.84-3.76 (m, 1H), 1.95-1.86
(m, 2H), 1.75-1.65 (m, 2H), 1.65-1.56 (m, 1H), 1.43-
1.29 (m, 2H), 1.24-1.10 (m, 3H).

(Iii) ChNHC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-Pa
bZ The title compound was prepared starting from H- (R) Cgl-Aze-Pab-Z (6 g; 10.4 mmol) and ChNHC (O) CH ₂ OOCCH ₂ Br (3.5 g; 12.4 mmol; from step (ii) above). It was produced in the same manner as described in Example 1 (iii). Heptane: EtOAc: isopropanol (5: 2:
Purify by flash chromatography using 2), concentrate, and use 50% in 0.1 M NH ₄ OAc as eluent.
Purified by preparative RPLC using% acetonitrile. Concentrated and lyophilized to give 2.6 g (36%) of the product as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.78-9.25 (bs, 1H), 7.9
0 (t, 1H), 7.78 (d, 2H), 7.44 (d, 2H), 7.38-7.24 (m, 5
H), 6.66 (t, 1H), 5.20 (s, 2H), 4.90-4.83 (dd, 1H),
4.60-4.45 (m, 2H), 4.18-3.93 (m, 4H), 3.73-3.62 (m, 1
H), (d, 1H), 3.23, 3.44 (AB, 2H), 2.87, 2.65-2.08
(m, 3H), 1.98-0.93 (m, 22H). ¹³ C NMR (125 MHz, CDCl ₃ ) amidine and carbonyl signals: δ 175.1, 171.7, 170.7, 168.8, 166.1, 164.
Four. FAB-MS: (m + 1) = 703

Example 12 (nPr) ₂ NC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOCC (C
H ₃ ) ₃ (i) (nPr) ₂ NC (O) CH ₂ OH 2,5-dioxo-1,4-dioxane (2.02 g; 17.4 mmol) and di-n-propylamine (5 ml; 36.5 mmol) The mixture was heated at 50 ° C. for 1 hour and 90 ° C. for 66 hours.
Toluene was added and removed under vacuum with excess di-n-propylamine. The residue was purified by flash chromatography using 10% methanol in methylene chloride as eluent to give 4.18 g (66%) of the desired compound. ¹ H NMR (300 MHz, CDCl ₃ ): δ 4.1 (d, 2H), 3.65 (t, 1
H), 3.25-3.35 (m, 2H), 2.9-3.0 (m, 2H), 1.45-1.6 (m, 4
H), 0.8-0.95 (m, 6H).

(Ii) (nPr) ₂ NC (O) CH ₂ OOCCH ₂ Br (nPr) ₂ NC (O) CH ₂ OH (0.74) in methylene chloride (15 ml)
3 g; 4.7 mmol; from step (i) above), DCC (0.951).
g, 4.6 mmol) and bromoacetic acid (0.704 g; 5.1 mmol) were stirred at room temperature for 1.5 hours. The precipitate was removed by filtration and the solvent was removed from the filtrate under vacuum. Kugelrohr distillation of the residue yielded 0.66 g (50%) of the desired compound. ¹ H NMR (300 MHz, CDCl ₃ ): δ 4.8 (s, 2H), 4.0 (s, 2
H), 3.2-3.3 (m, 2H), 3.05-3.15 (m, 2H), 1.5-1.7 (m, 4
H), 0.8-1.0 (dt, 6H).

(Iii) Pivaloyloxymethyl 4-nitrophenyl carbonate Silver pivalate (7.5 g; 25 mmol) and iodomethyl 4-nitrophenyl carbonate (Alexander et al., J. Me.
d. A mixture of Chem. 31, 318 (1988); 7.99 g; 25 mmol) was refluxed in benzene (50 ml) for 2 hours. Benzene was removed under vacuum and the residue was dissolved in toluene. Filter through Hyflo and purify by flash chromatography using toluene as eluent to obtain 4.00 g (54
%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.25 (d, 2H), 7.40 (d, 2
H), 5.85 (s, 2H), 1.2 (s, 2H). ¹³ C NMR (75 MHz, CDCl ₃ ) amidine and carbonyl signal: δ 176.77, 155.06.

(Iv) Boc- (R) Cgl-Aze-Pab-COOCH ₂ OOCC (CH
_{3) 3} peak in the methylene chloride (20ml) valyl oxymethyl 4
-Nitrophenyl carbonate (1.18 g; 4 mmol;
The solution of the above step (iii)) was treated at room temperature with methylene chloride (20m
Boc- (R) Cgl-Aze-Pab-H (1.88 g; 4 mmol) and triethylamine (0.66 ml; 4.75 mmol) in l)
Was added to the solution. After 1 hour, the methylene chloride was replaced with EtOAc and the mixture was purified by flash chromatography using EtOAc as eluent to give 1.27 g (50%) of the subtitle compound. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.5 (bs, 1 H), 8.25 (t, 1
H), 7.8 (d, 2H), 7.3 (d, 2H), 7.0 (bs, 1H), 5.0-4.8
(m, 2H), 4.65-4.5 (m, 1H), 4.5-4.3 (m, 2H), 4.2-4.05
(m, 1H), 3.75 (t, 1H), 2.7-2.4 (m, 2H), 1.9-1.45 (m, 5
H), 1.45-0.8 (m, 24H).

[0092] (v) H- (R) Cgl -Aze-Pab-COOCH 2 OOCC (CH 3) 3 Boc- (R) Cgl-Aze-Pab-COOCH 2 OOCC (CH 3) 3 (327mg; 0.52 mmol; Step (iv) above) was dissolved in a mixture of methylene chloride (5 ml) and TFA (1.2 ml). After 2 hours, the reaction mixture was concentrated under vacuum, acetonitrile was added and the solvent was removed again under vacuum to give the subtitle crude product, which was used for the next step without further purification.

(Vi) (nPr) ₂ NC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-
Pab-COOCH ₂ OOCC (CH ₃ ) ₃ The residue from the above step (v) was dissolved in THF (5 ml) in (nPr) ₂ NC (O) C
Mix with H ₂ OOCCH ₂ Br (150 mg; 0.53 mmol; from step (ii) above) and K ₂ CO ₃ (480 mg; 3.5 mmol) and add 40
Heated at C for 3 hours. The reaction mixture was filtered and concentrated to give the crude product, which was purified by preparative RPLC to 78 mg (21
%) Of the title compound. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.3-9.6 (bs, 1H), 8.5 (m,
1H), 7.95-8.15 (bs, 1H), 7.85-7.95 (d, 2H), 7.2-7.3
(d, 2H), 5.8 (s, 2H), 4.8-4.9 (dd, 1H), 4.5-4.7 (m, 3
H), 4.0-4.4 (m, 3H), 2.8-3.4 (m, 5H), 2.2-2.7 (m, 3
H), 1.75-1.3 (m, 9H), 1.3-1.0 (m, 14H), 1.0-0.7 (m, 7
H). ¹³ C NMR (75 MHz, CDCl ₃ ) amidine and carbonyl signals: δ 177.24, 175.30, 171.85, 170.79, 168.78,
165.82, 163.14.

Example 13 EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOCC (CH ₃ ) ₃ Crude Boc- (R) Cgl-Aze using acetonitrile (10 ml) as a solvent for the title compound. -Pab-COOCH ₂ OOCC (CH ₃ ) ₃ (0.41
g; 0.65 mmol; see Example 12 (iv) above) in a manner analogous to that described in Example 12 (vi) above. After stirring overnight at room temperature, the solvent was removed in vacuo and the residue was
Partitioned between OAc and water. The aqueous phase was extracted three times with EtOAc, the combined organic phases were dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo. The residue was subjected to flash chromatography using methylene chloride / methanol as eluent. Lyophilization from glacial acetic acid afforded 84 mg (21%) of the title compound. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.9 (bs, 1H), 8.5 (t, 1
H), 7.35 (d, 2H), 5.85 (s, 2H), 5.90 (dd, 2H), 4.6-4.3
5 (m, 2H), 4.15-4.0 (m, 4), 3.2 (s, 2H), 2.85 (d, 1H),
2.7-2.45 (m, 2), 2.0-1.9 (m, 2H), 1.8-1.45 (m, 5H), 1.
3-0.9 (m, 18H). ¹³ C NMR (75 MHz, CDCl ₃ ) amidine and carbonyl signals: δ 177.23, 175.48, 172.29, 170.80, 168.85,
163.14.

Example 14 EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH (CH ₃ ) OOCCH ₃ (i) Boc- (R) Cgl-Aze-Pab-COOCH (CH ₃ ) OOCCH ₃ Methylene chloride Boc- (R) Cgl-Aze-Pab-H in (40 ml)
(6.38 g; 13.5 mmol), 1-acetoxyethyl-4
Nitrophenyl carbonate (Alexander et al., J. Med.
Chem. 31, 318 (1988)) (3.05 g; 12 mmol) and triethylamine (1.95 ml; 14 mmol) at room temperature for 16 hours.
Stirred for hours, then added EtOAc. The resulting solution was slightly concentrated, washed with aqueous Na ₂ CO ₃ (10%) and concentrated to give the crude product, which was purified by flash chromatography using EtOAc as eluent, 5.59 g (77%)
Was obtained. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.5 (bs, 1 H), 8.25 (t, 1
H), 7.85 (d, 2H), 7.35 (d, 2H), 6.95 (q, 1H), 6.7 (bs,
1H), 5.0-4.85 (m, 2H), 4.65-4.5 (m, 1H), 4.5-4.25 (m,
2H), 4.2-4.05 (m, 1H), 3.75 (t, 1H), 2.65-2.45 (m, 2
H), 2.05 (s, 3H), 1.9-1.45 (m, 11H), 1.45-0.8 (m, 12
H). ¹³ C NMR (75 MHz, CDCl ₃ ) amidine and carbonyl signals: δ 172.61, 170.80, 169.54, 168.91, 162.50,
156.02.

(Ii) H- (R) Cgl-Aze-Pab-COOCH (CH ₃ ) OOCCH
₃ Boc- (R) Cgl-Aze-Pab-COOCH (CH ₃ ) OOCCH
Prepared according to the method described in Example 12 (v) above from ₃ (2.21 g; 3.68 mmol; from step (i) above).

(Iii) EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH (C
H ₃₎ OOCCH ₃ The crude from the above step (ii) H- (R) Cgl -Aze-Pab-COOCH (CH 3) O
OCCH ₃ was dissolved in methylene chloride (150ml). 10% mixture
Washed with Na ₂ CO ₃ solution, dried the organic phase over K ₂ CO ₃ and filtered. To the resulting solution was added K ₂ CO ₃ (756) in methylene chloride (5 ml).
mg; 5.5 mmol) and ethyl (O-trifluoromethanesulfonyl) -glycolate (790 mg; 3.3 mmol)
Was added. The reaction mixture was stirred at room temperature for 5-10 minutes and concentrated under vacuum. The residue was dissolved in EtOAc and the resulting mixture was filtered through celite. Et with filtrate as eluent
Flash chromatography using OAc, then HPL
C gave 475 mg (22%) of the title compound. ¹ H NMR (300 MHz, CDCl ₃ ): δ 9.5 (bs, 1H), 8.3 (t, 1
H), 7.7 (d, 2H), 7.2 (d, 2H), 6.85 (q, 1H), 4.8 (t, 1H),
4.45-4.25 (m, 2H), 4.1-3.85 (m, 4H), 3.1 (s, 2H), 2.75
(s, 1H), 2.5-2.3 (m, 2H), 1.95 (s, 3H), 1.9-1.8 (m, 1
H), 1.7-1.25 (m, 8H), 1.25-1.75 (m, 8H). ¹³ C NMR (75.5 MHz, CDCl ₃ ) amidine and carbonyl signals: δ 175.26, 172.34, 170.81, 169.49, 168.8
0, 162.43.

Example 15 MeOOCCH _2- (R) Cgl-Aze-Pab-OOCPh (i) Boc- (R) Cgl-Aze-Pab-OOCPh Boc- (R) in THF (45 ml) at 20 ° C. Cgl-Aze-Pab-H (1.0
g; 2.1 mmol) and Na ₂ HPO ₄ (18.7 g; 105 mmol) were added dropwise over 45 minutes dibenzoyl peroxide (556 mg; 2.3 mmol) dissolved in THF (10 ml). After stirring at 20 ° C. for 24 hours, the reaction mixture was concentrated, and the obtained crude product was subjected to preparative RPLC. This is 124m
g (10%) of the subtitle compound was obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.26 (m, 1H), 8.09 (m, 2
H), 7.72 (m, 2H), 7.59 (m, 1H), 7.48 (m, 2H), 7.36 (d,
2H), 5.13 (s, 2H), 4.87-4.98 (m, 2H), 4.54-4.61 (m,
1H), 4.33-4.47 (m, 2H), 4.13-4.19 (m, 1H), 3.81 (t, 1
H), 2.53-2.63 (m, 2H), 1.73-1.86 (m, 3H), 1.66-1.72
(m, 2H), 1.36 (s, 9H), 0.968-1.28 (m, 6H). ¹³ C NMR (10
0MHz, CDCl ₃ ) Amidine and carbonyl signal: δ
172.7, 170.6, 163.9, 157.0, 155.9. LC-MS: m / z 592 (M + H ⁺ ); m / z 614 (M + Na ⁺ ).

(Ii) H- (R) Cgl-Aze-Pab-OOCPh Boc- (R) Cgl-Aze-Pab-OOCh in methylene chloride (18 ml)
To a solution of Ph (600 mg; 1.01 mmol; from step (i) above) at 20 ° C. was added TFA (6 ml). After stirring for 14 hours, the reaction mixture was concentrated and the resulting crude product was extracted with EtOAc: 0.1 M NaOH
Distributed. The phases were separated, the organic phase was dried (Na ₂ SO _4), and evaporated. 480 mg (96%) were obtained as a white solid. ¹ H NMR (400 MHz, MeOH-d ₄ ): δ 8.18 (m, 2H), 7.77 (m,
2H), 7.64 (m, 1H), 7.52 (m, 2H), 7.43 (d, 2H), 4.75-
4.81 (m, 1H), 4.50 (s, 2H), 4.18-4.34 (m, 2H), 3.12 (d,
1H), 2.57-2.68 (m, 1H), 2.23-2.33 (m, 1H), 1.88-1.9
6 (m, 1H), 1.73-1.84 (m, 2H), 1.59-1.71 (m, 2H), 1.45
-1.57 (m, 1H), 0.80-1.34 (m, 5H). LC-MS: m / z 492 (M + H ⁺ ); m / z 514 (M + Na ⁺ ).

(Iii) MeOOCCH _2- (R) Cgl-Aze-Pab-OOCPh H- (R) Cgl-Aze-P in acetonitrile (5 ml) at 20 ° C.
ab-OOCPh (480 mg; 0.97 mmol; from step (ii) above),
It was added; (1.16 mmol 177 mg) of methyl bromoacetate to a solution of; (2 mmol 270mg) K ₂ CO _3. The reaction mixture was stirred at 20 ° C. for 14 hours. The reaction mixture was filtered and concentrated to give the crude product, which was purified by preparative RPLC to 269m
g (49%) of the title compound were obtained as a white solid. ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.43 (m, 1 H, NH), 8.09
(m, 2H), 7.69 (m, 2H), 7.59 (m, 1H), 7.47 (m, 2H), 7.3
4 (m, 2H), 5.27 (s, 2H), 4.93 (dd, 1H), 4.59 (dd, 1H),
4.40 (dd, 1H), 4.12 (m, 2H), 3.65 (s, 3H), 2.87 (d, 1
H), 2.72-2.63 (m, 1H), 2.55-2.48 (m, 1H), 1.96 (m, 1
H), 1.74 (m, 2H), 1.67 (d, 1H), 1.59 (d, 1H), 1.56-1.5
0 (m, 1H), 1.29-1.08 (m, 4H), 1.04-0.94 (m, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) amidine and carbonyl signals: δ 175.1, 172.5, 170.6, 164.0, 157.1. LC-MS: m / z 564 (M + H ⁺ ).

Example 16 MeOOCCH _2- (R) Cgl-Aze-Pab-OH MeOOCCH _2- (R) Cgl-Aze-Pab-OC (O) P in THF (4.6 ml)
h (260 mg; 0.46 mmol; see Example 15 (iii) above)
KOMe (1.6 ml; 0.29 M; 0.46 mmol) at 20 ° C.
Was added. After stirring for 15 minutes, the mixture is concentrated and the RP
Attached to LC. This afforded 109 mg (52%) of the title compound as a white solid. ¹ H NMR (500 MHz, MeOH-d ₄ ): δ 7.59 (d, 2H), 7.34 (d,
2H), 4.83 (s, 2H), 4.82-4.76 (m, 1H), 4.48 (d, 1H),
4.33 (d, 1H), 4.15-4.30 (m, 2H), 3.64 (s, 3H), 3.04 (d,
1H), 2.57 (m, 1H), 2.26 (m, 1H), 1.95 (m, 1H), 1.75
(m, 2H), 1.58-1.70 (m, 2H), 1.53 (m, 1H), 1.31-1.10
(m, 4H), 1.04 (m, 1H). ¹³ C NMR (100 MHz, MeOH-d ₄ ) amidine and carbonyl signals: δ 175.9, 174.3, 172.7, 155.2. LC-MS: m / z 460 (M + H ⁺ ); m / z 482 (M + Na ⁺ ).

Example 17 EtOOCCH _2- (R) Cgl-Aze-Pab-OH EtOOCCH _2- (R) Cgl-Aze-Pab-C (O) OCH (CH ₃ ) OOCCH ₃ (184 m
g; 0.31 mmol; see Example 14 (iii) above)
Hydroxylamine hydrochloride (1 in EtOH (95%; 4.0 ml)
20 mg; 1.72 mmol) and triethylamine (0.8 m
l; 5.7 mmol) was added and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated and the crude product was subjected to preparative RPLC. This gave 85 mg (58%) of the title compound. ¹ H NMR (300 MHz, CD ₃ OD): δ 7.6 (d, 2H), 7.35 (d, 2
H), 4.75-4.85 (m, 1H), 4.4-4.55 (m, 2H), 4.0-4.35 (m,
4H), 3.35 (d, 2H), 3.05 (d, 1H), 2.5-2.65 (m, 1H), 2.2
-2.35 (m, 1H), 1.9-2.05 (m, 1H), 1.4-1.85 (m, 5H), 0.8
5-1.35 (m, 8H). ¹³ C NMR (75.5 MHz, CD ₃ OD) amidine and carbonyl signals: δ 175.97, 173.91, 172.72, 155.23. LC-MS: (m + 1) = 474 (m / z)

[0103] [Example _{18] BnOOCCH 2 - (R)} Cgl-Aze-Pab-OH hydroxylamine hydrochloride in the EtOH (320 mg; 4.5
9 mmol) and triethylamine (1.7 ml; to a solution of 12.24 _{mmol) BnOOCCH 2 - (R) Cgl} -Aze-Pab-Z (1.0g;
1.52 mmol) was added. The reaction mixture was stirred at room temperature for 40 hours and concentrated. 0.1M NH ₄ OAc using crude product as eluent
Purification by preparative RPLC using 50% acetonitrile in yielded 0.34 g (42%) of the title compound. LC-MS: (m + 1) = 536 (m / z)

Example 19 nPrOOCCH _2- (R) Cgl-Aze-Pab-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z × 2HCl (700 mg; 1.2 mmol) and n-propyl bromoacetate (268m
g; 1.45 mmol) in the same manner as described in Example 1 (iii). Yield 259 mg (35%). FAB-MS: (m + 1) = 606 (m / z)

Example 20 nPrOOCCH _2- (R) Cgl-Aze-Pab-OH The title compound was converted to nPrOOCCH _2- (R) Cgl-Aze-Pab-Z (182 mg; 0.3 mg).
In the same manner as described in Example 18. Use crude product as eluent
Preparative RP using 40% acetonitrile in 1M NH ₄ OAc
Purification by LC yielded 74 mg (51%) of the desired compound. LC-MS: (m + 1) = 488 (m / z)

Example 21 iPrOOCCH _2- (R) Cgl-Aze-Pab-OH The title compound was converted to iPrOOCCH _2- (R) Cgl-Aze-Pab-Z (590 mg; 0.7
Mmol; see Example 39 below) in a manner analogous to that described in Example 18. Yield 110 mg (32%). LC-MS: (m + 1) = 488 (m / z)

Example 22 tBuOOCCH _2- (R) Cgl-Aze-Pab-OH The title compound was converted to tBuOOCCH _2- (R) Cgl-Aze-Pab-Z (738 mg; 1.2
Mmol; see Example 37 below) in a manner analogous to that described in Example 18. Yield 290 mg (48%). LC-MS: (m + 1) = 502 (m / z)

Example 23 (nPr) ₂ NCOCH ₂ OOCCH _2- (R) Cgl-Aze-Pab (OH) (i) HOOCCH _2- (R) Cgl (Boc) -Aze-Pab-O-Boc THF : HOOCCH _2- (R) Cgl-Aze-Pab-OH in water (10: 1)
(670 mg; 1.5 mmol; see Example 28 below), (Boc) 2O
(654 mg; 3 mmol) and DMAP (92 mg; 0.75 mmol) were stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative RPLC. Lyophilize 112 mg (12
%) To give the subtitle compound as a white solid. LC-MS: (m-1) = 643 (m / z)

(Ii) (nPr) ₂ NCOCH ₂ OOCCH _2- (R) Cgl (Boc) -A
ze-Pab-O-Boc HOOCCH _2- (R) Cgl (Boc)-in acetonitrile (5 ml)
Aze-Pab-O-Boc (100 mg; 0.15 mmol; from step (i) above), (nPr) ₂ NCOCH ₂ OH (27 mg; 0.17 mmol; see Example 12 (i) above), EDC (40 mg; 0.21 Mmol) and DM
A solution of AP (10 mg; 0.075 mmol) was stirred at room temperature for 4 days. The reaction mixture was concentrated and purified by preparative RPLC,
Lyophilization provided 21 mg (18%) of the subtitle compound. LC-MS: (m-1) = 787 (m / z)

(Iii) (nPr) ₂ NCOCH ₂ OOCCH _2- (R) Cgl-Aze-P
ab-OH TFA: (nPr) ₂ NCOCH _2- in methylene chloride (1: 1)
A solution of (R) Cgl (Boc) -Aze-Pab-O-Boc (20 mg; 0.025 mmol) was stirred at room temperature for 5 minutes. The reaction mixture was concentrated and lyophilized from acetonitrile and water to give 5 mg (34%) of the title compound. LC-MS: (m + 1) = 587 (m / z)

Example 24 ChNHCOCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-OH The title compound was converted to ChNHCOCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z (118 m
g; 0.17 mmol; see Example 11 (iii) above) in a manner analogous to that described in Example 18. Yield 1.8 mg. LC-MS: (m + 1) = 585 (m / z)

Example 25 MeNHCOCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-OH The title compound was converted to MeNHCOCH _2- (R) Cgl-Aze-Pab-Z (81 mg; 0.12
Mmol; see Example 36 below) in a manner analogous to that described in Example 18. Yield 10 mg (16%). LC-MS: (m + 1) = 517 (m / z)

Example 26 EtOOCCH _2- (R) Cgl-Aze-Pab-OAc (i) H- (R) Cgl-Aze-Pab-OAc The subtitle compound was obtained using acetic anhydride instead of propanoic anhydride. In the same manner as described in Example 27 (steps (i), (ii) and (iii)) below. LC-MS: (m + 1) = 430 (m / z)

(Ii) EtOOCCH _2- (R) Cgl-Aze-Pab-OAc The title compound was converted to H- (R) Cgl-Aze-Pab-OAc (370 mg; 0.6 mmol) and ethyl bromoacetate (105 mg; 0.63 mmol). In the same manner as in Example 1 (iii). Yield 67 mg (22%). LC-MS: (m + 1) = 516 (m / z)

Example 27 EtOOCCH _2- (R) Cgl-Aze-Pab-OC (O) Et (i) Boc- (R) Cgl-Aze-Pab-OH Hydroxylamine hydrochloride and triethylamine in EtOH Boc- (R) Cgl-Aze-Pab-Z (1.0 g; 1.52
Mmol). The reaction mixture was stirred at room temperature for 40 hours and concentrated. The crude product was purified by preparative RPLC. LC-MS: (m + 1) = 488 (m / z)

(Ii) Boc- (R) Cgl-Aze-Pab-OC (O) Et Boc- (R) Cgl-Aze-Pab-OH (500 mg; 0.91 mmol; from step (i) above) and anhydrous propane A solution of the acid (3.5 ml) was stirred at room temperature for 45 minutes and concentrated. Crude product as eluent
For preparative use of 50% acetonitrile in 0.1M NH ₄ OAc
Purification by RPCL provided 266 mg (54%) of the subtitle compound. LC-MS: (m + 1) = 544 (m / z)

(Iii) H- (R) Cgl-Aze-Pab-OC (O) Et The subtitle compound was converted to Boc- (R) Cgl-Aze-Pab-OC (O) Et (238 mg; 0.4
4 mmol; from step (ii) above), analogously to the method described in Example 1 (ii). Yield 290 mg (100%). LC-MS: (m + 1) = 444 (m / z)

(Iv) EtOOCCH _2- (R) Cgl-Aze-Pab-OC (O) Et H- (R) Cgl-Aze-Pab in methylene chloride (6 ml) at 0 ° C.
-OOCEt (300mg; 0.45 mmol; from the step (iii)) and K ₂ CO _3; To a solution of (308 mg 2.23 mmol), EtOOCCH ₂
OSO ₂ CF ₃ (105 mg; 0.45 mmol, made from triflic anhydride and ethyl glycolate) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was washed with water, citric acid and water, dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by preparative RPLC using 45% acetonitrile in 0.1 M NH ₄ OAc as eluent to give 63 mg (27%) of the title compound. LC-MS: (m + 1) = 530 (m / z)

Example 28 HOOCCH _2- (R) Cgl-Aze-Pab-OH (i) tBuOOCCH _2- (R) Cgl-Aze-Pab-OOCPh The subtitle compound was converted to H- (R) Cgl-Aze-Pab. Example 1 (ii) from -OOCPh (250 mg; 0.5 mmol; see Example 15 (ii) above) and t-butyl bromoacetate (119 mg; 0.6 mmol).
It was produced in the same manner as described in i). Yield 211 mg (69
%). LC-MS: (m + 1) = 606 (m / z)

(Ii) HOOCCH _2- (R) Cgl-Aze-Pab-OOCPh The subtitle compound was converted to tBuOOCCH _2- (R) Cgl-Aze-Pab-OOCPh (233 m
g; 0.3 mmol; from step (i) above) to Example 1 (ii)
In the same manner as described in Example 1. Yield 65 mg (37%). LC-MS: (m + 1) = 550 (m / z)

[0121] _{(iii) HOOCCH 2 - (R} ) Cgl-Aze-Pab-OH THF (10ml) and HOOCCH in methanol (1.5 ml) ₂ -
(R) Cgl-Aze-Pab-OOCPh (60 mg; 0.1 mmol; the above step)
(from (ii)) and a solution of KOMe (0.2 M; 0.2 mmol) were stirred at room temperature for 5 minutes. The reaction mixture was concentrated and lyophilized from water and acetonitrile to give 28 mg (63%) of the title compound. LC-MS: (m + 1) = 446 (m / z)

Example 29 HOOCCH _2- (R) Cgl-Aze-Pab-O-cis-oleyl (i) tBuOOCCH _2- (R) Cgl (Boc) -Aze-Pab-Z THF (30 ml) tBuOOCCH _2- (R) Cgl-Aze-Pab-Z (1.7
g, 2.8 mmol; see Example 37 below), (Boc) 2O (672
mg; 3.08 mmol) and DMAP (68 mg; 0.56 mmol)
Was stirred at room temperature for 24 hours. Furthermore, (Boc) 2O (305m
g; 1.4 mmol) at 5 ° C. After a further 24 hours, the reaction mixture was concentrated and purified by preparative RPLC to 587 mg (30 mg).
%) Of the desired compound. EC-MS: (m + 1) = 720 (m / z)

(Ii) tBuOOCCH _2- (R) Cgl (Boc) -Aze-Pab-OH The subtitle compound was converted to tBuOOCCH _2- (R) Cgl (Boc) -Aze-Pab-Z (580 m
g; 0.8 mmol; from step (i) above) analogously to the method described in Example 18. Yield 341 mg (71%). EC-MS: (m + 1) = 602 (m / z)

(Iii) tBuOOCCH _2- (R) Cgl (Boc) -Aze-Pab-O
-Cis-oleyl tBuOOCCH _2- (R) Cgl (Boc) -Aze-Pa in methylene chloride
A solution of b-OH (340 mg; 0.56 mmol; from step (ii) above), cis-oleyl chloride (170 mg; 0.56 mmol) and triethylamine (62 mg; 0.61 mmol) was stirred for 5 minutes. The reaction mixture was concentrated and purified by preparative RPLC to give 326 mg (67%) of the subtitle compound. EC-MS: (m + 1) = 867 (m / z)

(Iv) HOOCCH _2- (R) Cgl-Aze-Pab-O-cis-
Oleyl The title compound was prepared from tBuOOCCH _2- (R) Cgl (Boc) -Aze-Pab-O-cis-oleyl (223 mg; 0.25 mmol; from step (iii) above) in a manner similar to that described in Example 1 (ii). It was manufactured. LC-MS: (m + 1) = 710 (m / z)

[0126] [Example 30] cyclooctyl _{-OOCCH 2 - (R) Cgl-} Aze-Pab-Z (i) cyclooctyl - bromoacetate cyclooctanol (1.3 g; 10 mmol) and DMAP
(0.3 g) was dissolved in methylene chloride, and then bromoacetyl chloride (1 ml; 12 mmol) was added. After stirring for 18 hours, the reaction mixture was washed with aqueous Na ₂ CO ₃ (2M) and HCl (1M), dried, concentrated, and petroleum ether: methylene chloride (50:
Purification by flash chromatography using 50) gave 1.8 g (72%) of the subtitle compound.

(Ii) cyclooctyl-OOCCH _2- (R) Cgl-Az
e-Pab-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z x 2HCl (703 mg; 1.2 mmol) and cyclooctyl bromoacetate (363 m
g; 1.46 mmol; from step (i) above) to Example 1 (ii)
It was produced in the same manner as described in i). Yield 379mg (46
%). FAB-MS: (m + 1) = 674 (m / z)

Example 31 tBuCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z × 2HCl (2.5 g; 4.3 mmol) and t- Butyl methyl bromoacetate (1.
08 g; 5.2 mmol) in the same manner as described in Example 1 (iii). Yield 1.87 g (69%). FAB-MS: (m + 1) = 634 (m / z)

Example 32 (2-Me) BnOOCCH _2- (R) Cgl-Aze-Pab-Z (i) Methylbenzyl bromoacetate The subtitle compound was converted to 2-methylbenzyl alcohol (5 g; 41).
Mmol) and bromoacetyl chloride (12.6 g; 80 mmol) in a manner analogous to that described in Example 30 (i). Yield 8.2 g (82%).

(Ii) (2-Me) BnOOCCH _2- (R) Cgl-Aze-Pab-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z × 2HCl (580 mg; 1 mmol) and Prepared from methylbenzyl bromoacetate (290 mg; 1.2 mmol; from step (i) above) in a manner similar to that described in Example 1 (iii). 30mg yield
(4.5%). LC-MS: (m + 1) = 668 (m / z)

Example 33 ChCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z BnOOCCH _2- (R) Cgl-Aze-Pab-Z (1.41) in triethylamine (474 μl) and methylene chloride (3 ml) g; 1.7 mmol) and cyclohexylmethyl alcohol (6 ml) were refluxed for 4 days. The reaction mixture was worked up to give a crude product, which was eluted with methylene chloride: methanol
Purification by flash chromatography using (95: 5) gave 801 mg (71%) of the title compound. FAB-MS: (m + 1) = 660 (m / z)

Example 34 ChOOCCH _2- (R) Cgl-Aze-Pab-Z (i) Cyclohexylbromoacetate The subtitle compound was cyclohexanol (1 g; 10 mmol).
And from bromoacetyl chloride (1 ml; 12 mmol) in a manner analogous to that described in Example 32 (i) above.

(Ii) ChOOCCH _2- (R) Cgl-Aze-Pab-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z × 2HCl (2.5 g; 4.32
Mmol) and cyclohexyl bromoacetate (1.
5 g; 5.2 mmol) in the same manner as described in Example 1 (iii). Yield 1.7 g (60%). FAB-MS: (m + 1) = 646 (m / z)

Example 35 PhC (Me) ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z (i) 2-phenyl-2-propylbromoacetate The subtitle compound was converted to 2-phenyl-2-propanol (3 g). ;
Prepared from 22 mmol) and bromoacetyl chloride (4.16 g; 26 mmol) in a manner analogous to that described in Example 30 (i). Yield 1.2 g (44%).

(Ii) PhC (Me) ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z × 2HCl (1.2 g; 2.2 mmol) and 2 Prepared from -phenyl-2-propylbromoacetate (640 mg; 2.5 mmol; from step (i) above) in a manner similar to that described in Example 1 (iii). Yield 1.3 g (86%). ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.3 (br s, 1H), 8.35 (t,
1H), 7.75 (d, 2H), 7.45 (d, 2H), 7.30-7.05 (m, 10H or 11H), 5.15 (s, 2H), 4.78 (t, 1H), 4.40-4.30 (ABX
AB part of spectrum, 2H), 3.95 (q, 1H), 3.74 (q, 1H),
3.27-3.19 (AB-spectrum, 2H), 2.72 (d, 1H), 2.43
(q, 2H), 1.93 (br d, 1H), 1.75-1.60 (m, 9H or 10
H), 1.54 (d, 1H), 1.49-1.40 (m, 1H), 1.25-1.0 (m, 4
H), 0.92 (q, 1H).

Example 36 MeNHCOCH ₂ OOCCH ₂ — (R) Cgl-Aze-Pab-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z × 2HCl (1.0 g; 1.7 mmol) and MeNHCOCH ₂ OOCCH ₂ Br (440 mg; 2 mmol; prepared in analogy to the procedure described in Example 11 above (steps (i), (ii) and (iii)) using methylamine instead of cyclohexylamine) It was produced in the same manner as described in Example 1 (iii). Yield 380 mg (35%). FAB-MS: (m + 1) = 635 (m / z)

Example 37 tBuOOCCH _2- (R) Cgl-Aze-Pab-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z × 2HCl (500 mg; 1.0 mmol) and t-butyl bromoacetate (231 mg;
1.2 mmol) in the same manner as in Example 1 (iii). Yield 420 mg (69%). LC-MS: (m + 1) = 620 (m / z)

Example 38 (Me) ₂ CHC (Me) ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z (787 mg; 1.4 mmol) )) And 2,3-dimethyl-2-butylbromoacetate (364 mg; 1.63 mmol) in a manner analogous to that described in Example 1 (iii). Yield 590 mg (67%). FAB-MS: (m + 1) = 648 (m / z)

Example 39 iPrOOCCH _2- (R) Cgl-Aze-Pab-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z (700 mg; 1.2 mmol) and isopropyl bromoacetate (262 mg; 1.5).
Mmol) in the same manner as described in Example 1 (iii). Yield 225 mg (31%). FAB-MS: (m + 1) = 606 (m / z)

Example 40 BnOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-OMe) (i) Boc- (R) Cgl-Aze-Pab-COOPh (4-OMe) Prepared from-(R) Cgl-Aze-Pab-H and 4-methoxyphenyl chloroformate in the same manner as described in Example 1 (i). FAB-MS: (m + 1) = 622 (m / z)

(Ii) H- (R) Cgl-Aze-Pab-COOPh (4-OMe) × 2
HCl The subtitle compound was prepared from Boc- (R) Cgl-Aze-Pab-COOPh (4-OMe) (from step (i) above) in a manner similar to that described in Example 4 (ii).

(Iii) BnOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4
-OMe) The title compound was converted to H- (R) Cgl-Aze-Pab-COOPh (4-OMe) × 2HCl (8
5 mg; 0.16 mmol; from step (ii) above) and benzyl bromoacetate (90 mg; 0.2 mmol) as described in Example 1 (iii). Yield 60mg
(56%). FAB-MS: (m + 1) = 670 (m / z)

Example 41 ChCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-OMe) The title compound was converted to H- (R) Cgl-Aze-Pab-COOPh (4-OMe) (554 mg). ;
0.64 mmol; see Example 40 (ii) above) and cyclohexylmethyl bromoacetate (165 mg; 0.7 mmol), analogously to the procedure described in Example 1 (iii). Yield 34 mg (8%). FAB-MS: (m + 1) = 676 (m / z)

Example 42 (2-Me) BnOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-OMe) The title compound was converted to H- (R) Cgl-Aze-Pab-COOPh (4-OMe ) (522 mg;
1 mmol; see Example 40 (ii) above) and 2- (methyl) benzyl bromoacetate (365 mg; 1.5 mmol) in a manner analogous to that described in Example 1 (iii). Yield 158 mg (23%). LC-MS: (m + 1) = 684 (m / z)

Example 43 EtOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-OMe) (i) Boc- (R) Cgl-Aze-Pab-COOPh (4-Me) -(R) Cgl-Aze-Pab (1.96 g; 4.56 mmol) and 4-tolyl-chloroformate (850 mg; 4.9
9 mmol) in the same manner as described in Example 1 (i). Yield 1.39 g (55%). FAB-MS: (m + 1) = 606 (m / z)

(Ii) H- (R) Cgl-Aze-Pab-COOPh (4-Me) The subtitle compound was converted to Boc- (R) Cgl-Aze-Pab-COOPh (4-Me) (388 m
g; 0.64 mmol; from step (i) above) to Example 4 (i
It was produced in the same manner as described in i). Yield 293 mg (91
%). FAB-MS: (m + 1) = 506 (m / z)

(Iii) EtOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4
-Me) The title compound was converted to H- (R) Cgl-Aze-Pab-COOPh (4-Me) (288 mg;
0.6 mmol; from step (ii) above) and ethyl bromoacetate (114 mg; 0.7 mmol) from Example 1 (iii)
In the same manner as described in Example 1. Yield 81 mg (24%). FAB-MS: (m + 1) = 592 (m / z)

Example 44 BnOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-Me) The title compound was converted to H- (R) Cgl-Aze-Pab-COOPh (4-Me) (272 mg;
0.54 mmol; see Example 43 (ii) above) and benzyl bromoacetate (147 mg; 0.6 mmol) in a manner analogous to that described in Example 1 (iii). Yield 107mg
(31%). FAB-MS: (m + 1) = 654 (m / z)

Example 45 BnOOCCH _2- (R) Cgl-Aze-Pab-COO-nBu The title compound was converted to H- (R) Cgl-Aze-Pab-COO-nBu × 2HCl (400 m
g; 0.74 mmol; see Example 9 (ii) above) and benzyl bromoacetate (210 mg; 0.88 mmol) in a manner analogous to that described in Example 1 (iii). Yield 2
20 mg (48%). FAB-MS: (m + 1) = 620 (m / z)

Example 46 iPrOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH _{2 The} title compound was converted to H- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ × 2TFA (4
56 mg; 0.67 mmol; see Example 1 (ii) above) and isopropyl bromoacetate (145 mg; 0.8 mmol)
In the same manner as described in Example 1 (iii). Yield 294 mg (79%). FAB-MS: (m + 1) = 556 (m / z)

Example 47 EtOOCCH _2- (R) Cgl-Aze-Pab-COO-iBu (i) Boc-Pab-COO-iBu Boc-Pab-H (500 mg; 2.0 mg) in methylene chloride (10 ml)
Mmol; prepared from Bab-Z and (Boc) 2O to produce Boc-Pab-Z, followed by hydrogenation over Pd / C) and triethylamine (400 mg; 4.0 mmol) in solution.
At C, i-butyl chloroformate (270 mg; 2.2 mmol) was added. After stirring for 5 hours, water was added. The organic phase was dried (Na ₂ SO _4), to give the subtitle compound 530 mg (76%) and concentrated. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.5 (bs, 1 H), 7.82 (d, 2
H), 7.31 (d, 2H), 6.6 (bs, 1H), 5.0 (bs, 1H), 4.33 (bd,
2H), 3.93 (d, 2H), 2.04 (m, 1H), 1.45 (s, 9H), 0.97
(d, 6H).

(Ii) H-Pab-COO-iBu × 2HCl The subtitle compound was converted to Boc-Pab-COO-iBu (520 mg; 1.5 mmol;
It was prepared in the same manner as described in Example 4 (ii) from the above step (i). Yield 430 mg (88%). ¹ H NMR (500 MHz, MeOD) δ 7.89 (d, 2H), 7.75 (d, 2H),
4.30 (s, 2H), 4.17 (d, 2H), 2.11-2.05 (m, 1H), 1.02
(d, 6H).

(Iii) Boc- (R) Cgl-Aze-Pab-COO-iBu Boc- (R) Cgl-Aze-OH (4 ml) in acetonitrile (20 ml)
80 mg; 1.4 mmol), H-Pab-COO-iBu x 2HCl (430 mg; 1.
3 mmol; from step (ii) above) and DMAP (650 mg; 5.
EDC (270 mg; 1.4 mmol)
Was. After stirring at room temperature for 3 days, the reaction mixture was concentrated and extracted with water
And dissolved in EtOAc. NaHCO organic phase _ThreeWash with (aqueous)
And dried (Na_TwoSO_Four), Concentrate and use EtOAc as eluent
Purification by flash chromatography using
Obtained 0 mg (52%) of the subtitle compound.

(Iv) H- (R) Cgl-Aze-Pab-COO-iBu × 2HCl The subtitle compound was converted to Boc- (R) Cgl-Aze-Pab-COO-iBu (500 mg; 0.8 mg).
8 mmol; from step (iii) above) in a manner analogous to that described in Example 4 (ii). Yield 360 mg (87%).

(V) EtOOCCH _2- (R) Cgl-Aze-Pab-COO-iBu The title compound was converted to H- (R) Cgl-Aze-Pab-COO-iBu × 2HCl (290 m
g; 0.53 mmol; from step (iv) above) and ethyl bromoacetate (110 mg; 0.64 mmol) from Example 1.
It was produced in the same manner as described in (iii). 140mg yield
(47%). FAB-MS: (m + 1) = 558 (m / z)

Example 48 BnOOCCH _2- (R) Cgl-Aze-Pab-COO-nPr The title compound was converted to H- (R) Cgl-Aze-Pab-COO-nPr × 2TFA (902 m
g; 1.3 mmol; see Example 5 (ii) above) and benzyl bromoacetate (362 mg; 1.6 mmol) in a manner analogous to that described in Example 1 (iii). Yield 199
mg (25%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (bs, 1H), 7.78 (d, 2
H), 7.38-7.27 (m, 7H), 5.05 (s, 2H), 4.90 (dd, 1H), 4.
56-4.39 (AB part of ABX spectrum, 2H), 4.12-4.03 (m, 3
H), 3.98-3.91 (q, 1H), 3.33-3.22 (AB-spectrum, 2
H), 2.85 (d, 1H), 2.65-0.94 (m, 19H).

Example 49 EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOCCh (i) EtSCOOCH ₂ OOCCh Tetrabutylammonium hydrogen sulfate (15.6 g, 45.6 mmol) in methylene chloride and cyclohexanecarboxylic acid ( 5.85 g (46 mmol) in NaOH at 0 ° C.
(9.1 ml, 10 M; 68 mmol) was added. After stirring for 5 minutes, the reaction mixture is filtered, washed with methylene chloride, dissolved in toluene, concentrated, dissolved in THF and [Bu ₄ N] ⁺ [OOCC
h] ^- was obtained. EtSCOOCH ₂ Cl (4 g; 25.9 mmol; Folkman
n and Lund, J. Synthesis, 1159 (1990)) were added to a solution of [Bu ₄ N] ⁺ [OOCCh] ⁻ in THF at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated and purified by flash chromatography to give 2.57 g (40%) of the subtitle compound. ¹ H NMR (400 MHz, CDCl ₃ ) characteristic peak δ 5.80 (s, 2H, O
_{-CH 2 -O), 2.85 (q} , 2H, CH 2 -S).

(Ii) ClCOOCH ₂ OOCCh EtSCOOCH ₂ OOCCh (2.9 g; 11.8 mmol; the above step (i)
To) at 0 ° C. was added SO ₂ Cl ₂ (3.18 g; 23.6 mmol) dropwise. After stirring for 30 minutes, the reaction mixture is concentrated to 1.82 g
(70%) of the desired compound was obtained. ¹ H NMR (500 MHz, CDCl ₃ ) characteristic peak δ 5.82 (s, 2H, O
-CH ₂ -O).

(Iii) Boc- (R) Cgl-Aze-Pab-COOCH ₂ OOCCh The subtitle compound was converted to Boc- (R) Cgl-Aze-Pab-H (750 mg; 1.59 mmol) and ClCOOCH ₂ OOCCh (460 mg; 2.1 mmol) From the above step (ii)) in the same manner as in the method described in Example 1 (i). The crude product was purified by preparative RPLC. Yield 355 mg (9%). FAB-MS: (m + 1) = 656 (m / z)

(Iv) H- (R) Cgl-Aze-Pab-COOCH ₂ OOCCh × 2T
The FA subtitle compound was prepared from Boc- (R) Cgl-Aze-Pab-COOCH ₂ OOCCh (from step (iii) above) in a manner similar to that described in Example 1 (ii).

(V) EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOC
Ch The title compound was H- (R) Cgl-Aze-Pab-COOCH ₂ OOCCh × 2TFA (19
3 mg; 0.35 mmol; from step (iv) above) and ethyl trifluoroacetate (83 mg; 0.35 mmol) prepared analogously to the method described in Example 1 (iii). Yield 8
7 mg (39%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (t br, 1 H), 7.83 (d,
2H), 7.37 (d, 2H), 5.86 (s, 2H), 4.95 (dd, 1H), 4.15-
4.39 (AB part of ABX spectrum, 2H), 4.18-4.05 (m, 5H),
3.26-3.17 (AB-spectrum, 2H), 2.87 (d, 1H), 2.75-
0.95 (m, 29H).

Example 50 EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOCCH ₂ Ch The title compound was prepared in the same manner as in the method described in Example 49 above, except that cyclohexylacetic acid was used instead of cyclohexanecarboxylic acid. It was manufactured. Yield 74 mg (17%). FAB-MS: (m + 1) = 656 (m / z)

Example 51 EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH (Me) OOCPh The title compound was replaced by EtSCOOCH (CH ₃ ) Cl instead of EtSCOOCH ₂ Cl.
(Prepared from ClCOCH (CH ₃ ) Cl and EtSH using the method described in Folkmann et al., J. Synthesis, 1159 (1990))
In the same manner as described in Example 49 above. Yield 70 mg (23%). FAB-MS: (m + 1) = 650 (m / z)

Example 52 EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOCPh The title compound was prepared in the same manner as described in Example 49 above, except that benzoic acid was used instead of cyclohexanecarboxylic acid. Manufactured. Yield 50 mg (39%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.73-9.25 (s br, 1 H), 8.4
5 (t, 1H), 8.05 (d, 2H), 7.83 (d, 2H), 7.60-7.10 (m, 6
H), 6.10 (s, 2H), 4.96-4.84 (dd, 1H), 4.62-4.30 (ABX,
2H), 4.20-3.93 (m, 4H), 3.25 (s, 2H), 2.84 (d, 1H),
2.73-2.41 (m, 2H), 2.41-0.87 (m, 15H). ¹³ C NMR (300 MHz, CDCl ₃ , amidine and carbonyl carbon) δ 163.1, 165.3, 169.0, 170.8, 172.3, 175.5.

Example 53 BnOOCCH _2- (R) Cgl-Aze-Pab-COOCH (Me) OAc The title compound was converted to H- (R) Cgl-Aze-Pab-COOCH (CH ₃ ) OC (O) CH ₃ (1
08 mg; 0.21 mmol; see Example 14 (ii) above) and benzyl bromoacetate (36 μl; 0.23 mmol), prepared in a manner analogous to that described in Example 1 (iii).
Yield 41 mg (30%). FAB-MS: (m + 1) = 650 (m / z)

Example 54 EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OAc (i) H- (R) Cgl-Aze-Pab-COOCH ₂ OAc × 2TFA The subtitle compound was acetoxymethyl 4-nitro Example 14 (steps (i) and (ii)) using phenyl carbonate (prepared in a manner similar to that described in Example 12 (iii) using silver acetate instead of silver pivalate) In the same manner as described in Example 1. Work-up afforded the sub-title compound, which was used in the next step without further purification.

(Ii) EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OA
c The title compound was H- (R) Cgl-Aze-Pab-COOCH ₂ OAc × 2TFA (0.83
(From step (i) above) and from ethyl bromoacetate (2.2 mmol) in a manner analogous to that described in Example 1 (iii) above. Yield 286 mg. FAB-MS: (m + 1) = 574 (m / z)

Example 55 tBuOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OAc The title compound was converted to H- (R) Cgl-Aze-Pab-COOCH ₂ OAc × 2TFA (0.31
3 mmol; see Example 54 (i) above) and t-butyl bromoacetate (73 mg; 0.376 mmol), prepared analogously to the procedure described in Example 1 (iii) above. Yield 1
56 mg (83%). FAB-MS: (m + 1) = 602 (m / z)

Example 56 BnOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOC-tBu The title compound was converted to H- (R) Cgl-Aze-Pab-COOCH ₂ OOC-tBu (379 m
g; 0.71 mmol; see Example 12 (v) above) and benzyl bromoacetate (135 μl; 0.85 mmol) in a manner analogous to that described in Example 1 (iii). Yield 1
46 mg (30%). FAB-MS: (m + 1) = 678 (m / z)

Example 57 EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CCl ₃ (i) Boc- (R) Cgl-Aze-Pab-COOCH ₂ CCl _{3 The} subtitle compound was Boc- (R) Example 1 from Cgl-Aze-Pab-H (1.0 g; 2.12 mmol), 2M NaOH (11.7 ml) and trichloroethyl chloroformate (494 mg; 2.33 mmol).
It was produced in the same manner as described in (i). Yield 1.08 g (7
9%).

(Ii) H- (R) Cgl-Aze-Pab-COOCH ₂ CCl _{3 The} subtitle compound was converted to Boc- (R) Cgl-Aze-Pab-COOCH ₂ CCl ₃ (1.04
g; 1.607 mmol; from step (i) above) to Example 1 (i
It was produced in the same manner as described in i). Yield 1.43 g (99
%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.79 (d, 2H), 7.61 (d, 2
H), 5.10 (s, 2H), 4.87-4.81 (m, 2H), 4.63-4.52 (q, 2
H), 4.41-4.34 (m, 1H), 4.30-4.24 (m, 1H), 3.72 (d, 1H),
2.72-2.63 (m, 1H), 2.32-2.25 (m, 1H), 1.88-1.10 (m, 1
4H).

(Iii) EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ C
Cl ₃ title compound was converted to H- (R) Cgl-Aze-Pab-COOCH ₂ CCl ₃ (400 mg;
52 mmol; from step (ii) above) and ethyl bromoacetate (95 mg; 0.57 mmol) prepared analogously to the method described in Example 1 (iii). Yield 8 mg (23%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.47 (bt, 1H), 7.83 (d, 2
H), 7.48 (bs, 1H), 7.31 (d, 2H), 4.92 (dd, 1H), 4.85
(s, 2H), 4.58-4.39 (AB part of ABX spectrum, 2H), 4.1
6-4.06 (m, 4H), 3.24 (s, 2H), 4.87 (d, 1H), 2.65-2.59
(m, 1H), 2.56-2.48 (m, 1H), 2.10-0.95 (m, 16H).

Example 58 MeOOC-C (= CEt) CH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z (i) MeOOC-C (= CH) C (OH) Et propionaldehyde (10.1 g ; 0.174 mol) was added dropwise to a solution of methyl acrylate (10 g; 0.116 mol) and 1,4-diazobicyclo [2,2,2] octane (1.3 g; 0.0116 mol). The reaction mixture was stirred at room temperature for 14 days. Ethyl acetate (150ml) was added. The organic phase was washed with water and brine, dried (Na ₂ SO _4), filtered to give the desired compound was concentrated. Yield 15.5 g (93%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.24 (s, 1H), 5.81 (s, 1
H), 4.34 (t, 1H), 3.78 (s, 3H), 2.82 (bs, 1H), 1.69 (m,
2H), 0.95 (t, 3H).

(Ii) MeOOC-C (= CEt) CH ₂ Br HBr (6.5 ml, ~ 48%) was converted to MeOOC-C (= CH) C (OH) Et (3 g;
8 mmol; from step (i) above) at 0 ° C. 5
After minutes, H ₂ SO ₄ (conc .; 6 ml) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours. The two phases were separated and the upper phase was diluted with ether. The ether phase was washed with water and aqueous NaHCO _3, dried (Na ₂ SO ₄ and charcoal) and concentrated. The residue was purified by flash chromatography. Yield 1.7
g (40%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.97 (t, 3H), 4.23 (s, 2
H), 3.8 (s, 3H), 2.32 (m, 2H), 1.13 (t, 3H).

(Iii) tBuOOCCH _2- (R) Cgl-Aze-Pab-Z The subtitle compound was converted to H- (R) Cgl-Aze-Pab-Z (2.1 g; 3.6 mmol) and t-butyl bromoacetate (780 mg; 4.0 mmol) in the same manner as described in Example 1 (iii). Yield 1.73 g (78%).

[0176] _{(iv) HOOCCH 2 - (R} ) Cgl-Aze-Pab-Z tBuOOCCH in methylene chloride _{2 - (R) Cgl-Aze} -Pab-Z
The solution of TFA (from step (iii) above) and TFA was stirred at room temperature for 3 hours. The reaction mixture was concentrated and lyophilized from water and HCl (conc .; 10 eq).

(V) MeOOC-C (= CEt) CH ₂ OOCCH _2- (R) Cgl-Aze
-Pab-Z HOOCCH _2- (R) Cgl-Aze-Pab-Z (263 mg; 0.41 mmol; from step (iv) above), freeze a solution of NaOH (1 M; 1.239 ml; 1.239 mmol) and water (4 ml) Dried. DMF (5 ml) was added and then at 0 ° C. Me-OOC-C (= CEt) CH ₂ Br (103 mg; 0.496
Mmol; from step (ii) above) was added dropwise. The reaction mixture was stirred for 24 hours at room temperature, diluted with toluene (5 ml), washed with water, dried (Na ₂ SO ₄₎ and concentrated. The residue was purified by flash chromatography using EtOAc: Methanol (95: 5) as eluent. Yield 95 mg (33%). FAB-MS: (m + 1) = 690 (m / z)

Example 59 MenOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-OMe) (i) MenOOCCH ₂ Br The subtitle compound was prepared from MenOH (10 mmol) and bromoacetyl chloride (12 mmol) as described above. It was prepared in the same manner as described in Example 30 (i). Yield 1.5 g (54%).

(Ii) MenOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4
-OMe) The title compound was converted to H- (R) Cgl-Aze-Pab-COO-Ph (4-OMe) (521m
g; 1 mmol; see Example 40 (ii) above) and MenOO
Prepared from CCH ₂ Br (416 mg; 1.5 mmol; from step (i) above) in a manner similar to that described in Example 1 (iii). Yield 36 mg (5%). FAB-MS: (m + 1) = 718 (m / z)

Example 60 tBuOOCCH _2- (R) Cgl-Aze-Pab-COOnPr The title compound was converted to H- (R) Cgl-Aze-Pab-COO-nPr (575 mg; 0.837).
Mmol; see Example 5 (ii) above) and t-butyl bromoacetate (196 mg; 1.01 mmol) in a manner analogous to that described in Example 1 (iii). 110mg yield
(twenty three%). LC-MS: (m + 1) = 572 (m / z)

Example 61 MenOOCCH _2- (R) Cgl-Aze-Pab-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z (0.7 g; 1.21 mmol) and MenOOCCH ₂ Br (0.4 g). 1.45 mmol; see Example 59 (i) above) in a manner similar to that described in Example 1 (iii). Yield 0.33 g (38%). FAB-MS: (m + 1) = 702 (m / z)

Example 62 BnOOCCH _2- (R) Cgl-Aze-Pab-COO-Bn (4-NO ₂ ) (i) Boc- (R) Cgl-Aze-Pab-COO-Bn (4-NO ₂₎ the subtitle compound Boc- (R) Cgl-Aze- Pab-H (1.03g; 2.18 mmol), 2M NaOH (24 ml) and 4-NO ₂ - benzyl chloroformate (518 mg; implemented from 2.4 mmol) example 1 (i)
In the same manner as described in Example 1. Yield 1.32 g (93
%). FAB-MS: (m + 1) = 651 (m / z)

(Ii) H- (R) Cgl-Aze-Pab-COO-Bn (4-NO ₂ ) The subtitle compound was converted to Boc- (R) Cgl-Aze-Pab-COO-Bn (4-NO ₂ ) ( 1.32
mg; 2.03 mmol; from step (i) above) to Example 4 (i
It was produced in the same manner as described in i). Yield 1.0 g (79
%). FAB-MS: (m + 1) = 551 (m / z)

(Iii) BnOOCCH _2- (R) Cgl-Aze-Pab-COO-Bn
(4-NO ₂ ) The title compound was converted to H- (R) Cgl-Aze-Pab-COO-Bn (4-NO ₂ ) (0.5
g; 0.80 mmol; from step (ii) above) and benzyl bromoacetate (220 mg; 0.90 mmol) in a manner analogous to that described in Example 1 (iii). FAB-MS: (m + 1) = 699 (m / z)

Example 63 EtOOCCH _2- (R) Cgl-Aze-Pab-Bn (4-NO ₂ ) The title compound was converted to H- (R) Cgl-Aze-Pab-COO-Bn (4-NO ₂ ) (211m
g; 0.38 mmol; see Example 62 (ii) above) and ethyl bromoacetate (47 μl; 0.42 mmol) in a manner analogous to that described in Example 1 (iii). Yield 4
4 mg (18%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.55 (bs, 1H), 8.50 (bt, 1
H), 8.20 (d, 2H), 7.80 (d, 2H), 7.60 (d, 2H), 7.35 (d,
2H), 6.87 (bs, 1H), 4.95 (dd, 1H), 4.65-4.40 (AB part of ABX spectrum, 2H), 4.18-4.04 (m, 5H), 3.27-3.15 (A
B-spectrum, 2H), 2.87 (d, 1H), 2.75-2.60 (m, 1H),
2.57-2.45 (m, 1H), 2.00-0.95 (m, 16H).

Example 64 PrlC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z (i) PrlC (O) CH ₂ OH 2,5-dioxo-1,4-dioxane (2.0 g; 17 mmol) and pyrrolidine (8 ml; 97 mmol) were refluxed for 1 hour. Excess pyrrolidine was removed by evaporation. Yield 4.4 g (99%). FAB-MS: (m + 1) = 130 (m / z)

(Ii) Bromination to a solution of PrlC (O) CH ₂ OH (0.4 g; 3.1 mmol; from step (i) above) in PrlC (O) CH ₂ OOCCH ₂ Br DMF (15 ml) at 0 ° C. Bromoacetyl (0.63 g; 3.1 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C. for 1.5 hours and at room temperature for 3 hours. Further bromoacetyl bromide (0.63 g; 3.1 mmol) was added and the reaction mixture was heated to 80 ° C., stirred at room temperature for 12 hours and concentrated. Yield 320 mg (41%). FAB-MS: (m + 1) = 252 (m / z)

(Iii) PrlC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-Pab
-Z The title compound was converted to H- (R) Cgl-Aze-Pab-Z (580 mg; 1 mmol) and PrlC (O) CH ₂ OOCCH ₂ Br (300 mg; 1.2 mmol;
From the above step (ii)), it was produced in the same manner as in the method described in Example 1 (iii). Yield 400 mg (60%). FAB-MS: (m + 1) = 675 (m / z) ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.66-9.42 (bs, 1H), 8.64-
8.56 (m, 1H), 8.03-7.93 (d, 2H), 7.89-7.66 (bs, 1H),
7.45 (d, 2H), 7.45-7.25 (m, 5H), 5.20 (s, 2H), 4.98-
4.92 (dd, 1H), 4.82-4.74 (m, 1H), 4.62, 4.58 (AB spectrum, 2H), 4.26-4.05 (m, 3H), 3.47-3.16 (m, 6H),
2.95 (d, 1H), 2.78-2.68 (m, 1H), 2.54-2.42 (m, 1H),
2.03-1.95 (m, 16H).

Example 65 (2-Me) BnOOCCH _2- (R) Cgl-Aze-Pab-COO-Bn (4-NO ₂ ) The title compound was converted to H- (R) Cgl-Aze-Pab-COO- Bn (4-NO ₂ ) (500m
g; 0.80 mmol; see Example 62 (ii) above) and 2
-(Methyl) benzyl bromoacetate (234 mg; 0.96 mmol; see Example 32 (i) above) to Example 1 (iii)
In the same manner as described in Example 1. Yield 528 mg (92
%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.34 (bs, 1H), 8.38 (t, 1
H), 8.09 (d, 2H), 7.72 (d, 2H), 7.48 (d, 2H), 7.37 (bs,
1H), 7.23 (d, 2H), 7.17-7.05 (m, 4H), 5.18 (s, 2H),
5.00 (s, 2H), 4.81 (dd, 1H), 4.45-4.34 (AB part of ABX spectrum, 2H), 4.04-3.97 (q, 1H), 3.93-3.86 (q, 1H),
3.27-3.17 (AB spectrum, 2H), 2.79 (d, 1H), 2.54-2.35
(m, 2H), 2.22 (s, 3H), 1.91-1.84 (bd, 1H), 1.71-1.39
(m, 5H), 1.19-0.84 (m, 4H).

Example 66 MeOOCCH _2- (R) Cgl-Aze-Pab-COOEt The title compound was converted to H- (R) Cgl-Aze-Pab-COOEt (305 mg; 0.69 mmol; see Example 4 (ii)). )) And methyl bromoacetate (126 mg; 0.83 mmol) in the same manner as described in Example 1 (iii). Yield 188 mg (53%). LC-MS: (m + 1) = 516 (m / z)

Example 67 (nPr) ₂ NC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-Pab-COO-Bn (4-NO ₂ ) (i) (nPr) ₂ NC (O) CH ₂ OOCCH ₂ Cl (nPr) ₂ NC (O) CH ₂ OH (244 mg; 1.53 mmol; Example 1 above)
2 (i)) and bromoacetyl chloride (270 mg; 1.72
Mmol) was stirred at room temperature for 12 hours. The mixture was poured into aqueous NaHCO ₃ and extracted with methylene chloride. The organic phase was washed aqueous KHSO ₄ (0.2M) and brine, dried and concentrated. FAB-MS: (m + 1) = 237 (m / z) ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.82 (s, 2H), 4.22 (s, 2)
H), 3.31-3.26 (t, 2H), 3.10-3.15 (t, 2H), 1.68-1.52
(m, 2H), 1.97-0.86 (m, 6H).

(Ii) (nPr) ₂ NC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-P
ab-COO-Bn (4- NO 2) The title compound H- (R) Cgl-Aze- Pab-COO-Bn (4-NO 2) (343m
g; 0.62 mmol; see Example 62 (ii) above) and (nP
r) ₂ NC (O) CH ₂ OOCCH ₂ Cl (160 mg; 0.68 mmol; above step)
from (i)) in the same manner as described in Example 1 (iii). Yield 89 mg (19%). FAB-MS: (m + 1) = 750 (m / z)

Example 68 (2-Me) BnOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOCtBu The title compound was converted to H- (R) Cgl-Aze-Pab-COOCH ₂ OOCtBu (380 mg;
0.71 mmol; see Example 12 (v) above) and 2- (methyl) benzylbromoacetate (215 mg; 0.88 mmol; see Example 32 (i) above) from the method described in Example 1 (iii). It was manufactured in the same manner. Yield 37 mg (7.5%). FAB-MS: (m + 1) = 692 (m / z)

Example 69 All of the compounds of Examples 1 to 68 were tested in Test A above and were found to all exhibit IC ₅₀ TT values greater than 1.0 μM (ie, these compounds exhibited thrombin itself). Inactive against; 0.
Active inhibitor HOOC-CH _2- (R) Cgl-Aze showing an IC ₅₀ TT of 01 μM
-Pab-H).

Example 70 The compounds of Examples 1 to 68 were tested in one, two or all of the above Tests B, C and / or D. As a result, they were all free bases and / or one or more thereof. active inhibitor HOOC-CH ₂ as esters of - as (R) Cgl-Aze-Pab -H, it was found to exhibit oral and / or parenteral bioavailability in the rat. _{HOOC-CH 2 - (R)} Cgl-Aze-Pab-H is based on the assumption that generated in rats was calculated according to the formula described in vivo efficacy rate test B and / or testing C.

Abbreviations Ac = acetyl aq = aqueous Aze = S-azetidine-2-carboxylic acid Boc = t-butyloxycarbonyl (Boc) ₂ O = di-t-butyl dicarbonate Bn = benzyl Bu = butyl Cgl = cyclohexyl Glycine Ch = cyclohexyl DCC = dicyclohexylcarbodiimide DMAP = N, N-dimethylaminopyridine EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Et = ethyl EtOH = ethanol EtOAc = ethyl acetate h = time HCl = Hydrochloric acid H-Pab-H = 1-amidino-4-aminomethylbenzene H-Pab-Z = 4-aminomethyl-1- (N-benzyloxycarbonylamidino) benzene HPLC = high-performance liquid chromatography K ₂ CO ₃ = anhydrous Potassium carbonate Me = methyl Men = (1R, 2S, 5R) -menthyl Pab-OH = 4-aminomethyl-benzamide oxime (4
-Aminomethyl-1- (amino-hydroxyiminomethyl) benzene) Piv (aloyl) = 2,2-dimethylacetyl Pr = propyl Prl = N-pyrrolidinyl RPLC = reverse phase high performance liquid chromatography TFA = trifluoroacetic acid THF = tetrahydrofuran Z = benzyloxycarbonyl The prefixes n, s, i and t have their usual meaning: normal, iso, secondary and tertiary. The prefixes s, d, t, q and b in the NMR spectrum mean singlet, doublet, triplet, quadruplet and broad signals, respectively. Unless otherwise specified, the stereochemistry of amino acids is in the (S) form.

 ────────────────────────────────────────────────── ─── Continuing from the front page (72) Inventor Gustavson, Darweed S-42932 Kravík. Enghagavägen (No address) (72) Inventor Hoffmann, Kurt-Jürgen S-42931 Kravík. Lindome. Flindsteinswegen 36 (72) Inventor Sorensen, Henrys S. Sweden 43435 Mornrique. Veedevägen 37 (72) Inventor Selene, Meekael S. Sweden 41411 Gothenburg. Tan 3

Claims (51)

[Claims] 1. Formula I R¹O (O) C-CH_Two-(R) Cgl-Aze-Pab-R^Two (I) [wherein, R¹Is -R^Three, -A¹C (O) N (R^Four) R^FiveOr -A¹C (O) OR^Fourso
Yes; A¹Is C_1-5R is alkylene;^Two(Amidino of Pab-H
Replaces one of the hydrogen atoms in the unit) is OH, OC (O) R⁶, C (O)
OR ⁷Or C (O) OCH (R⁸) OC (O) R⁹And R^ThreeIs H, C_1-10A
Lucil or C_1-3Alkylphenyl (the latter group
More C _1-6Alkyl, C_1-6Alkoxy, nitro or halo
R)^FourAnd R^FiveIndependently
H, C_1-6Alkyl, phenyl and 2-naphthyl;
Or R¹But -A¹C (O) N (R^Four) R^FiveIf they are joined
Pyrrolidinyl or pipette together with the nitrogen atom
Represents lysinyl; R⁶Is C_1-17Alkyl, phenyl or
2-naphthyl (these are all optionally C_1-6Alkyl
Or substituted by halogen); R⁷Is 2-na
Futyl, phenyl, C_1-3Alkylphenyl (the latter three
Is optionally C_1-6Alkyl, C_1-6Alkoxy, Nito
B) or C)_1-12A
Lequil (the latter group may be C_1-6Alkoxy, C_1-6A
Substituted by siloxy or halogen);
R⁸Is H or C_1-4Alkyl; and R⁹Is 2-naph
Chill, phenyl, C_1-6Alkoxy or C_1-8Alkyl
(The latter group may optionally be halogen, C_1-6Alkoxy or
Is C_1-6Substituted by acyloxy). However,
R¹Is R^ThreeAnd R^ThreeIs benzyl, methyl, ethyl, n-butyl
Tyl or n-hexyl; and R^TwoIs C (O) OR⁷so
If so, R⁷Is not benzyl. ] Or the compound
Pharmaceutically acceptable salts of 2. When R ¹ is —A ¹ C (O) N (R ⁴ ) R ⁵ , A ¹ is C
The compound of formula I according to claim 1, which is _1-3 alkylene. 3. When R ¹ is —A ¹ C (O) N (R ⁴ ) R ⁵ , R ⁴ is H
Or a C _1-6 alkyl.
Compound. 4. When R ¹ is —A ¹ C (O) N (R ⁴ ) R ⁵ , R ⁵ is C
_1-6 alkyl or C _{4 -6} compound of Formula I of any of claims 1 to 3 is cycloalkyl. 5. When R ¹ is —A ¹ C (O) N (R ⁴ ) R ⁵ , R ⁴ and R ⁵ together are pyrrolidinyl.
A compound of formula I according to any of the preceding claims. 6. A ¹ is C _1-3 alkylene, R ⁴ is H or C _1-3 alkyl, and R ⁵ is C _2-6 alkyl or
C _5-6 cycloalkyl, or R ⁴ and R ⁵ are compounds of formula I according to one of claims 2 to 5 is a pyrrolidinyl together. 7. The compound of formula I according to claim ¹ , wherein when R ¹ is —A ¹ C (O) OR ⁴ , A ¹ is C _1-5 alkylene. 8. The compound of formula I according to claims 1 to 7, wherein when R ¹ is —A ¹ C (O) OR ⁴ , R ⁴ is C _1-6 alkyl. 9. A ¹ is C _1-5 alkylene and R ⁴ is
_9. A compound of formula I according to claim 7 or 8, which is _C1-4alkyl . 10. When R ¹ is R ³ , R ³ is H, C _1-10 alkyl (the latter group is straight-chain or branched if there is a sufficient number of carbon atoms, and And / or C _1-3 alkylphenyl (the latter group is optionally substituted and may be straight-chain or branched if there is a sufficient number of carbon atoms) Or a compound of formula I according to claim 1. 11. R ¹ is H, linear C _1-10 alkyl, branched C _3-10 alkyl, partially cyclic C _4-10 alkyl, C
_4-10 cycloalkyl, optionally substituted linear C _1-3
Alkylphenyl, when the compound of claim 1 or 10, wherein a branched C ₃ alkylphenyl substituted by. 12. The compound of claim 11, wherein R ¹ is linear C _1-6 alkyl, C _6-10 cycloalkyl, or optionally substituted linear C _1-3 alkylphenyl. 13. The compound of formula I according to claim 1, wherein R ² is OH. 14. When R ² is OC (O) R ⁶ , R ⁶ is optionally substituted phenyl or C _1-17 alkyl (the latter group is straight-chain or has a sufficient number of carbon atoms. Is branched, cyclic or partially cyclic, and / or may be saturated or unsaturated).
13. A compound of formula I according to any of claims 12 to 12. 15. R ⁶ is optionally substituted phenyl,
Linear C _1-4 alkyl, branched C _3-4 alkyl or cis-
15. The compound according to claim 14, which is oleyl. 16. R ⁶ is linear C _1-3 alkyl or branched
C ₃ alkyl as claimed in claim 15 A compound according. 17. When R ² is C (O) OR ⁷ , R ⁷ is optionally substituted phenyl, C _1-12 alkyl (the latter group being optionally substituted, straight-chain or If any, is branched, cyclic or partially cyclic, and / or may be saturated or unsaturated, or C _1-3 alkylphenyl (the latter group optionally being 13. A compound of formula I according to any of the preceding claims, which is substituted and may be straight-chain or branched if there is a sufficient number of carbon atoms. 18. R ⁷ is optionally substituted and / or optionally unsaturated linear C _1-4 alkyl; optionally substituted and / or optionally unsaturated branched
C _3-4 alkyl; optionally substituted phenyl, optionally compound of claim 17, wherein a branched C ₃ alkylphenyl substituted linear C _1-3 alkylphenyl or optionally by substituted. 19. R ⁷ linear C _1-4 is optionally substituted with
Alkyl, optionally substituted branched C _3-4 alkyl,
The compound of claim 18 wherein the linear C _1-3 alkyl-phenyl or branched C ₃ alkylphenyl are optionally substituted. 20. When R ² is C (O) OCH (R ⁸ ) OC (O) R ⁹ ,
R ⁸ is a compound of formula I according to one of claims 1 to 12 is H or methyl. 21. When R ² is C (O) OCH (R ⁸ ) OC (O) R ⁹ ,
R ⁹ is phenyl, or C _1-8 alkyl (the latter group being optionally substituted, straight-chain or branched if there is a sufficient number of carbon atoms, and / or cyclic or partially cyclic 21. A compound of formula I according to any one of claims 1 to 12 or 20. 22. R ⁸ is H or methyl and R ⁹
Is phenyl, C _5-7 cycloalkyl, linear C _1-6 alkyl, branched C _3-6 alkyl or partially cyclic C _7-8 alkyl. Compound. 23. R ⁸ is H, and R ⁹ is C _5-7 cycloalkyl, linear C _{1 -6} alkyl or partially cyclic C
_23. The compound according to claim 22, which is _7-8 alkyl. 24. The method of claim ^{1, wherein} when R ¹ is R ³ and R ³ is optionally substituted C _1-3 alkylphenyl, the optional substituent is C _1-6 alkyl. The compound according to any one of the above items. 25. The compound according to claim 24, wherein said substituent is methyl. 26. R ² is C (O) OR ^7, and where R ⁷ is C _1-12 optionally substituted alkyl, the optional substituents are selected from halogen and C _1-6 alkoxy A compound according to any one of claims 1 to 25. 27. The compound of claim 26, wherein said substituent is selected from chloro and methoxy. 28. When R ² is C (O) OR ⁷ and R ⁷ is optionally substituted phenyl, an optional substituent is
C _1-6 alkyl, a compound of according to one of claims 1 to 27 which is selected from C _1-6 alkoxy and halogen. 29. The compound of claim 28, wherein said substituent is selected from methyl, methoxy and chloro. 30. R ² is C (O) is OR ^7, and where R ⁷ is C _1-3 alkyl phenyl optionally substituted with, according to claim 1 to 29 optional substituent is nitro The compound according to any one of the above items. 31.EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = C
H ₂ ; nPrOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ ; tBuOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ ; EtOOCCH _2- (R) Cgl-Aze -Pab-COOEt; EtOOCCH _2- (R) Cgl-Aze-Pab-COO-nBu; PrlC (O) CH ₂ CH ₂ CH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z; ChNHC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z; (nPr) ₂ NC (O) CH ₂ OOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOCC (C
_{H 3) 3; EtOOCCH 2 -} (R) Cgl-Aze-Pab-COOCH 2 OOCC (CH 3) 3; EtOOCCH 2 - (R) Cgl-Aze-Pab-COOCH (CH 3) OOCCH 3; MeOOCCH 2 - ( R) Cgl-Aze-Pab-OOCPh; MeOOCCH _2- (R) Cgl-Aze-Pab-OH; EtOOCCH _2- (R) Cgl-Aze-Pab-OH; BnOOCCH _2- (R) Cgl-Aze-Pab- OH; nPrOOCCH _2- (R) Cgl-Aze-Pab-Z; nPrOOCCH _2- (R) Cgl-Aze-Pab-OH; iPrOOCCH _2- (R) Cgl-Aze-Pab-OH; tBuOOCCH _2- (R) (NPr) ₂ NCOCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-OH; ChNHCOCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-OH; EtOOCCH _2- (R) Cgl-Aze-Pab-OAc; HOOCCH _2- (R) Cgl-Aze-Pab-OH; HOOCCH _2- (R) Cgl-Aze-Pab-O-cis-oleyl; Cyclooctyl-OOCCH _2- (R) Cgl -Aze-Pab-Z; tBuCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z; (2-Me) BnOOCCH _2- (R) Cgl-Aze-Pab-Z; ChCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-Z; ChOOCCH 2 - (R) Cgl-Aze-Pab-Z; PhC (Me) 2 OOCCH 2 - (R) Cgl-Aze-Pab-Z; (Me) 2 CHC (Me) 2 OOCCH _2- (R) Cgl-Aze-Pab-Z; BnOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-OMe); ChCH ₂ OOCCH _2- (R) Cgl-Aze-Pab-COOPh (4 -OMe); (2-Me) BnOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-OMe); EtOOCCH ₂ -(R) Cgl-Aze-Pab-COOPh (4-Me); BnOOCCH _2- (R) Cgl-Aze-Pab-COOPh (4-Me); BnOOCCH _2- (R) Cgl-Aze-Pab-COO- nBu; iPrOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CH = CH ₂ ; EtOOCCH _2- (R) Cgl-Aze-Pab-COO-iBu; BnOOCCH _2- (R) Cgl-Aze-Pab-COO _{-nPr; EtOOCCH 2 - (R)} Cgl-Aze-Pab-COOCH 2 OOCCh; EtOOCCH 2 - (R) Cgl-Aze-Pab-COOCH 2 OOCCH 2 Ch; EtOOCCH 2 - (R) Cgl-Aze-Pab-COOCH (Me) OOCPh; EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OOCPh; BnOOCCH _2- (R) Cgl-Aze-Pab-COOCH (Me) OAc; EtOOCCH _2- (R) Cgl-Aze-Pab -COOCH ₂ OAc; tBuOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ OAc; MeOOC-C (= CHEt) CH ₂ -OOCCH _2- (R) Cgl-Aze-Pab-Z; Men-OOCCH _2- (R) Cgl-Aze-Pab -COOPh (4-OMe); and _{EtOOCCH 2 - (R) Cgl-} Aze-Pab-COOCH 2 CCl 3 is a compound of claim 1. 32. EtOOCCH _2- (R) Cgl-Aze-Pab-COOCH ₂ CC
l ₃ ; BnOOCCH _2- (R) Cgl-Aze-Pab-COOnBu; nPrOOCCH _2- (R) Cgl-Aze-Pab-Z; Cyclooctyl-OOCCH _2- (R) Cgl-Aze-Pab-Z; EtOOCCH ₂ -(R) Cgl-Aze-Pab-COOCH ₂ OOCCh; MeOOCCH _2- (R) Cgl-Aze-Pab-OH; EtOOCCH _2- (R) Cgl-Aze-Pab-OH; nPrOOCCH _2- (R) Cgl- Aze-Pab-OH; iPrOOCCH _2- (R) Cgl-Aze-Pab-OH; BnOOCCH _2- (R) Cgl-Aze-Pab-OH; and EtOOCCH _2- (R) Cgl-Aze-Pab-OAc. A compound according to claim 1. 33. The compound of formula I according to claim 1, with the additional proviso that R ¹ is not —A ¹ C (O) OR ⁴ . 34. The compound of formula I according to claim 1, with the additional proviso that R ⁴ and R ⁵ are not independently H. 35. The compound of formula I according to claim 1, wherein R ² is OC (O) R ^6, with the additional proviso that R ⁶ is not C _1-17 alkyl. 36. The compound of formula I according to claim ^{1, wherein} R ¹ is —A ¹ C (O) OR ⁴ . 37. The compound of formula I according to claim 1, wherein R ⁴ and R ⁵ are independently H. 38. The compound of formula I according to claim 1, wherein when R ² is OC (O) R ⁶ , R ⁶ is C _1-17 alkyl. 39. A compound of formula I according to any of claims 1 to 38 or a pharmaceutically acceptable salt thereof, which is mixed with a pharmaceutically acceptable auxiliary, diluent or carrier. Pharmaceutical formulations. 40. The method according to claim 1, which is used as a medicament.
Or a pharmaceutically acceptable salt thereof. 41. A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 38 for use in the treatment of a condition requiring inhibition of thrombin. 42. A compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 38 for use in the treatment of thrombosis. 43. The method according to claim 1, which is used as an anticoagulant.
38. A compound of Formula I according to any of the items 38 or a pharmaceutically acceptable salt thereof. 44. A compound of formula I according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof as an active ingredient in the manufacture of a medicament for the treatment of a condition requiring inhibition of thrombin. Use of. 45. The use according to claim 44, wherein the condition is thrombosis. 46. Use of a compound of formula I according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof as an active ingredient in the manufacture of an anticoagulant. 47. A method of treating a condition requiring inhibition of thrombin, wherein said compound is a therapeutically effective amount of a compound of formula I according to any one of claims 1-38, or a pharmaceutically acceptable salt thereof. The above method, which comprises administering the salt to a human suffering from or susceptible to such symptoms. 48. The method of claim 47, wherein said condition is thrombosis. 49. The method of claim 47, wherein the condition is hypercoagulability in blood and tissues. 50. Use of a compound of formula I as defined in claim 1, but without proviso, as a prodrug. (51) R^TwoFor a compound of formula I wherein is OH
If R^TwoIs OC (O) R⁶And R⁶Is defined in claim 1
Alkoxide salts of the corresponding compounds of formula I
(B) R^TwoIs a compound of formula I wherein is OH,^TwoIs C (O) OR⁷
And R⁷Is as defined in claim 1
The corresponding compound of formula I or an acid addition salt thereof
Reacting with an amine; (c) the corresponding formula II H- (R) Cgl-Aze-Pab-R^Two (II) (where R^TwoIs as defined in claim 1)
Object with formula III R¹O (O) C-CH_Two-L¹ (III) (where L¹Is a leaving group, and R¹Is defined in claim 1
(D) R¹Is H, and R^TwoIs OH or C (O) OR⁷In
In the case of compounds of formula I¹Is C_1-10Alkyl or C_1-3
Alkylphenyl and R^TwoIs OH or C (O) OR⁷
Reacting the corresponding compound of formula I with a base; (e) R^TwoIs OC (O) R⁶And R⁶Is defined in claim 1
In the case of a compound of formula I as^TwoIs OH
The corresponding compound of formula I is represented by the formula IV R⁶C (O) -O-C (O) R⁶ (IV) (where R⁶Is as defined in claim 1)
Object or formula VR⁶C (O) Hal (V) wherein Hal is Cl or Br, and R⁶Is claim 1
(F) R¹Is H and R^TwoIs OC (O) R⁶And R⁶But
For compounds of formula I as defined in claim 1,
Equivalent expression VIP¹O (O) C-CH_Two-(R) Cgl-Aze-Pab-R^Two (VI) (where P¹Is an acid-labile ester protecting group, R^TwoIs
OC (O) R⁶And R ⁶Is as defined in claim 1
Is reacted with an acid; (g) R¹Is R^ThreeAnd R^ThreeIs C_1-10Alkyl or C_1-3A
Alkenylphenyl and R^TwoIs OH or C (O) OR⁷And
And R⁷Is a compound of formula I wherein is as defined in claim 1
Product, the corresponding formula VII R^1aO (O) C-CH_Two-(R) Cgl-Aze-Pab-R^Two (VII) (wherein, R^1aIs C other than the one to generate_1-10Alkyl or
C_1-3Alkylphenyl group or unstable alkyl group
A substituent, and R^TwoIs as defined in claim 1
Of compounds of formula I by transesterification of a compound of formula I)
Law.