D-amino acid induced inhibitors of cysteine and serine protease

专利摘要:
The present invention relates to novel (D) -amino acid containing inhibitors of cysteine or serine protease. Methods of using protease inhibitors are also described.
公开号:KR19990071683A
申请号:KR1019980703959
申请日:1996-11-27
公开日:1999-09-27
发明作者:생카 채터지
申请人:바바라 에스. 쉴버그；세파론, 인크.；
IPC主号:

专利说明:

D-amino acid induced inhibitors of cysteine and serine protease
Cross Literature for Related Applications
This application claims the benefit of US Provisional Application No. 60 / 007,651, filed November 28, 1995, which is hereby incorporated by reference in its entirety.
Many cysteine and serine proteases have been identified in human tissues. A "protease" is an enzyme that breaks down proteins into smaller components (peptides). The terms "cysteine protease" and "serine protease" refer to proteases characterized by the internal presence of cysteine or serine residues that play a decisive role in a catalytic method. Mammalian systems, including humans, typically degrade and process proteins through a variety of enzymes, including cysteine and serine proteases. However, when present at elevated levels or abnormally activated, cysteine and serine proteases may be involved in pathophysiological processes.
For example, calcium-activated neutral proteases (“calpine”) include intracellular cysteine protease families expressed anywhere in mammalian tissue. Two important calpines have been identified as Calpine I and Calpine II. While Calpine II is the dominant form in many tissues, Calpine I is taught to be the dominant form that is active in the pathological state of neural tissue. The Calpine family of cysteine proteases is associated with a number of diseases and disorders including neurodegeneration, seizures, Alzheimer's disease, muscular dystrophy, motor neuron injury, acute central nervous system injury, muscle malnutrition, bone resorption, platelet aggregation, cataracts and inflammation It has been included. Calpine I has been included in excitatory amino acid induced neurotoxicity disorders including ischemia, hypoglycemia, Huntington's disease and epilepsy.
Lysosomal cysteine protease cathepsin B has been included in the following disorders: arthritis, inflammation, myocardial contraction, tumor metastasis and muscle malnutrition. Other lysosomal cysteine proteases include cathepsin C, H, L and S. Interleukin-1β converting enzyme (“ICE”) is a cysteine protease that catalyzes interleukin-1β formation. Interleukin-1β is an immunomodulatory protein involved in the following disorders: inflammation, diabetes, septic shock, rheumatoid arthritis and Alzheimer's disease. ICE has also been linked to apoptotic cell death of neurons, which is involved in various neurodegenerative disorders, including Parkinson's disease, ischemia and amyotrophic lateral sclerosis (ALS).
Cysteine proteases are also produced by various pathogens. Cysteine protease Clostripine is produced by Clostridium histolyticum. Other proteases are produced by Trypanosoma cruzi, malaria parasite Plasmodium falciparum and P. vinckei and Streptococcus. Hepatitis A virus protease HAV C3 is a cysteine protease essential for the processing of picornavirus structural proteins and enzymes.
Exemplary serine proteases included in degeneration disorders include thrombin, human leukocyte elastase, pancreatic elastase, kinase and cathepsin G. Specifically, thrombin is produced in a blood coagulation cascade, splits fibrinogen to form fibrin, and activates factor VIII; Thrombin is included in thrombophlebitis, thrombosis and asthma. Human leukocyte elastase is involved in tissue degeneration disorders such as rheumatoid arthritis, osteoarthritis, atherosclerosis, bronchitis, gallbladder fibrosis and emphysema. Pancreatic elastase is included in pancreatitis. Kinase, an important enzyme in angiotensin synthesis, is involved in hypertension, myocardial contraction and coronary heart disease. Cathepsin G is involved in abnormal connective tissue degradation, especially in the lungs.
Linked between cysteine and serine proteases and various degradable disorders, compounds that inhibit these proteases will be useful and will provide advantages in both research and clinical medicine. The present invention relates not only to these but also to other important objects.
Summary of the Invention
The present invention relates to novel cysteine and serine protease inhibitors containing (D) -amino acids at the P2 position. Exemplary compounds are represented by Formula I:
Where
C ^* is a carbon atom having a D- configuration;
Q is the general formula GB- (CHR ²⁰ ) _q- ;
R ²⁰ is independently H or C _1-4 alkyl;
q is 0, 1 or 2;
B is selected from the group consisting of C (= 0), S (= 0), S (= 0) ₂ , S, CH ₂ , a bond, NH and O;
G is aryl having about 6 to about 14 carbon atoms, heteroaryl having about 5 to about 14 ring atoms, aralkyl having about 7 to about 15 carbon atoms, alkyl having 1 to about 10 carbon atoms, heteroalkyl having 2 to about 7 carbon atoms, Carbohydrate moieties optionally containing alkoxy, arylsulfonyl, alkylsulfonyl, alkylsulfonyl, aralkyloxy, amino, and one or more alkylated hydroxyl groups of 1 to about 10 carbon atoms, wherein aryl, Heteroaryl, aralkyl, alkyl and amino groups are optionally substituted with one or more K groups);
K is halogen, CN, NO ₂ , lower alkyl, aryl, heteroaryl, aralkyl, aralkyloxy, guanidino, alkoxycarbonyl, alkoxy, hydroxy, carboxy and amino, wherein the amino group is an acyl group or 1 To optionally substituted with 3 aryl or lower alkyl groups;
R ¹ is H, alkyl having 1 to about 14 carbon atoms, cycloalkyl having 3 to about 10 carbon atoms, aralkyl having about 7 to about 15 carbon atoms, heteroarylalkyl having about 5 to about 14 ring atoms, and D- Or a natural side chain of L-amino acid, and a synthetic side chain of D- or L-amino acid, wherein alkyl, cycloalkyl, aralkyl and heteroarylalkyl groups are optionally substituted by one or more K groups, and ;
R ² is selected from the group consisting of C (═O) R ⁶ , S (═O) ₂ R ⁶ and a protecting group;
R ⁶ is aryl having about 6 to about 14 carbon atoms, heteroaryl having about 5 to about 14 ring atoms, aralkyl having about 7 to about 15 carbon atoms, alkyl having 1 to about 10 carbon atoms, wherein aryl, heteroaryl, Aralkyl and alkyl group optionally substituted by one or more K groups), heteroalkyl having 2 to about 7 carbon atoms, alkoxy having 1 to about 10 carbon atoms, and amino optionally substituted by one or more alkyl groups, and ;
R ³ is selected from the group consisting of H, lower alkyl, aralkyl and a group of the formula —CO ₂ —R ²¹ , wherein R ²¹ is a lower alkyl group; or
R ³ may form a phthalimido group with R ² ; or
Q and R ^{3 together} with -C ^* and -N (R ² )- Can form groups;
R ⁷ optionally contains a carbon-carbon double bond, wherein the aryl, azide, CN, protected amino group and OSO ₂ -aryl, wherein the aryl group is optionally substituted by one or more K groups, said OSO ₂ -aryl group The aryl moiety of is C _2-5 alkylene optionally substituted by a group selected from the group consisting of one or more K groups; or
R ⁷ is a general formula Can be;
p and y are independently 0 or 1,
R ²² , R ²³ , R ²⁴ and R ²⁵ are independently H or K groups;
R ⁴ and R ⁵ are each independently selected from the group consisting of H and lower alkyl;
W ¹ and W ² are selected such that W ¹ is H and W ² is OC (═O) NH—R ²⁶ , wherein R ²⁶ is alkyl, or W ¹ and W ² are both alkoxy, or W ¹ is OH and W ² is aralkyl, aralkyloxy, aryloxy, heteroaryloxy, heteroaralkyloxy and SO ₃ Z ¹ (wherein Z ¹ is preferably a group I or group II ions , Preferably Na); or
W ¹ and W ² together are = O, = NR ⁸ , = N (→ O) R ⁹ , -S (CH ₂ ) ₂ O- and -N (R ¹² ) (CH ₂ ) ₂ N (R ¹² )- Can form a group selected from the group consisting of;
R ⁸ is selected from the group consisting of NH (C═O) NH ₂ , hydroxyl and lower alkoxy;
R ⁹ is selected from the group consisting of alkyl and aralkyl;
R ¹² is selected from the group consisting of C _1-4 alkyl and phenyl;
Y is selected from the group consisting of H, C (= 0) NR ¹⁰ R ¹¹ , C (= 0) OR ¹⁰ , CH = N ₂ and CH ₂ R ¹³ ; or
Y and R ¹ may together form — (CH ₂ ) ₄ N (Pr) —, where Pr is H or a protecting group, provided that Y and R ¹ together form — (CH ₂ ) ₄ N (Pr When forming)-, W ¹ and W ² together form ═O;
R ¹⁰ and R ¹¹ are each independently H, alkyl having 1 to about 10 carbon atoms, wherein the alkyl group is optionally substituted by one or more K groups, aryl having about 6 to about 14 carbon atoms, and about 7 to about 15 carbon atoms. Aralkyl is selected from the group consisting of;
R ¹³ is selected from the group consisting of L, lower alkyl, aralkyl, halogen and the group OM;
M is a general formula ego;
Z is selected from the group consisting of N and CR ¹⁴ ;
W is selected from the group consisting of double bonds and single bonds;
D is selected from the group consisting of C═O and a single bond;
E and F are independently selected from the group consisting of R ¹⁴ , R ¹⁵ and J; or
E and F together represent a C _5-7 aliphatic carbocyclic ring, a C _5-7 aromatic carbocyclic ring, an aliphatic heterocyclic ring having 5 to 7 atoms and 1 to 4 heteroatoms, and 5 to 7 atoms And aromatic heterocyclic rings having 1 to 4 heteroatoms, wherein aliphatic heterocyclic rings, aromatic carbocyclic rings, aliphatic heterocyclic rings and aromatic heterocyclic rings are each optionally substituted by J. To form a linked residue selected from the group;
R ¹⁴ and R ¹⁵ are independently H, C _1-10 alkyl, C _1-10 heteroaryl, C _1-10 alkanoyl and aroyl, wherein the alkyl, heteroaryl, alkanoyl and aroyl groups are Optionally substituted);
J is halogen, C (= 0) OR ¹⁶ , R ¹⁶ OC (= 0), R ¹⁶ OC (= 0) NH, OH, CN, NO ₂ , NR ¹⁶ R ¹⁷ , N = C (R ¹⁶ ) R ¹⁷ , N = C (NR ¹⁶ R ¹⁷ ) ₂ , SR ¹⁶ , OR ¹⁶ , phenyl, naphthyl, heteroaryl and C _3-8 cycloalkyl group;
R ¹⁶ and R ¹⁷ are independently H, C _1-10 alkyl, aryl or heteroaryl, wherein the alkyl, aryl and heteroaryl groups are optionally substituted by K;
L is preferably of the general formula Phosphorus-containing enzyme reactor; From here,
m, n and b are each independently 0 or 1;
R ¹⁸ and R ¹⁹ are each independently selected from the group consisting of lower alkyl optionally substituted by H, K, aryl optionally substituted by K and heteroaryl optionally substituted by K; or
Or R ¹⁸ and R ¹⁹ may form a 5- to 8-membered ring having 3 or less heteroatoms with — (O) _m —P (═O) — (O) _n —; or
R ¹⁸ and R ^{19 together} with — (O) _m —P (═O) — (O) _n — may form a 5- to 8-membered ring optionally substituted by K.
In some preferred embodiments of compounds of Formula (I), G is alkyl, benzyl, tetrahydroisoquinolyl, 3-indolyl, phenyl, N-methylbenzylamino, substituted benzyl, 2-thienyl or p-benzyloxyphenyl to be. In other preferred embodiments of compounds of Formula (I), Q and R ³ are taken together-(CH ₂ ) _3- , -CH ₂ -CH (OSO ₂ C ₆ H ₅ ) -CH _2- , -CH ₂ -CH (OSO ₂ C ₆ H ₄ CH ₃ ) -CH _2- , -CH ₂ -CH (N ₃ ) -CH _2- , -CH ₂ -CH (CN) -CH _2- , -CH ₂ -CH = CH- and Formula selected from the group consisting of.
In other preferred embodiments of compounds of Formula (I), B is selected from the group consisting of -C (= 0)-, -O-, -S-, -S (= 0) ₂ -and a bond.
In a further preferred embodiment of the compound of formula (I), R ¹ is selected from the group consisting of benzyl, substituted benzyl, lysyl side chains and substituted lysyl side chains. In a more preferred embodiment, R ¹ is alkyl, preferably ethyl, isobutyl or tertiary butyl, benzyl, p-benzyloxybenzyl, 2-pyridylmethyl,-(CH ₂ ) ₄ -NHC (= 0) -O -CH ₂ -C ₆ H ₅ ,-(CH ₂ ) ₄ -NHC (= 0) -OtC ₄ H ₉ or-(CH ₂ ) ₄ -NHSO ₂ -C ₆ H ₅ .
In other preferred embodiments of compounds of Formula (I), W ¹ and W ² together form -C (= 0), R ¹ and Y together form-(CH ₂ ) ₄ -N (Pr)-, wherein In which Pr is H or tert-butoxycarbonyl.
In some preferred embodiments of the compound of formula (I), R ² is selected from the group consisting of tertiary butyloxycarbonyl, -S (= 0) ₂ R ⁶ and -C (= 0) CH ₃ . More preferably, R ² is —S (═O) ₂ R ⁶ , wherein R ⁶ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In still more preferred embodiments of compounds of Formula (I), R ² is —S (═O) ₂ CH ₃ , —S (═O) ₂ CH ₂ CH ₃ , p-fluorophenylsulfonyl, —S (═O) ₂ N (CH ₃ ) ₂ , 2-thienylsulfonyl, 2-isoxazolesulfonyl, phenylsulfonyl, p-methylphenylsulfonyl, 4- (N-methylimidazole) sulfonyl and 2-naphthylsulfonyl It is selected from the group which consists of.
In other preferred embodiments of compounds of Formula (I), Y is selected from the group consisting of H and CH ₂ F.
Preferably, W ¹ and W ² together form —C (═O), or W ¹ and W ² are W ¹ is OH and W ² is SO ₃ Z ¹ (wherein Z ¹ is preferably Na Phosphorus group I), or W ¹ is H and W ² is OC (= 0) NH-R ²⁶ , wherein R ²⁶ is alkyl, or W ¹ is OH and W ² is aralkyl Or W ¹ is OH and W ² is aralkyloxy, or W ¹ is OH and W ² is aryloxy, or W ¹ is OH and W ² is heteroaryloxy, or W ¹ is OH and W ^So that di is heteroaralkyloxy, or that W ¹ and W ² are both alkoxy, or W ¹ and W ² together are = NR ⁸ , = N (→ O) R ⁹ , -S (CH ₂ ) ₂ O- and -N (R ¹² ) (CH ₂ ) ₂ N (R ¹² )-is selected to form a group selected from the group consisting of.
In a particularly preferred embodiment of the compound of formula (I), B is selected from the group consisting of-(C = 0)-, -O-, a bond, SO ₂ and -S-; Y is selected from the group consisting of H and CH ₂ F; R ¹ is selected from the group consisting of benzyl, substituted benzyl, lysyl side chains and substituted lysyl side chains; R ² is selected from the group consisting of tertiary butyloxycarbonyl, -C (= 0) CH ₃ and -S (= 0) ₂ R ⁶ . Preferably, R ⁶ is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
In a particularly preferred embodiment, Q is benzyloxymethyl; R ¹ is benzyl; R ² is —SO ₂ CH ₃ ; R ³ , R ⁴ , R ⁵ and Y are each H; W ¹ and W ² together form —C (═O) —.
The compounds of the present invention are useful for the inhibition of cysteine and serine proteases. Advantageously, the compounds have been found to be useful under various circumstances. For example, in the research community, the claimed compounds can be used, for example, as a basis for screening natural and synthetic cysteine proteases and serine protease inhibitors having the same or similar functional characteristics as the described compounds. In clinical practice, the target compounds can be used to alleviate, mediate, alleviate and / or prevent disorders associated with abnormal and / or abnormal activity of cysteine proteases and / or serine proteases. Therefore, a composition containing the target compound and a method of using the target compound such as the above protease inhibition method comprising contacting a serine protease or cysteine protease with the compound inhibitory amount of the present invention are described. Also described are methods of preparing the present (D) -amino acid containing inhibitors. Other useful methodologies, for the purpose of this application, will be apparent to those skilled in the art. These and other features of the compounds of the present invention are described in more detail below.
P2 (D) -amino acid inhibitors of cysteine or serine proteases, methods of making these compounds, and methods of using them are described.
1 shows the effect of compound 40 on spectrin degradation in the CA1 hippocampal sector of Gerville.
2 depicts the effect of compound 40 on the survival of CA1 neurons at 4 days after ischemia injury.
3 shows the dose response to neuroprotective efficacy of Compound 40 when administered 3 hours after ischemia.
Novel cysteine and serine protease inhibitors of formula I have been found.
<Formula I>

Where
C ^* is a carbon atom having a D- configuration;
Q is the general formula GB- (CHR ²⁰ ) _q- ;
R ²⁰ is independently H or C _1-4 alkyl;
q is 0, 1 or 2;
B is selected from the group consisting of C (= 0), S (= 0), S (= 0) ₂ , S, CH ₂ , a bond, NH and O;
G is aryl having about 6 to about 14 carbon atoms, heteroaryl having about 5 to about 14 ring atoms, aralkyl having about 7 to about 15 carbon atoms, alkyl having 1 to about 10 carbon atoms, heteroalkyl having 2 to about 7 carbon atoms, Carbohydrate moieties optionally containing alkoxy, arylsulfonyl, alkylsulfonyl, alkylsulfonyl, aralkyloxy, amino, and one or more alkylated hydroxyl groups of 1 to about 10 carbon atoms, wherein aryl, Heteroaryl, aralkyl, alkyl and amino groups are optionally substituted with one or more K groups);
K is halogen, CN, NO ₂ , lower alkyl, aryl, heteroaryl, aralkyl, aralkyloxy, guanidino, alkoxycarbonyl, alkoxy, hydroxy, carboxy and amino, wherein the amino group is an acyl group or 1 To optionally substituted with 3 aryl or lower alkyl groups;
R ¹ is H, alkyl having 1 to about 14 carbon atoms, cycloalkyl having 3 to about 10 carbon atoms, aralkyl having about 7 to about 15 carbon atoms, heteroarylalkyl having about 5 to about 14 ring atoms, and D- Or a natural side chain of L-amino acid, and a synthetic side chain of D- or L-amino acid, wherein alkyl, cycloalkyl, aralkyl and heteroarylalkyl groups are optionally substituted by one or more K groups, and ;
R ² is selected from the group consisting of C (═O) R ⁶ , S (═O) ₂ R ⁶ and a protecting group;
R ⁶ is aryl having about 6 to about 14 carbon atoms, heteroaryl having about 5 to about 14 ring atoms, aralkyl having about 7 to about 15 carbon atoms, alkyl having 1 to about 10 carbon atoms, wherein aryl, heteroaryl, Aralkyl and alkyl group optionally substituted by one or more K groups), heteroalkyl having 2 to about 7 carbon atoms, alkoxy having 1 to about 10 carbon atoms, and amino optionally substituted by one or more alkyl groups, and ;
R ³ is selected from the group consisting of H, lower alkyl, aralkyl and a group of the formula —CO ₂ —R ²¹ , wherein R ²¹ is a lower alkyl group; or
R ³ may form a phthalimido group with R ² ; or
Q and R ^{3 together} with -C ^* and -N (R ² )- Can form groups;
R ⁷ optionally contains a carbon-carbon double bond, wherein the aryl, azide, CN, protected amino group and OSO ₂ -aryl, wherein the aryl group is optionally substituted by one or more K groups, said OSO ₂ -aryl group The aryl moiety of is C _2-5 alkylene optionally substituted by a group selected from the group consisting of one or more K groups; or
R ⁷ is a general formula Can be;
p and y are independently 0 or 1,
R ²² , R ²³ , R ²⁴ and R ²⁵ are independently H or K groups;
R ⁴ and R ⁵ are each independently selected from the group consisting of H and lower alkyl;
W ¹ and W ² are selected such that W ¹ is H and W ² is OC (═O) NH—R ²⁶ , wherein R ²⁶ is alkyl, or W ¹ and W ² are both alkoxy, or W ¹ is OH and W ² is aralkyl, aralkyloxy, aryloxy, heteroaryloxy, heteroaralkyloxy and SO ₃ Z ¹ wherein Z ¹ is preferably a Group I or II counterion, preferably Is Na); or
W ¹ and W ² together are = O, = NR ⁸ , = N (→ O) R ⁹ , -S (CH ₂ ) ₂ O- and -N (R ¹² ) (CH ₂ ) ₂ N (R ¹² )- Can form a group selected from the group consisting of;
R ⁸ is selected from the group consisting of NH (C═O) NH ₂ , hydroxyl and lower alkoxy;
R ⁹ is selected from the group consisting of alkyl and aralkyl;
R ¹² is selected from the group consisting of C _1-4 alkyl and phenyl;
Y is selected from the group consisting of H, C (= 0) NR ¹⁰ R ¹¹ , C (= 0) OR ¹⁰ , CH = N ₂ and CH ₂ R ¹³ ; or
Y and R ¹ may together form — (CH ₂ ) ₄ N (Pr) —, where Pr is H or a protecting group, provided that Y and R ¹ together form — (CH ₂ ) ₄ N (Pr When forming)-, W ¹ and W ² together form ═O;
R ¹⁰ and R ¹¹ are each independently H, alkyl having 1 to about 10 carbon atoms, wherein the alkyl group is optionally substituted by one or more K groups, aryl having about 6 to about 14 carbon atoms, and about 7 to about 15 carbon atoms. Aralkyl is selected from the group consisting of;
R ¹³ is selected from the group consisting of L, lower alkyl, aralkyl, halogen and the group OM;
M is ego;
Z is selected from the group consisting of N and CR ¹⁴ ;
W is selected from the group consisting of double bonds and single bonds;
D is selected from the group consisting of C═O and a single bond;
E and F are independently selected from the group consisting of R ¹⁴ , R ¹⁵ and J; or
E and F together represent a C _5-7 aliphatic carbocyclic ring, a C _5-7 aromatic carbocyclic ring, an aliphatic heterocyclic ring having 5 to 7 atoms and 1 to 4 heteroatoms, and 5 to 7 atoms And aromatic heterocyclic rings having 1 to 4 heteroatoms, wherein aliphatic carbocyclic rings, aromatic carbocyclic rings, aliphatic heterocyclic rings, and aromatic heterocyclic rings are each optionally substituted by J. To form a linked residue selected from the group;
R ¹⁴ and R ¹⁵ are independently H, C _1-10 alkyl, C _1-10 heteroaryl, C _1-10 alkanoyl and aroyl, wherein the alkyl, heteroaryl, alkanoyl and aroyl groups are Optionally substituted);
J is halogen, C (= 0) OR ¹⁶ , R ¹⁶ OC (= 0), R ¹⁶ OC (= 0) NH, OH, CN, NO ₂ , NR ¹⁶ R ¹⁷ , N = C (R ¹⁶ ) R ¹⁷ , N = C (NR ¹⁶ R ¹⁷ ) ₂ , SR ¹⁶ , OR ¹⁶ , phenyl, naphthyl, heteroaryl and C _3-8 cycloalkyl group;
R ¹⁶ and R ¹⁷ are independently H, C _1-10 alkyl, aryl or heteroaryl, wherein the alkyl, aryl and heteroaryl groups are optionally substituted by K;
L preferably has a structure Phosphorus-containing enzyme reactors; From here,
m, n and b are each independently 0 or 1;
R ¹⁸ and R ¹⁹ are each independently selected from the group consisting of lower alkyl optionally substituted by H, K, aryl optionally substituted by K and heteroaryl optionally substituted by K; or
Or R ¹⁸ and R ¹⁹ may form a 5- to 8-membered ring having 3 or less heteroatoms with — (O) _m —P (═O) — (O) _n —; or
R ¹⁸ and R ^{19 together} with — (O) _m —P (═O) — (O) _n — may form a 5- to 8-membered ring optionally substituted by K.
In some preferred embodiments of compounds of Formula (I), R ¹ is benzyl, p-benzyloxybenzyl,-(CH ₂ ) ₄ -NHC (= 0) -O-CH ₂ -C ₆ H ₅ ,-(CH ₂ ) ₄ -NHC (= 0) -OtC ₄ H ₉ or-(CH ₂ ) ₄ -NHSO ₂ -C ₆ H ₅ ; R ³ , R ⁴ and R ⁵ are each H; W ¹ and W ² together are —C (═O) —; Y is H or CH ₂ F; B is CO, O, S, SO ₂ or a bond; R ² is —C (═O) CH ₃ and —S (═O) ₂ R ⁶ , wherein R ⁶ is methyl, p-fluorophenyl, dimethylamino, ethyl, 2-thienyl, 2-isoxa Zolyl, phenyl, p-methylphenyl, 4-N-methylimidazolyl and 2-naphthyl; G is tetrahydroisoquinolinyl, benzyl, 3-indolyl, phenyl, N-methylbenzylamino, p-benzyloxyphenyl or 2-thienyl; Or Q and R ³ together are — (CH ₂ ) ₃ —.
In other preferred embodiments of compounds of Formula (I), q is 0; B is a bond; G is benzyl or 2-thienyl; Y is H; R ¹ is benzyl; R ² is —S (═O) ₂ R ⁶ , wherein R ⁶ is methyl, phenyl or 2-thienyl.
In a further preferred embodiment of the compound of formula (I), q is 1; G is tetrahydroisoquinolinyl, benzyl, 3-indolyl, phenyl, N-methylbenzylamino or p-benzyloxyphenyl; R ² is —C (═O) CH ₃ or —S (═O) ₂ R ⁶ , wherein R ⁶ is methyl, p-fluorophenyl, dimethylamino, ethyl, 2-thienyl, 2-isoxa Zolyl, p-methylphenyl, 4-N-methylimidazolyl or 2-naphthyl.
In a more preferred embodiment of the compound of formula (I), q is 1 and G is benzyl; R ² is —C (═O) CH ₃ or —S (═O) ₂ R ⁶ , wherein R ⁶ is methyl, p-fluorophenyl, dimethylamino, ethyl, 2-isoxazolyl, p-methylphenyl , 4-N-methylimidazolyl or 2-naphthyl, with methyl being preferred.
In other preferred embodiments of compounds of Formula (I), q is 2 and B is S; G is benzyl; Y is H; R ¹ is benzyl; R ² is -S (= 0) ₂ CH ₃ .
"P2" as used herein in connection with an enzyme substrate name is described in Schechter et al., Biochem. Biophys. Res. Comm. 27: 157-162, 1967.
As used herein, the term "alkyl" includes straight chain, branched and cyclic hydrocarbon groups such as, for example, ethyl, isopropyl and cyclopropyl groups. Preferred alkyl groups have 1 to about 10 carbon atoms. A "cycloalkyl" group is a cyclic alkyl group. The term "alkylene" means a divalent alkyl group; That is, methylene (-CH _2- ), ethylene (-CH ₂ CH _2- ), propylene (-CH ₂ CH ₂ CH _2- ), and the like. “Aryl” groups are aromatic cyclic compounds including, but not limited to, phenyl, tolyl, naphthyl, anthracyl, phenanthryl, pyrenyl and xylyl. Preferred aryl groups include phenyl and naphthyl. As used herein, the term "carbocyclic" means a cyclic group in which the ring portion consists only of carbon atoms. The term "heterocyclic" means a cyclic group where the ring portion comprises one or more heteroatoms such as O, N or S. Typically, the term “hetero” when used as a prefix means the presence of one or more heteroatoms. Thus, a "heterocycloalkyl" group is a heterocycle containing only a single bond in its ring portion, ie a saturated heteroatom ring system. The term "lower alkyl" refers to a C _1-4 alkyl group. The term "halogen" means F, Cl, Br and I atoms. The term "aralkyl" means an alkyl group comprising an aryl group, such as a benzyl group.
As used herein, an "alkoxy" group is an alkyl group linked via an oxygen atom. Examples of the alkoxy group include methoxy (-OCH ₃ ) and ethoxy (-OCH ₂ CH ₃ ) groups. Typically, the term "oxy" when used as a suffix means a bond through an oxygen atom. Thus, the alkoxycarbonyl group is a carbonyl group containing an alkoxy substituent, ie a group of the formula -C (= 0) -OR, wherein R is alkyl. The term "aralkyloxy" means an aralkyl group linked via an oxygen atom. The term "heteroaryl" means an aryl group containing at least one heteroatom in an aromatic ring. The term "heteroarylalkyl" refers to a heteroaryl group bonded through an alkyl group. A "heteroaralkyl" group is an aralkyl group having one or more heteroatoms in its aromatic ring portion. The term "carbohydrate" includes monosaccharides, disaccharides and polysaccharides, as well as their protected derivatives such as, for example, mono- and diisopropylidine and benzylidene derivatives.
As used herein, the term "alkanoyl" refers to an alkyl group bonded through a carbonyl group, ie -C (= 0) -R, wherein R is alkyl. The term "aroyl" similarly means an aryl group bonded through a carbonyl group. The term "sulfonyl" when used as a suffix means a bond via a -SO ₂ -group. As used herein, the term Group I counterions means Li ⁺ , Na ⁺ , K ⁺ , Rb ⁺ and Cs ⁺ .
As used herein, the term "amino acid" refers to a molecule containing both amino and carboxyl groups. As used herein, the term “L-amino acid” means an α-amino acid having an L configuration around α-carbon, ie a carboxylic acid of formula CH (COOH) (NH ₂ ) — (side chain) having an L-configuration. do. The term “D-amino acid” similarly means a carboxylic acid of the formula CH (COOH) (NH ₂ ) — (side chain) having a D-configuration around α-carbon. Amino acid α-carbon atoms having a D-configuration are represented herein by the symbol “C ^* ”. Side chains of L-amino acids include naturally occurring and non-naturally occurring residues. Non-naturally occurring (ie unnatural) amino acid side chains are residues used in place of naturally occurring amino acid side chains, for example, in amino acid analogs. See, eg, Lehninger, Biochemistry, Second Edition, Worth Publishers, Inc, 1975, pages 73-75. One typical amino acid side chain is the lysyl side chain, ie-(CH ₂ ) ₄ -NH ₂ . Other typical α-amino acid side chains are shown in Table I below.
The functional groups present on the compounds of formula (I) may contain protecting groups. For example, the amino acid side chain substituents of compounds of formula (I) may be substituted by protecting groups such as benzyloxycarbonyl or tert-butoxycarbonyl groups. Protecting groups are known per se as chemical functional groups that can optionally be added to and removed from functional groups such as hydroxyl groups and carboxyl groups. These groups are present in the chemical compound such that such functional groups are inert to the chemical reaction conditions to which the compound is exposed. Any of various protecting groups can be used in the present invention. One such protecting group is a benzyloxycarbonyl (Cbz; Z) group. Other preferred protecting groups according to the invention are described in Greene, T.W. And Wuts, P.G.M., "Protective Groups in Organic Synthesis" 2d, Ed., Wiley & Sons, 1991.
Since the D-amino acid-containing compounds of the present invention inhibit cysteine proteases and serine proteases, they can be used in both research and therapeutic environments.
Under the research environment, preferred compounds with defined properties can be used to screen natural and synthetic compounds that are evidence of similar properties in inhibiting protease activity. The compounds may also be used in the purification of in vitro and in vivo models to determine the inhibitory effects of particular proteases on particular cell types or biological conditions. In a therapeutic setting, given the link between cysteine protease and certain defined disorders, and serine protease and certain defined disorders, the compounds of the present invention may be used to determine abnormalities of cysteine proteases and / or serine proteases, and ( Or) alleviate, mediate, alleviate and / or prevent a disorder associated with aberrant activity.
In a preferred embodiment, there is provided a composition for inhibiting serine protease or cysteine protease, comprising the compound of the present invention. In another preferred aspect, there is provided a serine protease or cysteine protease inhibition method comprising contacting a protease selected from the group consisting of a serine protease and a cysteine protease with a compound inhibitory amount of the invention.
The compounds described herein are useful for the inhibition of cysteine proteases and serine proteases. As used herein, the terms "inhibit" and "inhibit" are meant to have adverse effects on enzyme activity. The inhibitory amount is an amount of a compound of the present invention effective to inhibit cysteine and / or serine protease.
Pharmaceutically acceptable salts of cysteine and serine protease inhibitors are also included within the scope of compounds as described herein. As used herein, the term “pharmaceutically acceptable salts” refers to inorganic acid addition salts such as hydrochlorides, sulfates and phosphates, or organic acid addition salts such as acetates, maleates, fumarates, tartrates and citrates. Examples of pharmaceutically acceptable metal salts are alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts and zinc salts. Examples of pharmaceutically acceptable organic amine addition salts are salts with morpholine and piperidine. Examples of pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine and phenylalanine.
The compounds provided herein can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable non-toxic excipients and carriers. As noted above, such compositions are intended for parenteral administration, in particular in the form of liquid solutions or suspensions; Or oral administration, in particular in the form of tablets or capsules; Or intranasally, especially in the form of powders, nasal drops or aerosols; Or for use as skin, for example via a percutaneous patch; Or in other forms suitable for these and other dosage forms as will be apparent to those skilled in the art.
The composition may conveniently be administered in unit dosage form and may be administered as is well known in the art of pharmacy, for example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980). Formulations for parenteral administration may contain polyalkylene glycols such as polyethylene glycol, oils and vegetable raw materials, hydrogenated naphthalene, etc., as conventional excipient sterilizing water or saline. Compatible, biodegradable lactide polymers, lactide / glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers may be useful excipients for controlling the release of the active compounds Other potentially useful parenterals for these active compounds Quadrant delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, investment systems, and liposomes. Formulations for administration may contain, for example, lactose as excipients, or for example aqueous solutions containing polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily liquids for administration in the form of non-dropping agents. Or as a gel to be applied intranasally, Formulations for parenteral administration may also include glycocholates for oral administration, salicylates for rectal administration or citric acid for vaginal administration. Is preferably a lipophilic emulsion.
The substances of the present invention may be used as the sole active ingredient in pharmaceuticals or in combination with other active ingredients which may facilitate cysteine and serine protease inhibition in diseases or disorders.
As used herein, the expression “enantiomerically rich amount” refers to a compound of Formula I having the carbon atom represented by C ^* in Formula I having a D-configuration when used in connection with a compound of Formula I in a composition of the present invention. At this position is greater (ie more than 50%) than the corresponding L-isomer. In a preferred embodiment of the compositions of the present invention, the compound enantiomerically rich amount of the compound of formula (I) is greater than about 75% (ie, the D-isomer compound of formula (I) is the combined amount of the compound of formula (I) and the corresponding L-isomer More than about 75% of)). In a more preferred embodiment of the compositions of the present invention, the compound enantiomerically rich amount of the compound of formula (I) is more than about 85%, more preferably more than about 90%, still more preferably more than about 95%, Most preferably about 100%.
The concentration in the therapeutic compositions of the compounds described herein will vary depending on a number of factors, including the drug formulation to be administered, the chemical characteristics (eg, hydrophobicity) of the compound used, and the route of administration. Typically, the compounds of the present invention may be provided in effective inhibitory amounts in aqueous physiological buffer solutions containing about 0.1 to 10% w / compound v for parenteral administration. A typical dosage range is about 1 μg / kg to about 1 g / kg body weight / day; Preferred dosage ranges are about 0.01 to 100 mg / kg body weight / day. Such formulations typically provide the amount of compound inhibition of the present invention. However, the preferred dosage of the drug to be administered is similarly dependent on such variables as the type or extent of the disease or disorder, the overall health of the particular patient, the relative physiological efficacy of the selected compound, the formulation of the compound excipient, and the route of administration thereof. Depends.
As used herein, the term “contacting” means to induce two or more residues to physically associate, directly or indirectly, with each other. Thus, contacting includes physical actions such as placing a compound of the invention in a container with a protease, or administering a compound of the invention to a patient. Thus, for example, the administration of a compound of the invention to a human patient that is evidence of a disease or disorder associated with abnormal and / or abnormal activity of such protease is within the scope of the definition of the term “contacting”.
The invention is further illustrated through the following examples which are intended to illustrate the invention. These examples are not intended to limit the scope of this disclosure, nor will they be considered as such.
The compound of the present invention was prepared by the following process. R _f values are reported using standard silica gel and assay plate.
Synthesis of compounds of Formulas 1-9 is summarized in Scheme I below:
The symbol "*" represents the D-array around the indicated carbon atom.
Examples 1-5 show the synthesis of intermediate compounds 3-7. Examples 6 and 7 show the preparation of compounds 8 and 9 of the present invention.
<Example 1>
Synthesis of Compound 3
To a stirred mixture of compound 1 (0.65 g, 2 mmol) and compound 2 (available from Bachem Bioscience, Inc., King of Prussia, Pa.) (0.27 g, 2 mmol) in methylene chloride (5 mL) at room temperature Ethylamine (0.45 g, 4.4 mmol) was added followed by bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (BOP-Cl, 0.51 g, 2 mmol). The mixture was stirred for another 2 h, poured slowly into ice-water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed successively with 2% citric acid solution (2 x 5 mL), 2% NaHCO ₃ solution (2 x 5 mL), H ₂ O (1 x 5 mL), brine (1 x 5 mL), Na Dried over ₂ SO ₄ and concentrated to afford the crude product. Purification by flash column chromatography (silica gel, 30% ethyl acetate in hexanes) gave compound 3 (0.64 g).
3: white gum; R _f (50% ethyl acetate in hexane): 0.60; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.05 (m, 9H), 5.90 (d, 1H), 5.25-5.10 (m, 2H), 4.70-4.55 (m, 3H), 3.80-3.55 (2 T, 2H), 3.30-3.15 (m, 1H), 2.95-2.80 (m, 3H), 1.40 (s, 9H).
<Example 2>
Synthesis of Compound 4
A mixture of compound 3 (0.61 g, 1.40 mmol) and 0.20 g 10% Pd-C (DeGussa type, 50% H ₂ O content) in methanol (40 mL) was hydrogenated (40 psi) in a Parr apparatus for 1 hour. . Filtration through Celite ^R pad and solvent evaporation gave compound 4 (0.47 g), which was used without further purification. The ¹ H-NMR spectrum of Compound 4 showed the absence of peaks for the benzyl group.
<Example 3>
Synthesis of Compound 5
To a cooled (0 ° C.) solution of compound 4 (0.20 g, 0.574 mmol) in anhydrous DMF (4 mL) N-methylmorpholine (0.174 g, 1.722 mmol) followed by 1-HOBt (0.080 g, 0.574 m) Mol) and BOP (0.254 g, 0.574 mmol) were added. The mixture was stirred for 15 minutes, to which (s) -phenylalaninol (0.112 g, 0.7463 mmol) was added. The cold bath was removed and the mixture was stirred for another 2 h, poured into water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed successively with 2% citric acid solution (2 x 5 mL), 2% NaHCO ₃ solution (2 x 5 mL), H ₂ O (1 x 5 mL), brine (1 x 5 mL), Na Dried over ₂ SO ₄ and concentrated to afford the crude product. Purification by flash column chromatography (silica gel, 5% methanol in methylene chloride) afforded compound 5 (0.212 g).
5: white solid, Mp 63-72 ° C. (softening to melting); R _f (5% methanol in methylene chloride): 0.47: ¹ H-NMR (300 NHz, CDCl ₃ ) δ 7.30-7.00 (m, 9H), 6.80 (wide, 1H), 5.90 (d, 1H), 4.80- 4.45 (m, 4H), 4.30-4.10 (wide, 1H), 3.85-3.30 (m, 6H), 2.95-2.40 (m, 4H), 1.45 (s, 9H).
<Example 4>
Synthesis of Compound 6
A mixture of compound 5 (0.190 g, 0.3945 mmol) and 90% TFA (1.2 mL) in methylene chloride (3 mL) was stirred at rt for 1 h. Excess TFA was removed and the residue was diluted with methylene chloride (5 mL), washed with 2% NaHCO ₃ solution (2 x 4 mL), brine (1 x 5 mL), dried over Na ₂ S0 ₄ , Concentration gave compound 6 (0.15 g), which was used without further purification. The ¹ H-NMR (300 MHz, CDCl ₃ ) spectrum of the aliquots showed the absence of a peak at δ 1.45 for the t-boc group.
Example 5
Synthesis of Compound 7
Triethylamine (0.040 g, 0.3944 mmol) was added to a cooled (0 ° C.) solution of compound 6 (0.150 g, 0.3944 mmol) in anhydrous methylene chloride (4 mL). A solution of acetyl chloride (0.030 g, 0.3944 mmol) in methylene chloride (1 mL) was added dropwise to the reaction flask over 5 minutes. The cold bath was removed and the reaction mixture was stirred for an additional 30 minutes, poured into ice-water (5 mL) and the layers separated. The organic layer was washed with 3% hydrochloric acid solution (2 × 4 mL), saturated sodium bicarbonate solution (1 × 5 mL), brine (1 × 5 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated to give the crude product which was purified by flash column chromatography (silica gel, 3% methanol in methylene chloride) to give compound 7 (0.025 g).
7: white solid, mp 64-79 ° C. (softening to melting); R _f (5% methanol in methylene chloride): 0.34; ¹ H-NMR (300 MHz, CHCl ₃ ) δ 7.30-7.00 (m, 10H), 4.95-4.80 (m, 1H), 4.75-4.40 (m, 2H), 4.30-4.15 (m, 1H), 3.90-3.50 (m, 4H), 3.25-3.10 (m, 2H), 3.00-2.80 (m, 4H), 2.45-2.30 (m, 1H), 2.05 (m, 1H), 2.00 (d, 3H).
<Example 6>
Synthesis of Compound 8
Triethylamine (0.085 g, 0.839 mmol) was added to a cooled (0 ° C.) solution of compound 5 (0.100 g, 0.21 mmol) in anhydrous methylene chloride (2 mL) and anhydrous dimethyl sulfoxide (2 mL). . Sulfur trioxide-pyridine complex (0.133 g, 0.839 mmol) was added to the stirred mixture over 5 minutes and the ice-bath was removed. The mixture was stirred for another hour, poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with 2% citric acid solution (2 x 5 mL), saturated sodium bicarbonate solution (2 x 5 mL), brine (1 x 5 mL) and dried over anhydrous magnesium sulfate. Solvent evaporation gave a residue, which was washed with n-pentane (20 mL) and dried under vacuum to afford compound 8 (0.055 g) of the present invention. A comprehensive description of this preliminary process can be found in Luly, J.R. Et al., J. Org. Chem. 1987, 1487-1492.
8: white solid, mp 70-80 ° C. (softening to melting); R _f (ethyl acetate): 0.69; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (d, 1H), 7.50 (wide, 1H), 7.25-7.00 (m, 9H), 6.05 (d, 1H), 4.75-4.45 (m, 4H), 3.85-3.00 (m, 5H), 2.95-2.40 (m, 3H), 1.45 (s, 9H).
<Example 7>
Synthesis of Compound 9
The compound was synthesized according to the general procedure described for the synthesis of compound 8. Thus, compound 7 (0.110 g) was oxidized to 0.145 g of sulfur trioxide-pyridine complex in the presence of 0.092 g of triethylamine to give compound 9 (0.060 g) of the present invention.
9: white solid, mp 80-120 ° C. (softening to melting); R _f (5% methanol in methylene chloride): 0.31; ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.60 (d, 1H), 7.70-7.60 (t, 1H), 7.30-7.00 (m, 9H), 4.95-4.85 (m, 1H), 4.80-4.40 (m, 3H), 3.90-2.80 (m, 8H), 2.40-2.30 (m, 1H), 2.00 (s, 3H).
Scheme 2 shows the synthesis of compounds 10-14:
The symbol "*" represents the D-array around the indicated carbon atom.
Examples 8-11 show the synthesis of intermediate compounds 10-13. Example 12 shows the preparation of compound 14 of the present invention.
<Example 8>
Synthesis of Compound 10
The compound was synthesized according to the general procedure described for the synthesis of compound 6. Thus, 2.10 g of compound 3 was deesterified with 90% TFA (3 mL) in methylene chloride (7 mL) to give compound 10 (1.47 g), which was used without further purification. The ¹ H-NMR (300 MHz, CDCl ₃ ) spectra of the aliquots showed the absence of a peak at δ 1.40 for the t-boc group.
Example 9
Synthesis of Compound 11
Triethylamine (0.445 g, 4.3976 mmol) was added to a cooled (0 ° C.) solution of compound 10 (1.393 g, 4.1172 mmol) in methylene chloride (15 mL). A solution of methanesulfonyl chloride (0.504 g, 4.3998 mmol) in methylene chloride (4 mL) was added dropwise to the reaction flask over 5 minutes. The cold bath was removed and the reaction mixture was stirred for an additional 30 minutes, poured into ice-water (20 mL) and the layers separated. The organic layer was washed with 2% citric acid solution (2 x 10 mL), saturated sodium bicarbonate solution (2 x 10 mL), brine (1 x 10 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated to afford the crude product, which was purified by flash column chromatography (silica gel, 3% methanol in methylene chloride) to give compound 11 (0.720 g).
11: white solid, mp 55-85 ° C. (softening to melting); R _f (5% methanol in methylene chloride): 0.71; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.40-7.00 (m, 9H), 5.85 (dd, 1H), 5.25-5.05 (two sets of t, 2H), 4.65 (q, 1H), 4.50 (s, 1H ), 4.40 (m, 1H), 3.85 (m, 1H), 3.60 (m, 1H), 3.30 (m, 1H), 3.00 (s, 3H), 3.00-2.80 (m, 3H).
<Example 10>
Synthesis of Compound 12
The compound was synthesized according to the general procedure described for the synthesis of compound 4. Thus, compound 11 (0.69 g) was hydrogenated to compound 12 (0.50 g) in a Parr apparatus and the product was used without further purification. The ¹ H-NMR spectrum of the aliquots showed the absence of peaks for the benzyl group.
<Example 11>
Synthesis of Compound 13
The compound was synthesized according to the general procedure described for the synthesis of compound 5. Thus, the reaction between compound 12 (0.204 g) and 0.113 g of (S) -phenylalaninol produced the crude product, which was purified by flash column chromatography (silica gel, 3% methanol in methylene chloride) to give compound 13 (0.192 g) was obtained.
13: white solid, mp 55-85 ° C. (softening to melting); R _f (5% methanol in methylene chloride): 0.34; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35-7.00 (m, 10H), 6.00 (wide, 1H), 4.75-4.40 (two sets of q, 2H), 4.30 (m, 2H), 3.85-3.45 (m , 4H), 3.35-3.25 (m, 1H), 3.05-2.60 (m, 6H), 2.85 (s, 3H).
<Example 12>
Synthesis of Compound 14
The compound was synthesized according to the general procedure described for the synthesis of compound 8. Thus, compound 13 (0.110 g) was oxidized to 0.133 g of sulfur trioxide-pyridine complex in the presence of 0.085 g of triethylamine to give compound 14 (0.080 g) of the present invention.
14: white solid, mp 80-110 ° C. (softening to melting); R _f (5% methanol in methylene chloride): 0.36; ¹ H NMR (300MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.80 (d, 1H), 7.35-7.00 (m, 9H), 6.10 (d, 1H), 4.80 (m, 2H), 4.50 (m , 1H), 4.35 (m, 1H), 3.85-3.45 (m, 3H), 3.30-3.20 (m, 2H), 3.05-2.60 (m, 3H), 2.85 (s, 3H).
Scheme 3 shows the synthesis of compounds 16, 17a-b and 18a-b:
Examples 13 and 14 show the synthesis of intermediate compounds 16 and 17a-b. Example 15 shows the preparation of intermediate compounds 18a-b.
Example 13
Synthesis of Compound 16
To a stirred mixture of trans-β-nitrostyrene (compound 15, 5.25 g, 0.035 mol) and silica gel (10 g, 230-400 mesh) in chloroform (400 mL) and isopropanol (75 mL) at room temperature over 45 minutes. Sodium borohydride (5.50 g, 0.145 mol) was added slowly. The reaction mixture was stirred for an additional 15 minutes and then quenched carefully with 10% hydrochloric acid (20 mL). The solid separated off was filtered and washed with chloroform (50 mL). The combined filtrates and washes were washed with water (1 × 20 mL), brine (1 × 20 mL) and dried over anhydrous sodium sulfate. Solvent evaporation under reduced pressure afforded the crude material which was purified by flash column chromatography (silica gel, 8% ethyl acetate-hexane) to give compound 16 (2.86 g).
16: colorless oil (flavourful); R _f (10% ethyl acetate in hexane): 0.40; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.20 (m, 5H), 4.60 (t, 2H), 3.30 (t, 2H).
<Example 14>
Synthesis of Compound 17a-b
Dimethyl sulfoxide (3.65 g, 3.32 mL, 0.0467 mol) was slowly added to a cooled (-78 ° C) solution of oxalyl chloride (2M) in methylene chloride (11.60 mL, 0.0232 mol). The reaction mixture was stirred for 15 minutes. Then, a solution of 2-fluoroethanol (1.16 g, 0.0181 mol) in methylene chloride (10 mL) was slowly introduced into the reaction flask. After stirring for another 15 minutes, the reaction mixture was diluted with anhydrous methylene chloride (180 mL) and triethylamine (9.20 g, 12.63 mL, 0.090 mol) was added. Stirring was continued for 2 hours, at which time the reaction mixture was allowed to warm to room temperature. At this time, a solution of compound 16 (2.74 g, 0.0181 mol) in anhydrous methylene chloride (10 mL) was added to the reaction mixture and stirring continued overnight. The mixture was then washed with water (1 x 30 mL), 4% hydrochloric acid (3 x 20 mL), water (1 x 20 mL), saturated sodium bicarbonate solution (2 x 20 mL) and brine (1 x 20 mL). It was. Drying over anhydrous sodium sulfate and solvent evaporation gave the crude material, which was purified by flash column chromatography (silica gel, 25% ethyl acetate-hexane) to give compounds 17a and 17b as erythro / threo isomers. The combined yield was 3.01 g. In another set of experiments, compound 16 (13.94 g) was converted to compound 17a-b (12.5 g) and used in the next step without any separation. General techniques for this preliminary process can be found in Imperiali, B. et al., Tetrahedron Lett. 27 (2), 135, 1986 and Revesz, L. et al., Tetrahedron Lett. 35 (52), 9693, 1994).
17a: white solid, mp 71-73 ° C .; R _f (30% ethyl acetate in hexane): 0.46; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 5H), 4.90 (m, 1H), 4.60 (m, 1H), 4.50-4.30 (m, 2H), 3.45-3.25 (m, 2H ), 2.70 (d, 1 H).
17b: colorless oil; R _f (30% ethyl acetate in hexane): 0.42; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.15 (m, 5H), 4.90 (m, 1H), 4.65 (m, 1H), 4.50 (m, 1H), 4.20 (m, 1H), 3.40- 3.30 (m, 2 H), 2.90 (d, 1 H).
<Example 15>
Synthesis of Compound 18a-b
A mixture of compound 17a (0.48 g, 2.25 mmol), anhydrous ethanol (20 mL) and Raney-nickel (catalyst amount) was hydrogenated (60 psi) for 5 hours in a Parr apparatus. Filtration through Celite ^R pad and solvent evaporation gave compound 18a (0.41 g). Similar treatment of compound 17b (0.80 g, 3.75 mmol) gave compound 18b (0.51 g). Finally, the combined mixture of compounds 17a-b (10.00 g) was hydrogenated to yield 7.20 g of an arc of compounds 18a-b, which was used as a whole in the experiments described below.
18a: white solid, mp 64-67 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 5H), 4.70 (d, 1H), 4.50 (d, 1H), 3.90-3.70 (m, 1H), 3.30-3.10 (m, 1H ), 2.95 (dd, 1H), 2.60-2.45 (q, 1H), 2.20-1.70 (wide, 3H).
18b: white solid, mp 67-70 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 5H), 4.70 (d, 1H), 4.55 (d, 1H), 3.70-3.50 (m, 1H), 3.20-3.00 (m, 1H ), 2.95 (dd, 1H), 2.60-2.45 (q, 1H), 2.20-1.65 (wide, 3H).
Scheme 4 shows the synthesis of compounds 19 and 20:
The symbol "*" represents the D-array around the indicated carbon atom.
Example 16 shows the synthesis of intermediate compound 19. Example 17 shows the preparation of compound 20 of the present invention.
<Example 16>
Synthesis of Compound 19
The compound was synthesized according to the general procedure described for the synthesis of compound 5. Thus, the reaction between compound 12 (0.142 g) and compound 18a-b (0.088 g) gave a crude product which was purified by flash column chromatography (silica gel, 3% methanol in methylene chloride) to give compound 19 (0.138). g) was obtained as a mixture of diastereomers.
19: white solid, mp 75-115 ° C. (softening to melting); R _f (5% methanol in methylene chloride): 0.44; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.50-7.05 (m, 10H), 6.15-5.75 (m, 1H), 4.70-3.40 (m, 11H), 3.30-2.50 (m, 8H).
<Example 17>
Synthesis of Compound 20
To a cooled (0 ° C.) solution of compound 19 (0.126 g, 0.2563 mmol) in anhydrous methylene chloride (8 mL) was added Dess-Martin periodinan reagent (0.217 g, 0.5126 mmol). . The cold bath was removed and the mixture was stirred for an additional 45 minutes. It was then diluted with methylene chloride (15 mL) and washed with 10% sodium thiosulfate solution (4 x 10 mL), saturated sodium bicarbonate solution (1 x 10 mL) and brine (1 x 10 mL). Drying over anhydrous sodium sulfate and solvent removal under reduced pressure afforded the crude which was purified by flash column chromatography (silica, 70% ethyl acetate-hexane) to give compound 20 (0.094 g) of the two diastereomers of the present invention. Obtained as a mixture. General description of this preliminary process can be found in Patel, D.V. Et al., J. Med. Chem. 1993, 36, 2431-2447.
20: white solid, R _f (70% ethyl acetate in hexane): 0.44; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.80-7.65 (m, 1H), 7.40-7.05 (m, 9H), 6.10-6.00 (t, 1H), 5.10-4.40 (m, 6H), 4.35-4.25 (m, 1H), 3.90-3.50 (m, 2H), 3.30-2.50 (m, 5H), 2.85 (m, 3H).
Scheme 5 shows the synthesis of compounds 22-25:
The symbol "*" represents the D-array around the indicated carbon atom.
Examples 18-20 show the synthesis of intermediate compounds 22-24. Example 21 shows the preparation of compound 25 of the present invention.
Example 18
Synthesis of Compound 22
The compound was synthesized according to the general procedure described for the synthesis of compound 5. Thus, a crude product was obtained by reaction between 1.095 g of Compound 21 (Advanced ChemTech, Louisville, KY) and 0.532 g of (s) -phenylalaninol, which was flash column chromatography (silica gel, methylene chloride). In 3% methanol) afforded compound 22 (1.06 g).
22: white solid, mp 105-108 ° C., R _f (5% methanol in methylene chloride): 0.44; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.15 (m, 10H), 6.40 (d, 1H), 5.10 (wide, 1H), 4.25-4.05 (m, 2H), 3.75 (s, 2H), 3.70-3.50 (two sets of m, 2H), 2.95-2.55 (m, 5H), 1.45 (s, 9H).
Example 19
Synthesis of Compound 23
The compound was synthesized according to the general procedure described for the synthesis of compound 6. Thus, a reaction between compound 21 (0.512 g) and 90% TFA (1 mL) in 3 mL methylene chloride gave compound 23 (0.38 g), which was used without further purification. The ¹ H-NMR (300 MHz, CDCl ₃ ) spectrum of the aliquots showed the absence of a peak at δ 1.45 for the t-Boc group.
Example 20
Synthesis of Compound 24
The compound was synthesized according to the general procedure described for the synthesis of compound 7 (except for using acetyl bromide in place of acetyl chloride). Thus, a crude product was obtained by reaction between compound 23 (0.377 g) and 0.121 g acetyl bromide in the presence of 0.10 g of triethylamine in 5 ml of methylene chloride, which was flash column chromatography (silica gel, 4% methanol in methylene chloride). Purification) gave compound 24 (0.158 g).
24: white solid, mp 149-151 ° C., R _f (5% methanol in methylene chloride): 0.32; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.05 (m, 10H), 6.80 (d, 1H), 6.45 (d, 1H), 4.45 (q, 1H), 4.20 (m, 1H), 3.70 ( s, 2H), 3.75-3.50 (2 sets of m, 2H), 3.20-3.00 (m, 1H), 2.90-2.75 (m, 2H), 2.70-2.50 (2 sets of q, 2H), 1.95 (s , 3H).
Example 21
Synthesis of Compound 25
The compound was synthesized according to the general procedure described for the synthesis of compound 8. Thus, compound 24 (0.167 g) was oxidized to 0.240 g of sulfur trioxide-pyridine complex in the presence of 0.153 g of triethylamine to give compound 25 (0.085 g) of the present invention.
25: white solid, mp 45-70 ° C. (softening to melting); R _f (ethyl acetate): 0.34; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.05 (m, 10H), 6.80 (d, 1H), 6.20 (d, 1H), 4.70-4.40 (two sets of q, 2H), 3.70 (s, 2H), 3.10 (d, 1H), 2.90-2.50 (two sets of m, 2H), 1.95 (s, 3H).
Scheme 6 shows the synthesis of compounds 27-34:
The symbol "*" represents the D-array around the indicated carbon atom.
Examples 22-27 show the synthesis of intermediate compounds 27-32. Examples 28 and 29 show the preparation of compounds 33 and 34 of the present invention.
<Example 22>
Synthesis of Compound 27
The compound was synthesized according to the general procedure described for the synthesis of compound 5. Thus, a reaction between compound 21 (1.033 g) and compound 18a-b (0.668 g) gave the crude product, which was purified by flash column chromatography (silica gel, 3% methanol in methylene chloride) to give compound 27 (1.38). g) was obtained as a mixture of diastereomers.
27: white solid, mp 120-138 ° C. (softening to melting); R _f (5% methanol in methylene chloride) 0.72 and 0.61 (two sets of erythro and threoisomers overlapping); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.15 (m, 10H), 6.60-6.30 (2 sets of t, 1H), 5.20-5.05 (wide, 1H), 4.60-3.90 (5 sets of m, 5H), 3.75-3.60 (two sets of d, 2H), 3.00-2.80 (m, 3H), 2.75-2.55 (m, 2H), 1.50-1.30 (m, 9H).
<Example 23>
Synthesis of Compound 28
The compound was synthesized according to the general procedure described for the synthesis of compound 6. Thus, a reaction between compound 27 (1.02 g) and 3 mL of 90% TFA in 5 mL of methylene chloride afforded compound 28 (0.77 g), which was used without further purification. The ¹ H-NMR (300 MHz, CDCl ₃ ) spectrum of the aliquots showed the absence of a peak for the t-Boc group at δ 1.50-1.30.
<Example 24>
Synthesis of Compound 29
The compound was synthesized according to the general procedure described for the synthesis of compound 11. Thus, a crude product was obtained by reaction between compound 28 (0.644 g) and 0.183 g methanesulfonyl chloride in the presence of 0.162 g of triethylamine in 5 ml of methylene chloride, which was flash column chromatography (silica gel, 50 in hexane). % Ethyl acetate) gave compound 29 (0.347 g) as a mixture of diastereomers.
29: white solid, mp 135-150 ° C. (softening to melting); R _f (5% methanol in methylene chloride): 0.63 and 0.59 (two sets of overlapping erythro and threoisomers): ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 10H), 6.70-6.30 ( 2 sets of m, 1H), 5.40-5.00 (2 sets of m, 1H), 4.70-4.10 (m, 4H), 4.00-3.85 (m, 1H), 3.80-3.60 (m, 2H), 3.10-2.50 (m, 8 H).
<Example 25>
Synthesis of Compound 30
The compound was synthesized according to the general procedure described for the synthesis of compound 5. Thus, a reaction between 0.633 g of compound 26 (Advanced ChemTech, Louisville, KY) and compound 18a-b (0.432 g) yielded the crude product, which was flash column chromatography (silica gel, 3 in methylene chloride). % Methanol) gave compound 30 (0.865 g) as a mixture of diastereomers.
30: white semi-solid, R _f (5% methanol in methylene chloride): 0.72 and 0.65 (two sets of erythro and treo isomers overlapping); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.05 (m, 10H), 6.85-6.50 (one set of d and one set of t, 1H), 5.40-5.20 (wide, 1H), 4.60-4.30 ( m, 4H), 4.30-4.05 (m, 2H), 3.95-3.70 (m, 2H), 3.60-3.40 (m, 2H), 3.05-2.85 (m, 2H), 1.40 (2s, 9H).
Example 26
Synthesis of Compound 31
The compound was synthesized according to the general procedure described for the synthesis of compound 6. Thus, a reaction between compound 30 (0.820 g) and 2 mL of 90% TFA in 4 mL of methylene chloride afforded compound 31 (0.506 g), which was used without further purification. The ¹ H-NMR (300 MHz, CDCl ₃ ) spectrum of the aliquots showed the absence of a peak at δ 1.40 for the t-Boc group.
Example 27
Synthesis of Compound 32
The compound was synthesized according to the general procedure described for the synthesis of compound 11. Thus, a crude product was obtained by reaction between compound 31 (0.50 g) and 0.175 g methanesulfonyl chloride in the presence of 0.155 g of triethylamine in 6 ml of methylene chloride, which was flash column chromatography (silica gel, methylene chloride in 4% methanol) gave compound 32 (0.32 g) as a mixture of diastereomers.
32: white solid, mp 118-121 ° C .; R _f (5% methanol in methylene chloride): 0.43; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 10H), 7.10-6.90 (two sets of d, 1H), 5.40 (wide t, 1H), 4.60-4.10 (m, 5H), 4.05 -3.80 (m, 2H), 3.80-3.50 (2 sets of m, 2H), 3.30-3.20 (m, 1H), 3.00-2.60 (m, 5H)
<Example 28>
Synthesis of Compound 33
The compound was synthesized according to the general procedure described for the synthesis of compound 20. Thus, Compound 29 (0.296 g) was oxidized with 0.276 g of Dess-Martin reagent in 10 ml of methylene chloride to give the crude product, which was purified by flash column chromatography (silica gel, 50% ethyl acetate in hexanes) to obtain the crude product. Compound 33 (0.15 g) of was obtained as a mixture of diastereomers.
33: white solid, mp 40-70 ° C. (softening to melting); R _f (70% ethyl acetate in hexane): 0.75; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 10H), 6.85 (t, 1H), 5.25-4.75 (m, 4H), 3.90-3.75 (m, 1H), 3.70 (s, 2H ), 3.30-3.10 (m, 1H), 3.05-2.90 (m, 1H), 2.85-2.60 (m, 5H).
<Example 29>
Synthesis of Compound 34
The compound was synthesized according to the general procedure described for the synthesis of compound 20. Thus, Compound 32 (0.30 g) was oxidized with 0.725 g of Dess-Martin reagent in 10 ml of methylene chloride to synthesize the compound according to the general procedure described for the synthesis of Compound 11. Thus, compound 34 (0.25 g) was obtained as a mixture of two diastereomers.
34: white gum; R _f (50% ethyl acetate in hexane): 0.38; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.00 (m, 11H), 5.40 (m, 1H), 5.10-4.70 (m, 3H), 4.60-4.40 (t, 2H), 4.05 (m, 1H ), 3.80 (m, 1H), 3.60 (m, 1H), 3.20 (m, 1H), 2.90 (m, 1H), 2.80 (s, 3H).
Scheme 7 shows the synthesis of compounds 36-40.
The symbol "*" represents the D-array around the indicated carbon atom.
Examples 30-33 show the synthesis of intermediate compounds 36-39.
Example 34 shows the preparation of compound 40 of the present invention.
<Example 30>
Synthesis of Compound 36
The compound was synthesized according to the general procedure described for the synthesis of compound 5. Thus, a reaction between compound 26 (5.221 g) and compound 35 (4.20 g) yielded compound 36 (7.80 g), most of which was used in the next step without further purification. A partial sample of the crude product was purified by flash column chromatography (silica gel, 40% ethyl acetate in hexanes) to obtain an analytical sample.
36: white solid, mp 80-83 ° C .; R _f (30% ethyl acetate in hexane): 0.37; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.00 (m, 10H), 6.90 (wide d, 1H), 5.40 (wide, 1H), 4.90 (q, 1H), 4.50 (q, 2H), 4.30 (Wide, 1H), 3.90 (wide q, 1H), 3.70 (s, 3H), 3.50 (dd, 1H), 3.10 (m, 2H), 1.40 (s, 9H).
<Example 31>
Synthesis of Compound 37
The compound was synthesized according to the general procedure described for the synthesis of compound 6. Thus, a reaction between compound 36 (7.70 g) and 10 mL of 90% TFA in 15 mL of methylene chloride afforded compound 37 (6.00 g), which was used without further purification. The ¹ H-NMR (300 MHz, CDCl ₃ ) spectrum of the aliquots showed the absence of a peak at δ 1.40 for the t-Boc group.
<Example 32>
Synthesis of Compound 38
The compound was synthesized according to the general procedure described for the synthesis of compound 11. Thus, a crude product was obtained by reaction of compound 37 (6.00 g) with 2.70 g of methanesulfonyl chloride in the presence of 2.386 g of N-methylmorpholine (instead of triethylamine) in 20 ml of methylene chloride, which was flash column Purification by chromatography (silica gel, 45% ethyl acetate in methylene chloride) gave compound 38 (5.86 g).
38: white solid, mp 92-98 ° C. (softening to melting); R _f (50% ethyl acetate in hexane): 0.33; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.00 (m, 11H), 5.30 (d, 1H), 4.85 (m, 1H), 4.45 (q, 2H), 4.10 (q, 1H), 3.80 ( dd, 1H), 3.75 (s, 3H), 3.60 (dd, 1H), 3.20-3.00 (two sets of q, 2H), 2.85 (s, 3H).
<Example 33>
Synthesis of Compound 39
To a stirred solution of compound 38 (2.501 g, 5.7569 mmol) in dry THF (10 mL) at room temperature was slowly added a 2 (M) solution of LiBH ₄ in THF (4.31 mL) over 30 minutes. The mixture was stirred for another 30 minutes, slowly poured onto ice-water (about 20 g), acidified (0 ° C.) with 4 (N) hydrochloric acid and extracted with ethyl acetate (3 × 75 mL). The combined organic layers were washed successively with 2% NaHCO ₃ solution (2 × 20 mL), H ₂ O (1 × 10 mL), brine (1 × 20 mL), dried over Na ₂ SO ₄ , concentrated to crude product. Obtained. Purification by flash column chromatography (silica gel, 20% methylene chloride in ethyl acetate) gave compound 39 (1.275 g).
39: white solid, mp 140-142 ° C .; R _f (ethyl acetate): 0.53; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 10H), 6.90 (d, 1H), 5.50 (d, 1H), 4.50 (q, 2H), 4.20 (m, 1H), 4.00 ( m, 1H), 3.80 (dd, 1H), 3.70-3.45 (m, 3H), 2.90-2.70 (m, 2H), 2.85 (s, 3H), 2.60 (t, 1H).
<Example 34>
Synthesis of Compound 40
The compound was synthesized according to the general procedure described for the synthesis of compound 20. Thus, compound 39 (0.813 g) was oxidized with 1.70 g of Dess-Martin reagent in 20 ml of methylene chloride to obtain compound 40 (0.77 g) of the present invention.
40: white solid, mp 75-85 ° C. (softening to melting); R _f (ethyl acetate): 0.62; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.00 (m, 11H), 5.30 (d, 1H), 4.70 (q, 1H), 4.50 (q, 2H), 4.10 ( q, 1H), 3.85 (dd, 1H), 3.60 (dd, 1H), 3.15 (m, 2H), 2.85 (s, 3H).
<Example 35>
Synthesis of Compound 41
The compound was synthesized according to Scheme 7, as described above, except that (L) -Abu-OMe hydrochloride was used in place of (L) -Phe-OMe hydrochloride in step 1.
41: white solid, mp 75-83 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.52; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.30 (m, 6H), 5.65 (d, 1H), 4.55 (q, 2H), 4.45 (q, 1H), 4.20 (q, 1H), 3.85 (q, 1H), 3.75 (q, 1H), 2.95 (s, 3H), 1.95 (m, 1H), 1.70 (m, 1H), 0.90 (t, 3H).
<Example 36>
Synthesis of Compound 42
This compound was synthesized according to the following Scheme 7 as described above except that acetyl chloride was used in place of methanesulfonyl chloride in the preparation of the homologue of compound 38.
42: white solid, mp 118-123 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.45; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.30 (m, 8H), 7.10 (dd, 2H), 6.95 (d, 1H), 6.30 (d, 1H), 4.70 (q, 1H), 4.60 (m, 1H), 4.50 (q, 2H), 3.85 (dd, 1H), 3.45 (dd, 1H), 3.10 (d, 2H), 2.00 (s, 3H).
<Example 37>
Synthesis of Compound 43
The compound was synthesized according to Scheme 7 as described above, except that Boc- (D) -Thr (Bzl) was used in place of Boc- (D) -Ser (Bzl) in step 1.
43: white solid, mp 102-108 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.57; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.00 (m, 11H), 5.40 (d, 1H), 4.75 (q, 1H), 4.50 (d, 2H), 4.00 ( m, 2H), 3.20 (q, 1H), 3.00 (q, 1H), 2.80 (s, 3H), 1.05 (d, 3H).
<Example 38>
Synthesis of Compound 44
This compound was synthesized according to the following Scheme 7 as described above except that benzoyl chloride was used in place of methanesulfonyl chloride in the preparation of the homologue of compound 38.
44: white solid, mp 142-147 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.54; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.80 (d, 2H), 7.60-7.00 (m, 15H), 4.80 (m, 1H), 4.70 (q, 1H), 4.50 ( d, 2H), 4.00 (dd, 1H), 3.55 (dd, 1H), 3.10 (d, 2H).
<Example 39>
Synthesis of Compound 45
The compound was synthesized according to the following Scheme 7 as described above except that diphenylacetic acid (in the presence of DCC and HOBt) was used in place of methanesulfonyl chloride and NMM in the preparation of the homologue of compound 38.
45: white solid, mp 148-153 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.60; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.40-7.00 (m, 20H), 6.85 (d, 1H), 6.45 (d, 1H), 4.95 (s, 1H), 4.65 ( m, 2H), 4.40 (q, 2H), 3.85 (dd, 1H), 3.45 (dd, 1H), 3.10 (m, 2H).
<Example 40>
Synthesis of Compound 46
This compound was synthesized according to the following Scheme 7 as described above except that 4-fluorobenzenesulfonyl chloride was used in place of methanesulfonyl chloride in preparing the homologue of compound 38.
46: white solid, mp 132-136 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.54; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.80 (q, 2H), 7.40-7.00 (m, 13H), 5.60 (d, 1H), 4.60 (q, 1H), 4.35 ( q, 2H), 3.80 (m, 2H), 3.25 (dd, 1H), 3.10 (d, 2H).
<Example 41>
Synthesis of Compound 47
This compound was synthesized according to the following Scheme 7 as described above, except that yeast hypodimethylsulfamoyl was used in place of methanesulfonyl chloride in the preparation of the homologue of compound 38.
47: white solid, mp 90-100 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.54; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.10 (m, 11H), 5.25 (d, 1H), 4.70 (q, 1H), 4.45 (q, 2H), 4.00 ( m, 1H), 3.90 (dd, 1H), 3.55 (dd, 1H), 3.15 (m, 2H), 2.70 (s, 6H).
<Example 42>
Synthesis of Compound 48
This compound was synthesized according to the following Scheme 7 as described above except that benzenesulfonyl chloride was used in place of methanesulfonyl chloride in the preparation of the homologue of compound 38. The compound contained a small amount of another diastereomer.
48: white solid, mp 110-115 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.63; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 and 9.50 (two singlet, 84:16, 1H), 7.80-7.00 (m, 16H), 5.60 (d, 1H), 4.60 (q, 1H), 4.30 (q, 2H), 3.80 (m, 2H), 3.30 and 3.20 (two sets of dd, 84:16, 1H), 3.10 and 3.05 (two sets of d, 84:16, 2H).
<Example 43>
Synthesis of Compound 49
The compound was synthesized according to the following Scheme 7 as described above except that p-toluenesulfonyl chloride was used in place of methanesulfonyl chloride in preparing the homologue of compound 38.
49: white solid, mp 113-124 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.58; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.35 (d, 2H), 7.40-7.20 (m, 9H), 7.15 (m, 4H), 5.50 (d, 1H), 4.60 ( q, 1H). 4.40 (d, 1H), 4.20 (d, 1H), 3.80 (m, 2H), 3.20 (dd, 1H), 3.10 (d, 2H), 2.40 (s, 3H).
<Example 44>
Synthesis of Compound 50
This compound was synthesized according to the following Scheme 7 as described above except that ethanesulfonyl chloride was used in place of methanesulfonyl chloride in preparing the homologue of compound 38.
50: white solid, mp 125-127 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.51; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1 H), 7.40-7.00 (m, 11 H), 5.25 (d, 1 H), 4.70 (q, 1H), 4.45 (q, 2H), 4.05 ( m, 1H), 3.85 (dd, 1H), 3.60 (dd, 1H), 3.15 (m, 2H), 2.90 (q, 2H), 1.25 (t, 3H).
<Example 45>
Synthesis of Compound 51
The compound was synthesized according to the following Scheme 7, as described above, except that 4-acetamidobenzenesulfonyl chloride was used in place of methanesulfonyl chloride in preparing the homologue of compound 38. Compound 51 contained a small amount of another diastereomer.
51: white solid, mp 150-156 ° C. (decomposition); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.36; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 10.45 (s, 1H), 9.40 and 9.30 (two sets of singlet, 86:14, 1H), 8.70 (two overlapping d, 1H), 8.20 ( t, 1H), 7.85 (m, 3H), 7.45 (m, 4H), 7.35 (m, 8H), 4.50-4.30 (m, 2H), 4.20 (m, 1H), 3.60 and 3.45 (two d, 2H), 3.20 (m, 1H), 2.85 (m, 1H), 2.20 (s, 3H).
Example 46
Synthesis of Compound 52
The compound was synthesized according to the following Scheme 7 as described above except that 2-naphthalenesulfonyl chloride was used in place of methanesulfonyl chloride in preparing the homologue of compound 38.
52: white solid, mp 95-105 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.54; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.50 (s, 1H), 8.40 (s, 1H), 7.90 (m, 4H), 7.70 (m, 4H), 7.40-7.00 (m, 9H), 65 ( d, 1H), 4.55 (q, 1H), 4.30 (q, 2H), 3.80 (m, 2H), 3.20 (dd, 1H), 3.05 (d, 2H).
<Example 47>
Synthesis of Compound 53
The compound was synthesized according to the following Scheme 7, as described above, except that morpholinosulfonyl chloride was used as a substitute for methanesulfonyl chloride in the preparation of the homologue of compound 38.
53: white gum; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.51; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.10 (m, 11H), 5.35 (d, 1H), 4.75 (q, 1H), 4.50 (q, 2H), 4.00 ( m, 1H), 3.85 (m, 1H), 3.80-3.50 (m, 5H), 3.30-3.00 (m, 6H).
<Example 48>
Synthesis of Compound 54
The compound was synthesized according to the following Scheme 7 as described above except that 2-thiophensulfonyl chloride was used in place of methanesulfonyl chloride in preparing the homologue of compound 38.
54: white solid, mp 105-115 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.56; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.60 (m, 2H), 7.40-7.00 (m, 12H), 5.65 (d, 1H), 4.60 (q, 1H), 4.35 ( q, 2H), 3.90 (m, 2H), 3.30 (m, 1H), 3.10 (d, 2H).
<Example 49>
Synthesis of Compound 55
The compound was synthesized according to the following Scheme 7 as described above, except that 3,5-dimethyl-4-isoxazolesulfonyl chloride was used in place of methanesulfonyl chloride in the preparation of the homologue of compound 38.
55: white gum, R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.39; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.50 (s, 1H), 7.30-7.10 (m, 11H), 5.65 (d, 1H), 4.60 (q, 1H), 4.30 (q, 2H), 3.70 ( m, 1H), 3.60 (m, 1H), 3.35 (t, 1H), 3.05 (d, 2H), 2.50 (s, 3H), 2.25 (s, 3H).
Scheme 8 shows the synthesis of compound 59.
<Example 50>
Synthesis of Compound 59
To a stirred suspension of (D) -Phe (compound 56, 2.00 g, 0.012 mol) in water (10 mL) was slowly added 1N NaOH (20 mL) followed by benzenesulfonyl chloride (3.20 g, 0.018 mol); The pH of the reaction mixture was maintained at about 10-11 with 1N NaOH intermittently. After 2 hours, the reaction mixture was acidified (pH about 2-3) with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (1 × 10 mL), brine (1 × 20 mL), dried (MgSO ₄ ) and concentrated to give crude compound 57 (2.00 g), which was used directly in the next step. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.80-7.00 (m, 11H), 5.10 (d, 1H), 4.25 (m, 1H), 3.10 (dd, 1H), 3.00 (dd, 1H).
Compound 57 (1 g) was coupled with 0.5 g of (s) -phenylalaninol, and then the coupling process of Scheme 1 was carried out to obtain compound 58 (1.00 g). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.70-7.10 (serial m, 13H), 6.90 (d, 2H), 6.40 (d, 1H), 5.05 (d, 1H), 4.05 (m, 1H), 3.85 (m, 1H), 3.50 (m, 2H), 2.85 (m, 2H), 2.75 (m, 2H), 2.30 (t, 1H).
Compound 58 was oxidized to Compound 59 with Dess-Martin reagent as described in Scheme 7 above for the preparation of Compound 40.
59: white solid, mp 70-75 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.50; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.45 (s, 1H), 7.60 (m, 4H), 7.40 (t, 3H), 7.30-7.10 (m, 6H), 6.90 (d, 2H), 6.70 ( d, 1H), 4.90 (d, 1H), 4.60 (q, 1H), 3.90 (q, 1H), 3.15 (dd, 1H), 3.00 (dd, 1H), 2.90 (d, 2H).
<Example 51>
Synthesis of Compound 60
The compound was synthesized according to Scheme 8, as described above, except that ethanesulfonyl chloride was used in place of benzenesulfonyl chloride in one step.
60: white solid, mp 112-116 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.53; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.20 (m, 8H), 7.10 (d, 2H), 6.65 (d, 1H), 5.10 (d, 1H), 4.70 ( q, 1H), 4.15 (q, 1H), 3.20-2.90 (m, 4H), 2.70-2.50 (m, 2H), 1.00 (t, 3H).
<Example 52>
Synthesis of Compound 61
The compound was synthesized according to Scheme 8 as described above, except that p-toluenesulfonyl chloride was used in place of benzenesulfonyl chloride in step 1.
61: white solid, mp 130-135 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.47; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.50 (d, 2H), 7.40-7.10 (m, 10H), 6.90 (d, 2H), 6.80 (d, 1H), 4.85 ( d, 1H), 4.60 (q, 1H), 3.85 (q, 1H), 3.15 (dd, 1H), 3.00 (dd, 1H), 2.90 (d, 2H), 2.40 (s, 3H).
<Example 53>
Synthesis of Compound 62
The compound was synthesized according to Scheme 8 as described above, except that in step 1 (D) -homophe and methanesulfonyl chloride were used in place of (D) -Phe and benzenesulfonyl chloride .
62: white solid, mp 125-130 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.45; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.65 (s, 1H), 7.40-7.00 (m, 10H), 6.30 (d, 1H), 5.05 (d, 1H), 4.80 (q, 1H), 3.90 ( m, 1H), 3.20 (m, 2H), 2.80 (s, 3H), 2.65 (m, 2H), 1.90 (m, 2H).
<Example 54>
Synthesis of Compound 63
The compounds described above, except that in step 1 (D) -Ser (Bzl) and N-methyl-4-imidazolesulfonyl chloride were used in place of (D) -Phe and methanesulfonyl chloride It was synthesized according to Scheme 8 as follows.
63: white solid, mp 47-56 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.40; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.60 (d, 1H), 7.40-7.10 (m, 12H), 5.85 (d, 1H), 4.60 (q, 1H), 4.40 ( q, 2H), 4.15 (m, 1H), 4.00 (dd, 1H), 3.70 (s, 3H), 3.50 (m, 1H), 3.10 (m, 2H).
<Example 55>
Synthesis of Compound 64
The compounds were prepared according to Scheme 8 as described above, except that in one step (D) -Ser (Bzl) and Cbz-OSuc were used instead of (D) -Phe and methanesulfonyl chloride, respectively. Synthesized.
64: white solid, mp 115-120 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.75; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.10 (m, 15H), 6.95 (wide d, 1H), 5.60 (wide d, 1H), 5.10 (s, 2H), 4.70 (wide q, 1H), 4.45 (q, 2H), 4.40 (m, 1H), 3.90 (d, 1H), 3.50 (dd, 1H), 3.10 (d, 2H).
Scheme 9 shows the synthesis of compound 70.
<Example 56>
Synthesis of Compound 70
Thionyl chloride (2.90 g, 0.024 mol) in a stirred solution of (D) -Phe (compound 56, 2.00 g, 0.012 mol) or Boc- (D) -Phe (compound 65) in methanol (40 mL) at 0 ° C. ) Was added slowly. The mixture is stirred at 0 ° C. for 1 h and then at rt overnight. Excess solvent and reagent were removed in vacuo to afford crude Compound 66 (2.50 g). This product was treated with methanesulfonyl chloride in the presence of triethylamine and methylene chloride to give compound 67; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.15 (m, 5H), 4.85 (d, 1H), 4.40 (m, 1H), 3.80 (s, 3H), 3.15 (dd, 1H), 3.05 ( dd, 1 H), 2.65 (s, 3 H).
Compound 67 was quantitatively hydrolyzed to Compound 68 (LiOH, THF-H ₂ O, room temperature, 3 hours), which in turn was converted to Compound 70 via Compound 69 using the process described in Scheme 7 for the preparation of Compound 40. Switched to
70: white solid, mp 65-70 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.44; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.40-7.00 (m, 10H), 6.80 (d, 1H), 5.30 (d, 1H), 4.75 (q, 1H), 4.10 ( m, 1H), 3.20-3.00 (m, 3H), 2.90 (dd, 1H), 2.40 (s, 3H).
<Example 57>
Synthesis of Compound 71
The compound was synthesized according to Scheme 9 as described above, except that (D) -Trp and benzenesulfonyl chloride were used in place of (D) -Phe and methanesulfonyl chloride in step 1, respectively. .
71: white solid, mp 125-135 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.55; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.35 (s, 1H), 8.40 (wide, 1H), 7.40-6.80 (m, 16H), 5.35 (d, 1H), 4.55 (q, 1H), 4.00 ( q, 1H), 3.20-2.90 (m, 4H).
<Example 58>
Synthesis of Compound 72
The compound was synthesized according to Scheme 9, as described above, except that 2-naphthalenesulfonyl chloride was used in place of 2-naphthalenesulfonyl chloride in step 1.
72: white solid, mp 120-130 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.51; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.40 (s, 1H), 8.05 (s, 1H), 7.90 (d, 2H), 7.80 (d, 1H), 7.65 (m, 2H), 7.55 (dd, 1H), 7.30 (m, 3H), 7.00 (m, 5H), 6.80 (m, 3H), 5.00 (d, 1H), 4.50 (q, 1H), 3.95 (q, 1H), 3.10 (dd, 1H) ), 2.95 (dd, 1H), 2.90 (m, 2H).
<Example 59>
Synthesis of Compound 73
The compounds are prepared in Scheme 9 as described above, except that in step 1 (D) -Trp and 2-thiophenesulfonyl chloride are used instead of (D) -Phe and methanesulfonyl chloride, respectively. Synthesized accordingly.
73: white solid, mp 90-100 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.39; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.40 (s, 1H), 8.10 (s, 1H), 7.40-7.00 (m, 11H), 6.85 (m, 2H), 6.75 (d, 1H), 5.15 ( d, 1H), 4.60 (q, 1H), 4.05 (q, 1H), 3.10 (m, 3H), 3.00 (dd, 1H).
<Example 60>
Synthesis of Compound 74
The compound was synthesized according to Scheme 9, as described above, except that 8-quinolinesulfonyl chloride was used in place of methanesulfonyl chloride in step 1.
74: white solid, mp 80-90 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.57; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.50 (s, 1H), 8.70 (m, 1H), 8.30 (m, 1H), 8.20 (m, 1H), 8.00 (m, 1H), 7.60 (t, 1H), 7.45 (q, 1H), 7.40-7.10 (m, 6H), 6.90-6.60 (m, 6H), 4.60 (q, 1H), 4.10 (m, 1H), 3.20 (dd, 1H), 3.05 (m, 2 H), 2.80 (dd, 1 H).
<Example 61>
Synthesis of Compound 75
The compound was synthesized according to Scheme 9, as described above, except that 2-thiophenesulfonyl chloride was used in place of methanesulfonyl chloride in step 1.
75: white solid, melting point 55-65 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.43; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.50 (s, 1H), 7.60 (dd, 1H), 7.40 (dd, 1H), 7.35-7.05 (m, 8H), 7.00 (t, 1H), 6.95 ( m, 2H), 6.65 (d, 1H), 5.00 (d, 1H), 4.65 (q, 1H), 4.00 (q, 1H), 3.15 (dd, 1H), 3.00 (dd, 1H), 2.95 (d , 2H).
<Example 62>
Synthesis of Compound 76
The compound was synthesized according to Scheme 9 below, except that (D) -phenylglycine was used in place of (D) -phenylalanine in step 1.
76: white solid, melting point 140-145 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.45; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.05 (m, 8H), 6.75 (d, 2H), 6.00 (d, 1H), 5.85 (d, 1H), 5.05 ( d, 1H), 4.80 (q, 1H), 3.05 (q, 2H), 2.65 (s, 3H).
<Example 63>
Synthesis of Compound 77
The compound was synthesized according to Scheme 9 as described above, except that (D) -Trp was used in place of (D) -phenylalanine in step 1.
77: white solid, melting point 105-115 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.35; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.50 (s, 1H), 8.15 (s, 1H), 7.60 (d, 1H), 7.40-7.00 (m, 9H), 6.50 (d, 1H), 4.95 ( d, 1H), 4.65 (q, 1H), 4.20 (q, 1H), 3.25 (m, 2H), 3.10 (dd, 1H), 2.95 (dd, 1H), 2.50 (s, 3H).
<Example 64>
Synthesis of Compound 78
The compound was synthesized according to Schemes 1 and 2 as described above, except that N-benzylmethylamine was used in place of 1,2,3,4-tetrahydroisoquinoline in one step.
78: white solid, melting point 75-85 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.30; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.65 and 9.55 (two singlet, rotomogenic 1H), 7.70 (m, 1H), 7.40-7.00 (m, 10H), 6.20 (m, 1H), 4.70- 4.30 (m, 4H), 3.30-2.90 (m, 4H), 2.85 (two sets of d, 6H)
<Example 65>
Synthesis of Compound 79
The compound was prepared by using N-benzylmethylamine and Boc- (D) -Glu-OBz in place of 1,2,3,4-tetrahydroisoquinoline and Boc- (D) -Asp-OBz in step 1. Except as described above, it was synthesized according to the following Schemes 1 and 2.
79: The white solid of this compound is a complex due to the presence of rotamers; Melting point 75-85 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.42; ¹ H-NMR (300 MHz, CDCl ₃ ).
Example 66
Synthesis of Compound 80
The compound was synthesized according to Scheme 7, as described above, in the first step, changing the following: Boc- (D) -Cys (Bzl) (Compound 21) was converted to Boc- (D in the first step of the synthesis. ) -Ser (Bzl) (Compound 26) was used instead; The sulfide residues were converted to sulfonyl residues with oxone (Oxone ^R ) in MeOH before the alcohol was finally aldehyde oxidized with Dess-Martin reagent.
80: white solid, melting point 125-135 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.41; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.60 (s, 1H), 8.90 (d, 1H), 8.05 (d, 1H), 7.50-7.20 (m, 10H), 4.50 (m, 4H), 3.30 (d, 2H), 3.10 (m, 1H), 2.95 (s, 3H), 2.90 (m, 1H).
<Example 67>
Synthesis of Compound 81
The compound is prepared by the method of 3 (S) -amino-2 (R, S) -hydroxy-4-phenylbutanoic acid ethyl amide (see, Harbeson et al., J. Med. Chem. 1994, 37, 2918). Prepared) was synthesized according to the process described in Scheme 6 above, except that it was used in place of compounds 18a-b in the synthesis.
81: white solid, melting point 137-143 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.56; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 9H), 7.00 (m, 2H), 6.80 (wide, 1H), 5.60 (m, 1H), 5.15 (d, 1H), 4.50 ( s, 1H), 4.45 (d, 1H), 4.00 (m, 1H), 3.80 (m, 1H), 3.60 (m, 1H), 3.35 (m, 3H), 3.05 (m, 1H), 2.80 (s , 3H), 1.20 (t, 3H).
<Example 68>
Synthesis of Compound 82
The compound was synthesized by coupling Boc- (D) -Ser (Bzl) and (S) -phenylalaninol, followed by oxidation using the method described in Scheme 1.
82: white gum; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.65; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.00 (m, 11H), 5.30 (wide, 1H), 4.70 (m, 1H), 4.50 (m, 2H), 4.30 ( m, 1H), 3.90 (m, 1H), 3.50 (m, 1H), 3.15 (d, 2H), 1.50 (s, 9H).
<Example 69>
Synthesis of Compound 83
The compound was prepared by N-methylation of compound 38 (MeI, K ₂ CO ₃ , DMF) (Scheme 7), then the methyl ester was reduced to the corresponding alcohol and the alcohol was oxidized to the product aldehyde.
83: white gum; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.53; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.00 (m, 11H), 4.60 (m, 2H), 4.45 (q, 2H), 3.95 (dd, 1H), 3.70 ( t, 1H), 3.10 (m, 2H), 2.85 (s, 3H), 2.75 (s, 3H).
<Example 70>
Synthesis of Compound 84
The compound used (D) -Ser (Bzl) in place of (D) -Phe in step 1, and (R) -phenylalaninol in place of (S) -phenylalaninol in the coupling step. Except where used, it was synthesized according to Scheme 9 as described above.
84: white gum; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.41; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.00 (m, 11H), 5.30 (d, 1H), 4.75 (m, 1H), 4.50 (s, 2H), 4.10 ( m, 1H), 3.85 (dd, 1H), 3.60 (dd, 1H), 3.10 (m, 2H), 2.90 (s, 3H).
<Example 71>
Synthesis of Compound 85
The compound was synthesized by coupling Cbz- (D) -Leu and (S) -phenylalaninol and then oxidizing (Scheme 9).
85: white solid, melting point 40-50 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.65; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.10 (m, 10H), 6.50 (wide, 1H), 5.15 (s, 2H), 5.10 (wide, 1H), 4.70 ( Wide q, 1H), 4.20 (wide, 1H), 3.15 (d, 2H), 1.60-1.20 (m, 3H), 0.85 (wide d, 6H).
<Example 72>
Synthesis of Compound 86
The compound was synthesized according to the procedure of Scheme 8 below as described above, except that (D) -Leu was used in place of (D) -Phe in step 1.
86: white solid, melting point 95-100 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.33; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.65 (s, 1H), 7.40-7.10 (m, 5H), 6.30 (d, 1H), 4.80 (m, 2H), 3.90 (m, 1H), 3.25 ( dd, 1H), 3.15 (dd, 1H), 2.85 (s, 3H), 1.65-1.20 (m, 3H), 0.90 (t, 6H).
<Example 73>
Synthesis of Compound 87
The compound used Boc- (D) -Leu in place of Boc- (D) -Ser (Bzl) in step 1, and (S) -roycinol in the coupling step of (S) -phenylalaninol. Except for using instead, it synthesize | combined according to the process of Reaction Formula 7 as described above.
87: white gum; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.40; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 6.15 (d, 1H), 5.00 (d, 1H), 4.60 (m, 1H), 4.00 (m, 1H), 3.00 (s, 3H), 1.90-1.40 (m, 6H), 1.00 (m, 12H).
<Example 74>
Synthesis of Compound 88
The compound used Boc- (D) -Ser (Bzl) in place of (D) -Phe in step 1 and (S) -leucineol in place of (S) -phenylalaninol in the middle step. Except as described above, it was synthesized according to the process of Scheme 9 below.
88: white gum; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.46; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.10 (m, 5H), 6.95 (d, 1H), 5.30 (d, 1H), 4.55 (m, 3H), 4.15 ( m, 1H), 3.90 (m, 1H), 3.75 (dd, 1H), 2.95 (s, 3H), 1.70-1.20 (m, 3H), 0.90 (m, 6H).
<Example 75>
Synthesis of Compound 89
The compound was synthesized according to the process of Scheme 9 below, except that Boc- (D) -Tyr (Bzl) was used in place of (D) -Phe in step 1.
89: white solid; Melting point 140-145 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.34; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.45-7.20 (m, 5H), 7.10 (d, 4H), 6.90 (d, 2H), 6.55 (d, 1H), 5.05 ( s, 2H), 4.85 (q, 1H), 4.70 (q, 1H), 4.05 (q, 1H), 3.10 (m, 2H), 2.90 (q, 1H), 2.45 (s, 3H).
<Example 76>
Synthesis of Compound 90
The compound was synthesized according to the process of Scheme 9 as described above with the following changes: In step 1, Boc- (D) -Ser (Bzl) was used instead of (D) -Phe; In the intermediate stage (L) -Tyr (Bzl) -OMe was used in place of (S) -phenylalaninol; Subsequently, the ester residue was reduced (NaBH ₄ , EtOH) to the alcohol residue before the final oxidation step.
90: white solid; Melting point 105-106 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.38; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.45-7.20 (m, 10H), 7.15 (d, 1H), 7.00 (d, 2H), 6.85 (d, 2H), 5.25 ( d, 1H), 5.00 (s, 2H), 4.70 (q, 1H), 4.45 (q, 2H), 4.10 (m, 1H), 3.85 (dd, 1H), 3.60 (dd, 1H), 3.10 (m , 2H), 2.85 (s, 3H).
<Example 77>
Synthesis of Compound 91
The compound was prepared according to the procedure of Scheme 7 as described above, except that 5-chloro-1,3-dimethylpyrazole-4-sulfonyl chloride was used in place of methanesulfonyl chloride in step 1 Synthesized.
91: white solid; Melting point 50-60 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.57; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 and 9.55 (two singlet, 5: 1, 1H), 7.40-7.00 (m, 11H), 5.70 (d, 1H), 4.65 (q, 1H), 4.40 (q, 2H), 3.90-3.60 (m, 2H), 3.80 (s, 3H), 3.40 (dd, 1H), 3.10 (two sets of d, 5: 1, 2H), 2.40 (s, 3H) .
<Example 78>
Synthesis of Compound 92
The compound was synthesized according to the process of Scheme 8 as described above with the following changes: (D) -Ser (Bzl) and methanesulfonyl chloride in step 1 (D) -Phe and benzene chloride Used as a substitute for ponyl; In the intermediate stage (L) -Lys (Cbz) -OMe hydrochloride was used in place of (S) -phenylalaninol; Subsequently, (NaBH ₄ , EtOH) was reduced to alcohol before the final oxidation step.
92: white solid, melting point 125-135 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.40; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.40-7.15 (m, 11H), 5.25 (d, 1H), 5.10 (s, 2H), 4.90 (wide, 1H), 4.55 ( q, 2H), 4.45 (m, 1H), 4.15 (q, 1H), 3.85 (dd, 1H), 3.70 (dd, 1H), 3.15 (q, 2H), 2.90 (s, 3H), 1.90 (m , 1H), 1.70 (m, 1H), 1.50 (m, 2H), 1.30 (m, 2H).
<Example 79>
Synthesis of Compound 93
The compound was synthesized according to the process of Scheme 8 as described above with the following changes: (D) -Ser (Bzl) and methanesulfonyl chloride in step 1 (D) -Phe and benzene chloride Used as a substitute for ponyl; In the intermediate stage (L) -Lys (Cbz) -OMe hydrochloride was used in place of (S) -phenylalaninol; Subsequently, (NaBH ₄ , EtOH) was reduced to alcohol before the final oxidation step.
93: white solid; Melting point 130-135 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.47; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.40-7.20 (m, 6H), 5.50 (wide d, 1H), 4.65-4.40 (m, 4H), 4.15 (q, 1H) , 3.85 (dd, 1H), 3.75 (dd, 1H), 3.05 (m, 2H), 2.95 (s, 3H), 1.90 (m, 1H), 1.65 (m, 1H), 1.60-1.20 (m, 4H ), 1.45 (s, 9 H).
<Example 80>
Synthesis of Compound 94
The compound was used in step 1 using (D) -Ser (Bzl) and N-carbethoxyphthalimide (in the presence of aqueous Na ₂ CO ₃ ) in place of (D) -Phe and benzenesulfonyl chloride. Except as described above, it was synthesized according to the process of Scheme 8 below. The final product showed some racemization occurred.
94: white solid; Melting point 40-50 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.70; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.65 and 9.60 (two singlet, 7: 3, 1H), 7.80 (m, 2H), 7.70 (m, 2H), 7.60 (t, 1H), 7.40- 7.10 (m, 10H), 5.00 (m, 1H), 4.75 (q, 1H), 4.60-4.30 (m, 3H), 3.70 (m, 1H), 3.25 and 3.15 (two sets of doublets, 2H).
<Example 81>
Synthesis of Compounds 95 and 96
These compounds were synthesized according to the procedure of Scheme 7 below, except that Boc- (D) -Tic was used in place of Boc- (D) -Ser (Bzl) in step 1. However, racemization was observed during the synthesis and the isomers separated after the sulfonylation step. Each isomer was converted in each of the last two steps to give the product aldehyde.
Isomer I (95): pale yellow solid; Melting point 55-65 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.70; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.40 (s, 1H), 7.30-7.10 (m, 9H), 7.00 (d, 1H), 7.55 (m, 3H), 7.35 (d, 1H), 3.20 ( d, 2H), 3.10 (d, 2H), 2.60 (s, 3H).
Isomer II (96): pale yellow solid; Melting point 65-75 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.53; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.30-7.00 (m, 10H), 4.60-4.40 (m, 3H), 4.05 (d, 1H), 3.20-3.05 (m, 3H ), 3.00 (q, 1 H), 2.60 (s, 3 H).
<Example 82>
Synthesis of Compounds 97 and 98
These compounds were synthesized according to the process of Scheme 8 below as described above, except that (D and L) -thiophenglycine was used in place of (D) -Phe in step 1. Diastereomers were separated after 1 step. Each isomer was each converted to product aldehyde. The stereochemistry around the chiral centers in isomers I and II is experimentally determined as (L) and (D) based on the comparison of their enzyme inhibitory activity with the enzyme inhibitory activity of other components in a series of known arrangements, respectively. Ordered.
Isomer I (97): pale yellow solid; Melting point 65-75 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.38; ¹ H-NMR (300 MHz, acetone-d ₆ ) δ 9.65 (s, 1H), 8.10 (d, 1H), 7.50-7.00 (m, 8H), 6.85 (d, 1H), 5.45 (d, 1H), 4.55 (m, 1H), 3.30 (dd, 1H), 3.00 (dd, 1H), 2.70 (s, 3H).
Isomer II (98): pale yellow solid; Melting point 151-154 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.33; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 9.05 (d, 1H), 8.30 (d, 1H), 7.65 (d, 1H), 7.35 (m, 5H), 7.10 ( t, 1H), 6.95 (d, 1H), 5.55 (d, 1H), 4.70 (m, 1H), 3.40 (dd, 1H), 3.00 (dd, 1H), 2.95 (s, 3H).
<Example 83>
Synthesis of Compounds 99 and 100
These compounds were synthesized according to the process of Scheme 8 below as described above, except that (D and L) -thiophenalanine was used in place of (D) -Phe in step 1. Diastereomers were separated after one step. Each isomer was each converted to product aldehyde. Isomer I was also prepared with (L) -thiophenalanine as starting material, respectively. Isomer II (Compound 100) thus has a (D) -configuration at the P ₂ position.
Isomer I (99): white solid; Melting point 93-98 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.53; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.20 (m, 4H), 7.15 (d, 2H), 6.95 (dd, 1H), 6.90 (d, 1H), 6.75 ( d, 1H), 5.00 (d, 1H), 4.70 (q, 1H), 4.15 (q, 1H), 3.30 (m, 2H), 3.10 (m, 2H), 2.65 (s, 3H).
Isomer II (100): white solid; Melting point 124-128 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.49; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.20 (m, 4H), 7.15 (d, 2H), 6.95 (dd, 1H), 6.90 (d, 1H), 6.80 ( d, 1H), 5.20 (d, 1H), 4.75 (q, 1H), 4.15 (m, 1H), 3.30 (dd, 1H), 3.20 (dd, 1H), 3.10 (m, 2H), 2.60 (s , 3H).
<Example 84>
Synthesis of Compound 101
The compound was synthesized according to the process of Scheme 8 as described above, except that in step 1 (D) -proline and methanesulfonyl chloride were used instead of (D) -Phe and benzenesulfonyl chloride It was.
101: white gum, R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.33; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.65 (s, 1H), 7.40-7.10 (m, 5H), 7.05 (d, 1H), 4.65 (q, 1H), 4.20 (dd, 1H), 3.50 ( m, 1H), 3.35 (q, 1H), 3.20 (d, 2H), 2.85 (s, 3H), 2.30 (m, 1H), 2.10 (m, 1H), 1.90 (m, 2H).
<Example 85>
Synthesis of Compound 102
In the first step, Boc- (D) -proline was used in place of Boc- (D) -Ser (Bzl), and α-toluenesulfonyl chloride was used for the preparation of the N-sulfonyl intermediate compound. Except for using as a substitute for ponyl, it was synthesized according to the process of Scheme 7 as described above.
102: white solid, melting point 40-50 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.66; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.45-7.10 (m, 10H), 6.85 (d, 1H), 4.55 (q, 1H), 4.25 (s, 2H), 4.05 ( dd, 1H), 3.15 (m, 2H), 3.10 (dd, 2H), 2.10 (m, 1H), 1.90 (m, 1H), 1.80 (m, 2H).
<Example 86>
Synthesis of Compound 103
The compound used Boc- (D) -proline in place of Boc- (D) -Ser (Bzl) in step 1, and 4-acetamidobenzenesulfonyl chloride was used to prepare the N-sulfonyl intermediate compound. Except for using instead of methanesulfonyl chloride, it was synthesized according to the procedure of Scheme 7 as described above.
103: white solid; Melting point 75-85 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.26; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.65 (s, 1H), 7.65 (m, 5H), 7.40-7.20 (m, 6H), 4.65 (q, 1H), 4.05 (dd, 1H), 3.45 ( m, 1H), 3.20 (m, 2H), 3.15 (m, 1H), 2.20 (s, 3H), 2.10 (m, 1H), 1.80-1.50 (m, 3H).
<Example 87>
Synthesis of Compound 104
The compound was synthesized according to the procedure of Scheme 8 as described above, except that (D) -Ala was used in place of (D) -Phe in step 1.
104: white gum, R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.33; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.50 (s, 1H), 7.85 (d, 2H), 7.55 (m, 3H), 7.30 (m, 3H), 7.15 (d, 2H), 6.60 (d, 1H), 5.25 (d, 1H), 4.60 (q, 1H), 3.80 (m, 1H), 3.10 (d, 2H), 1.20 (d, 3H).
<Example 88>
Synthesis of Compound 105
The compound is prepared as shown in Scheme 8 below, except that in one step (D) -α-Me-Phe and methanesulfonyl chloride are used in place of (D) -Phe and benzenesulfonyl chloride. It synthesize | combined according to the process. The crude product showed the presence of one product aldehyde. However, racemization occurred during purification of the product by chromatography over Florisil column.
105: white gum, R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.42; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 and 9.50 (two singlet, 1H), 7.40-7.00 (m, 10H), 6.65 and 6.60 (two sets of d, 1H), 4.85 (d, 1H) , 4.65 (q, 1H), 3.20-2.90 (m, 7H), 1.70 and 1.60 (two singlet, 3H).
<Example 89>
Synthesis of Compound 106
The synthesis of the compounds was initiated according to the process of Scheme 9 as described above with the following changes: In step 1, Boc- (D) -Cys (Bzl) was used in place of (D) -Phe; Phe-N (Me) OMe (Boc-Phe and HN (Me) OMe as starting materials in the condensation step according to the general procedure of Fehrentz et al., Synthesis, 1983, 676), followed by acidic hydrolysis. Prepared) was synthesized according to Scheme 8, as described above, except that it was used in place of (S) -phenylalaninol. Subsequently, the dipeptide Weinreb amide intermediate is reduced to the target aldehyde with lithium aluminum hydride, followed by the general procedure of the aforementioned document.
106: waxy solid; R _f (EtOAc): 0.55; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.10 (m, 10H), 6.90 (d, 1H), 5.50 (d, 1H), 4.75 (q, 1H), 3.95 ( q, 1H), 3.70 (s, 2H), 3.15 (m, 2H), 3.00-2.60 (m, 2H), 2.80 (s, 3H),
<Example 90>
Synthesis of Compounds 107 and 108
The synthesis of these compounds was initiated according to the process of Scheme 8 as described above with the following changes: (D and L) -homocysteine (Bzl) and methanesulfonyl chloride in (D) -Phe and Used as a substitute for benzenesulfonyl chloride; Synthesis was performed according to Scheme 8 as described above, except that Phe-N (Me) OMe was used in place of (S) -phenylalaninol in the condensation step. Subsequently, the separated diastereomeric dipeptide Weinleb amide intermediate was reduced to the target aldehyde with lithium aluminum hydride.
Isomer I (107): white solid, mp 54-56 ° C; R _f (EtOAC): 0.60; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.05 (m, 10H), 6.55 (d, 1H), 5.30 (d, 1H), 4.75 (q, 1H), 4.05 ( m, 1H), 3.65 (m, 2H), 3.20 (dd, 1H), 3.00 (dd, 1H), 2.70 (s, 3H), 2.40 (m, 2H), 1.90 (m, 2H).
Isomer II (108): waxy solid; R _f (EtOAC): 0.50; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.40-7.05 (m, 10H), 6.60 (d, 1H), 5.50 (d, 1H), 4.75 (q, 1H), 4.05 ( m, 1H), 3.65 (m, 2H), 3.20 (dd, 1H), 3.00 (dd, 1H), 2.85 (s, 3H), 2.40 (m, 2H), 1.80 (m, 2H).
<Example 91>
Synthesis of Compound 109
The compound used (D) -Ser (Bzl) in place of (D) -Phe in step 1, and (s) -pyridylalaninol in place of (s) -phenylalaninol in the coupling step. Except for the use, it was synthesized according to the following Scheme 8 as described above.
109: pale yellow foam; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.51; ^{The 1} H-NMR (300 MHz, CDCl ₃ ) spectrum was possibly a complex due to the presence of the ring-closed form depending on the parent molecule; Mass spectrum showed M + H-ion peak at m / e 406.
<Example 92>
Synthesis of Compound 110
The compound used (D) -Ser (Bzl) in place of (D) -Phe in step 1, and racemic α-methylroysinol was used in place of (S) -phenylalaninol in the coupling step. Except that, it was synthesized according to the following Scheme 8 as described above. Thus, the product aldehyde is an epimeric diastereomeric mixture at P ₁ .
110: white gum; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH); 0.71 and 0.62 (diastereomers); ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.30 and 9.25 (two units, 1H), 7.45 (d, 1H), 7.40-7.20 (m 5H), 5.40 (d, 1H), 4.55 (m, 2H) , 4.10 (m, 1H), 3.90 (m, 1H), 3.70 (dd, 1H), 2.95 and 2.90 (two singlets, 3H), 1.60-1.20 (m, 3H), 1.40 (s, 3H), 0.90 and 0.70 (two sets of doublets, 6H).
<Example 93>
Synthesis of Compound 111
The compound used (D) -Ser (Bzl) in place of (D) -Phe in step 1, and (s) -tert-butylglycinol in place of (S) -phenylalaninol in the coupling step. Except as used above, it synthesize | combined according to Reaction Scheme 8 as described above.
111: white foam; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH); 0.60; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.45-7.25 (m, 5H), 7.20 (d, 1H), 5.40 (d, 1H), 4.60 (q, 2H), 4.50 ( d, 1H), 4.15 (q, 1H), 3.90 (dd, 1H), 3.75 (dd, 1H), 2.95 (s, 3H), 1.00 (s, 9H).
<Example 94>
Synthesis of Compound 112
The compound was used as described above, except that cis-4-hydroxy- (D) -proline was used in place of (D) -Phe in one step, and sulfonylated both NH and OH groups simultaneously. Likewise synthesized according to Scheme 8 below.
112: white solid, mp 160-165 ° C .; R _f (50% CH ₂ Cl ₂ -50% EtOAc): 0.61; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.40 (s, 1H), 7.80-7.25 (m, 16H), 4.90 (t, 1H), 4.55 (q, 1H), 4.25 (d, 1H), 3.55 ( dd, 1H), 3.35 (dd, 1H), 3.10 (d, 2H), 2.45 (d, 1H), 1.70 (m, 1H).
<Example 95>
Synthesis of Compound 113
The compound was synthesized according to Scheme 9 below, except that cis-4-hydroxy- (D) -proline was used in place of (D) -Phe in the first esterification step. Selective phenylsulfonylation of the NH-group and Mitsunobu substitution of the methyl-p-toluenesulfonate of the OH-group (with conversion, in the presence of Ph ₃ P and diethyl azidocarboxylate; literature Bis-sulfonylated intermediates were obtained by Mitsunobu, O. Synthesis, 1981, 1. The remaining synthesis followed the route described in Scheme 9.
113: white solid, mp 75-80 ° C .; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.43; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.80-7.20 (m, 14H), 7.10 (d, 1H), 4.80 (m, 1H), 4.65 (q, 1H), 4.15 ( t, 1H), 3.60 (m, 2H), 3.15 (m, 2H), 2.40 (s, 3H), 2.10 (m, 2H).
<Example 96>
Synthesis of Compound 114
The compound was synthesized according to Scheme 8 as described above with the following changes: in step 1 cis-4-hydroxy- (D) -proline was used in place of (D) -Phe; Both NH and OH groups were sulfonylated with p-toluenesulfonyl chloride; The disulfonylated derivative was coupled with (S) -phenylalaninol and the tosyl group in the dipeptide intermediate was substituted with the S _N 2 embodiment by azido groups (NaN ₃ , DMF). Oxidation to produce product aldehyde was carried out as follows.
114: white solid, mp 65-75 ° C .; R _f (softening to melting); _{R f (90% CH 2 Cl} 2 -9% CH 3 OH-1% concentration of NH ₄ OH)): 0.59; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.65 (s, 1H), 7.70 (d, 2H), 7.40-7.15 (m, 7H), 4.70 (q, 1H), 4.15 (dd, 1H), 4.00 ( m, 1H), 3.60 (dd, 1H), 3.20 (m, 4H), 2.45 (s, 3H), 2.25 (m, 1H), 1.85 (m, 1H).
<Example 97>
Synthesis of Compound 115
A mixture of compound 40 (0.20 g, 0.50 mmol), semicarbazide hydrochloride (0.056 g, 0.50 mmol), sodium acetate (0.040 g, 0.50 mmol), ethanol (7 mL) and water (3 mL) Stir at 0 ° C. for 1 h and then at rt overnight. The reaction mixture was concentrated, dissolved in water (15 mL) and extracted with methylene chloride (3 x 15 mL). The combined organic layers were washed with brine (1 × 10 mL), dried (Na ₂ SO ₄ ) and concentrated to afford crude product. It was purified by flash column chromatography (silica gel, 5% MeOH in methylene chloride) to give compound 115 (0.048 g).
115: white solid, mp 168-173 ° C; _{R f (90% CH 2 Cl} 2 -10% CH 3 OH): 0.44; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.65 (s, 1H), 7.45-7.10 (m, 11H), 7.15 (d, 2H), 7.00 (d, 1H), 6.40 (d, 1H), 4.80 ( m, 1H), 4.50 (q, 2H), 4.10 (m, 1H), 3.80 (dd, 1H), 3.70 (dd, 1H), 3.00 (m, 2H), 2.90 (s, 3H).
<Example 98>
Synthesis of Compound 116
The compound was produced according to the same synthesis protocol as described above for the synthesis of Compound 115 (Example 97), except that N-methylhydroxylamine hydrochloride was used in the synthesis instead of semicarbazide hydrochloride. .
116: white solid, mp 148-153 ° C. (tinting point to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.53; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.05 (d, 1H), 7.40-7.10 (m, 10H), 6.70 (d, 1H), 5.25 (d, 1H), 4.95 (m, 1H), 4.50 ( dd, 2H), 4.05 (m, 1H), 3.80 (dd, 1H), 3.65 (s, 3H), 3.60 (m, 1H), 3.20 (dd, 1H), 3.10 (dd, 1H), 2.90 (s , 3H).
<Example 99>
Synthesis of Compound 117
The compound was produced according to the same synthesis protocol as described above for the synthesis of Compound 115, except that N-benzylhydroxylamine hydrochloride was used in the synthesis instead of the semicarbazide hydrochloride.
117: white solid, mp 154-156 ° C; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.56; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.10 (d, 1H), 7.40-7.20 (m, 13H), 7.00 (m, 2H), 6.65 (d, 1H), 5.30 (d, 1H), 4.95 ( m, 1H), 4.80 (s, 2H), 4.50 (s, 2H), 4.00 (m, 1H), 3.80 (dd, 1H), 3.60 (dd, 1H), 3.15 (dd, 1H), 3.00 (dd , 1H), 2.90 (s, 3H).
<Example 100>
Synthesis of Compound 118
The compounds were synthesized by coupling Compound 40 and hydroxylamine hydrochloride in the presence of pyridine and ethanol (in the absence of sodium acetate and water) according to the general synthesis protocol for Compound 115.
118: white foam; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.51; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.20 (m, 10H), 7.10 (t, 2H), 5.35 (d, 1H), 4.85 (m, 1H), 4.45 (dd, 2H), 4.05 ( m, 1H), 3.85 (dd, 1H), 3.60 (dd, 1H), 3.00 (d, 2H), 2.85 (s, 3H), 1.55 (wide, 1H).
<Example 101>
Synthesis of Compound 119
The compound was synthesized according to the general synthesis protocol for Compound 115 after coupling Compound 40 and methoxylamine hydrochloride in the presence of pyridine and ethanol (in the absence of sodium acetate and water).
119: white gum; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.86; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 12H), 5.20 (two sets of d, 1H), 4.85 (m, 1H), 4.45 (q, 2H), 4.00 (m, 1H) , 3.90 and 3.75 (two singlets, 3H), 3.80 (m, 1H), 3.60 (m, 1H), 3.00 (d, 2H), 2.85 and 2.80 (two singlets, 3H).
<Example 102>
Synthesis of Compound 120
The compound was synthesized according to Scheme 8 as described above, except that in step 1 (D) -Pro and p-toluenesulfonyl chloride were used instead of (D) -Phe and methanesulfonyl chloride It was.
120: white solid; mp 55-60 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH) -1% concentration NH ₄ OH): 0.42; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.70 (d, 2H), 7.30 (m, 7H), 4.65 (q, 1H), 4.10 (dd, 1H), 3.45 (m, 1H), 3.15 (m, 4H), 2.40 (s, 3H), 2.05 (m, 1H), 1.80-1.50 (m, 3H).
<Example 103>
Synthesis of Compound 121
The compound was used in place of cis-4-hydroxy- (D) -proline in place of (D) -Phe, except that both NH and OH groups were sulfonylated with p-toluenesulfonyl chloride, As described above, it was synthesized according to Scheme 8 below.
121: white solid; mp 160-165 ° C. (softening to melting); R _f (EtOAc: CH ₂ Cl ₂ 2: 1): 0.65; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.35 (s, 1H), 7.65 (t, 4H), 7.45-7.20 (m, 10H), 4.85 (m, 1H), 4.50 (q, 1H), 4.20 ( d, 1H), 3.65 (d, 1H), 3.30 (dd, 1H), 3.10 (d, 2H), 2.45 and 2.40 (two singlet, 6H), 1.65 (m, 2H).
<Example 104>
Synthesis of Compound 122
Synthesis of the compounds was initiated by coupling (EDCI, HOBt, DMF) methanesulfonyl- (D) -Ser (Bzl) and (L) -Lys (Boc) -OMe hydrochloride; NHBoc was converted to free NH ₂ (90% TFA, CH ₂ Cl ₂ ), which was also converted to NHSO ₂ Ph (PhSO ₂ Cl, NMM, THF—CH ₂ Cl ₂ ). Finally, the COOMe group was converted to CHO and followed the process described in Scheme 7. The final product showed some racemization occurred.
122: white solid; mp 50-55 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.41; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.55 and 9.50 (two singlet, 1: 9, 1H), 7.85 (d, 2H), 7.55 (m, 3H), 7.30 (m, 5H), 5.60 ( d, 1H), 4.90 (wide t, 1H), 4.50 (m, 4H), 4.20 (m, 1H), 3.90 (dd, 1H), 3.80 (dd, 1H), 3.00 and 2.95 (two singlets, 9: 1, 3H), 2.85 (m, 2H), 1.95-1.30 (m, 6H).
<Example 105>
Synthesis of Compound 123
Synthesis of the compound was carried out in Scheme 8 as described above, except that (D) -Pro and p-toluenesulfonyl chloride were used in place of (D) -Phe and methanesulfonyl chloride in step 1 Accordingly. The intermediate dipeptide alcohol was treated with ethyl isocyanate in the presence of triethylamine to prepare the final product.
123: white solid; mp 45-55 ° C. (softening to melting); R _f (EtOAc: CH ₂ Cl ₂ 2: 1): 0.57; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.70 (d, 2H), 7.30 (m, 7H), 4.85 (wide, 1H), 4.30 (m, 1H), 4.10 (m, 3H), 3.50 (m, 1H), 3.25 (m, 2H), 3.15 (m, 1H), 3.00 (dd, 1H), 2.85 (dd, 1H), 2.45 (s, 3H), 2.10 (m, 1H), 1.80-1.40 (m , 4H), 1.15 (t, 3H).
<Example 106>
Synthesis of Compound 124
The compound is (EDCI, HOBt, DMF) methanesulfonyl- (D) -Ser (Bzl) and 4- (S) -amino-3- (R, S) -hydroxy-1,5-biphenylpentane ( Boc-Phe-H and benzylmagnesium chloride were coupled, followed by decoupling of the Boc group).
124: white solid; mp 108-110 ° C .; _{R f (90% CH 2 Cl} 2 -10% EtOAc): 0.27; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.05 (m, 15H), 6.90 (d, 1H), 5.25 (d, 1H), 4.50 (q, 2H), 4.20 (q, 1H), 4.00 ( q, 1H), 3.80 (dd, 1H), 3.65 (m, 1H), 3.50 (m, 2H), 2.85 (m, 4H), 2.65 (q, 2H), 2.00 (d, 1H), 1.70 (q , 2H).
<Example 107>
Synthesis of Compound 125
This compound was synthesized by des-martin oxidation of compound 124 prepared in Example 106.
125: white solid; mp 112-113 ° C .; _{R f (90% CH 2 Cl} 2 -10% EtOAc): 0.42; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 14H), 7.00 (m, 2H), 5.30 (d, 1H), 4.75 (q, 1H), 4.45 (q, 2H), 4.00 ( q, 1H), 3.80 (dd, 1H), 3.55 (dd, 1H), 3.05 (dd, 1H), 3.00-2.75 (m, 3H), 2.80 (s, 3H), 2.75 (m, 2H).
<Example 108>
Synthesis of Compound 126
The compound was synthesized by coupling methanesulfonyl- (D) -Ser (Bzl) and (L) -α-amino-ε-caprolactam (EDCI, HOBt, DMF).
126: white solid; mp 45-50 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.55; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.85 (d, 1H), 7.30 (m, 5H), 6.35 (wide t, 1H), 5.80 (d, 1H), 4.55 (m, 3H), 4.25 (m , 1H), 3.80 (dd, 1H), 3.70 (dd, 1H), 3.20 (m, 2H), 3.00 (s, 3H), 2.00 (m, 2H), 1.80 (m, 2H), 1.40 (m, 2H).
<Example 109>
Synthesis of Compound 127
This compound was treated with Compound 126 prepared in Example 108 with Boc ₂ O in the presence of Et ₃ N and 4-dimethylaminopyridine, followed by Grieco et al., J. Org. Chem. 1983, 48, 2426].
127: white solid; mp 55-60 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.90; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.15 (d, 1H), 7.50-7.20 (m, 5H), 5.05 (q, 1H), 4.70 (m, 2H), 4.30 (m, 2H), 3.75 ( q, 1H), 3.40 (s, 3H), 3.30 (m, 2H), 2.05-1.40 (series of m, 6H), 1.55 (s, 9H), 1.45 (s, 9H).
<Example 110>
Synthesis of Compound 128
The compound was synthesized by reacting compound 40 with sodium bisulfite under a biphasic system of methylene chloride and water.
128: white solid (hygroscopic); ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.25 and 7.85 (two sets of d, 1H), 7.40-7.00 (m, 10H), 5.75 and 5.60 (two sets of d, 1H), 4.50-4.20 ( m, 4H), 4.00 (m, 2H), 3.80 (m, 1H), 3.50-3.20 (m, 3H), 2.80 and 2.75 (two singlet, 3H). Elemental Analysis for C ₂₀ H ₂₅ N ₂ O ₈ S ₂ Na.0.3NaHSO ₃
Calc .: C, 44.51; H, 4.67, N, 5.19.
Found: C, 44.62; H, 4.75; N, 5.20.
<Example 111>
Synthesis of Compound 129
The compound was used in place of cis-4-hydroxy- (D) -proline in place of (D) -Phe, except that both NH and OH groups were sulfonylated with p-toluenesulfonyl chloride, As described above, it was synthesized according to the process of Scheme 8 below. The disulfonylated derivative was coupled with (S) -phenylalaninol and the OTs group in the dipeptide intermediate was substituted with cyano groups (KCN, DMSO, 65 ° C., overnight) in an S _N 2 embodiment. Finally, the alcohol moiety was oxidized to produce the target aldehyde, ie compound 129.
129: white solid; mp 65-75 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.44; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.70 (d, 2H), 7.40-7.15 (m, 8H), 4.70 (q, 1H), 4.20 (d, 1H), 3.75 ( dd, 1H), 3.30-3.10 (m, 3H), 3.00 (m, 1H), 2.55 (dd, 1H), 2.45 (s, 3H), 1.70 (m, 1H).
<Example 112>
Synthesis of Compound 130
Precursor alkoxy for this aldehyde was isolated as a small amount of product from cyanation step Example 111. Subsequently, the alcohol was des-martin oxidized to produce the target aldehyde, ie compound 130.
130: white solid; mp 55-65 ° C. (softening to melting); R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.52; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.60 (s, 1H), 7.70 (d, 2H), 7.40-7.20 (m, 8H), 5.70 (m, 2H), 4.85 (m, 1H), 4.60 ( q, 1H), 4.15 (m, 2H), 3.20 (m, 2H), 2.45 (s, 3H).
<Example 113>
Synthesis of Compound 131
The compound was synthesized by coupling compound 40 with 2-mercaptoethanol in the presence of ZnCl ₂ and Na ₂ SO ₄ in THF-Et ₂ O.
131: white gum; R _f (90% CH ₂ Cl ₂ -9% CH ₃ OH-1% concentration NH ₄ OH): 0.31; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 10H), 5.60 (d, 1H), 4.60 (m, 1H), 4.50 (q, 2H), 4.15 (d, 1H), 4.00 ( Wide d, 1H), 3.80 (m, 2H), 3.70 (t, 2H), 3.50 (dd, 1H), 3.20 (dd, 1H), 3.00-2.70 (m, 4H), 2.85 (s, 3H).
<Example 114>
Synthesis of Compound 132
The compound was synthesized by coupling compound 40 with 1,2-dianilinoethane.
132: white solid; mp 138-140 ° C .; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 and 6.90-6.70 (2 sets of m, 21H), 5.75 (d, 1H), 4.75 (d, 2H), 4.30 (s, 2H), 3.90 ( q, 1H), 3.75 (m, 3H), 3.45 (m, 2H), 3.35 (dd, 1H), 3.05 (dd, 1H), 2.70 (s, 3H), 2.50 (t, 1H).
<Example 115>
Synthesis of Compound 133
The compound was synthesized by coupling compound 40 with N, N'-dimethylethylenediamine.
133: white gum; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.40-7.10 (m, 10H), 5.25-4.90 (wide, 3H), 4.30 (q, 1H), 4.00 (t, 1H), 3.75 (dd, 1H), 3.50 (m, 4H), 3.10-2.70 (m, 5H), 2.85 (s, 3H), 2.50 (d, 6H).
<Example 116>
Synthesis of Compound 134
The compound was synthesized by coupling with methanesulfonyl- (D) -Ser (Bzl) and Phe-H diethyl acetal; The final product showed some racemization occurred.
134 white gums; R _f (EtOAc-hexanes: 1: 1): 0.30; ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.35-7.00 (m, 11H), 6.80 (d, 1H), 5.15 (t, 1H), 4.50-4.25 (m, 4H), 3.90 (m, 1H), 3.70-3.30 (m, 5H), 2.90 (m, 1H), 2.80 and 2.70 (two singlets, 3H), 2.65 (m, 1H), 1.10 (m, 6H).
<Example 117>
Synthesis of Compound 135
The compound was synthesized by stirring compound 40 overnight with excess benzyl alcohol at room temperature. Excess alcohol was removed by repeated washing with hexane and the residue was triturated with EtOAc-hexane to afford compound 135 as a solid (melting point 87-89 ° C.), which was immediately biologically tested. ¹ H-NMR (300 MHz, DMSO-d ₆ ) spectra of subsamples showed the absence of aldehyde residues in the molecule.
<Example 118>
Inhibition and Inactivation Rate of Cysteine Protease Activity
To assess the inhibitory activity, stock solutions (40-fold concentrated) of exemplary compounds of the invention were prepared in 100% anhydrous DMSO and 5 μl of each inhibitor formulation was aliquoted into three wells of a 96-well plate. Recombinant human calpine I (prepared by the method of Meyer et al., Biochem. J. 314: 511-519 (1996)) was prepared for assay buffers (ie, 50 mM Tris, 50 mM NaCl, 1 mM EDTA, 1 mM EGTA). And 5 mM-mercaptoethanol (pH 7.5) with 0.2 mM Succ-Leu-Tyr-MNA), and not only is 175 μl identical to a positive control well containing 5 μl DMSO but no compound, Partially aliquoted with the same wells containing independent inhibitor stocks. To start the reaction, 20 μl of 50 mM CaCl ₂ in assay buffer was added to all but three of the plates and used as background signal baseline control. Substrate hydrolysis was monitored every 5 minutes for a total of 30 minutes. Substrate hydrolysis without inhibitors was straight for no more than 15 minutes.
Inhibition of calpine I activity was calculated as the rate of decrease of the rate of substrate hydrolysis in the presence of inhibitor (V _I ) to the ratio of its absence (V ₀ ). The comparison between V ₀ and V _I was performed within a straight range for substrate hydrolysis. For screening, compounds were tested at 10 μM, 1.0 μM and 0.1 μM. Compounds with 50% inhibition at 10 μM were considered active. The IC _{50 of the} inhibitor (concentration yielding 50% inhibition) was determined from the rate of decrease of substrate hydrolysis rate in the presence of 5 to 7 different concentrations of test compound. Results were plotted as% inhibition versus log of inhibitor concentration and IC ₅₀ was calculated from linear regression of the data. The apparent second order rate constant was determined from the analysis of the reaction progress curve under the conditions of pseudo-first order. Each measurement is shown using three or more independent single cuvette assays that were continuously monitored with a Perkin-Elmer LS50B spectrofluorometer. The inhibition of hydrolysis was obtained by fitting the curve to the following exponential equation (1):
(One)
Where y is the product formed at time t, K _obs is the rate constant of the order-first order for inactivation, and A and B are constants. A, the reaction width is given by [P ₀ -P _∞ ] and B (= P _∞ ) is the maximum product formed when the reaction is completed. The apparent second order rate constant k _app was measured as K _obs / [I]. This was corrected for the presence of the substrate to obtain the rate constant k ₂ of the second order according to equation (2):
(2)
To show activity against two other cysteine proteases, namely cathepsin B (Calbiochem, Cat. No. 219364) and cathepsin L (Calbiochem, Cat. No. 219402), cathepsin B and cathepsin L were converted to 50 mM sodium acetate (pH 6.0). ) Was diluted with different assay buffers consisting of EDTA / 1 mM dithiothreitol and the substrate used was Cbz-Phe-Arg-AMC (Bachem Cat. No. I-1160; 0.1 mM for cathepsin B; cathepsin L Analysis was performed substantially the same as described above, except that 0.006 mM) was used. The order of the reagents added to the plates was also changed because both enzymes are structurally active. After addition of the inhibitor to the plate, approximately 2-fold concentrated stock dilutions of the enzyme preparation were prepared in assay buffer and 100 μl was added to each well. The assay was initiated by the addition of 100 μl of a 2-fold concentrated stock dilution of the substrate in assay buffer. Substrate hydrolysis was monitored using Fluoroskan II (ex = 390 nm; em = 460 nm). The results are shown in Tables II and III.
<Example 119>
Inhibition of Serine Protease Activity
To measure activity against the serine protease α-chymotrypsin (Sigma Chem. Co. Catalog No. C-3142), the enzyme was diluted with an assay buffer consisting of 50 mM Hepes pH 7.5 / 0.5 M NaCl and the final substrate used. The protocol of Example 118 was performed except that the concentration was 0.03 mM Succ-Ala-Ala-Pro-Phe-AMC (Bachem Cat. No. I-1465). In addition, since α-chymotrypsin is structurally active and not a calcium sensitive enzyme, inhibitor stock was added to a 96 well plate, followed by 100 μl of a 2-fold concentrated enzyme stock in dilution buffer, followed by substrate in assay buffer. The reaction was started by adding 100 μl of a 2-fold concentrated stock of. Substrate hydrolysis was monitored every 5 minutes for up to 30 minutes using Fluoroskan II (em = 390 nm; ex = 460 nm). The results expressed as the α-chymotrypsin inhibition rate at 10 μM are shown in Tables II and III.
Inhibition of thrombin (Sigma Chem. Co. Cat. No. T-7009) was performed in 50 mM Tris, 10 mM CaCl ₂ (pH 7.5) and the substrate was 25 μM Bz-Phe-Val-Arg-AMC (Bachem Catalog No. I- Was evaluated as described for chymotrypsin, except 1080). The results are shown in Tables II and III.


<Example 120>
Inhibition of Compound 40 of Spectrin Degradation in the Gerbil Global Ischemia Model
Gerbil was anesthetized using 4% isoflurane volatilized using a gas mixture consisting of 30% O ₂ and 70% N ₂ . After induction of anesthesia, a preferred compound of the present invention, Compound 40 (Example 34), was administered immediately after induction of ischemia or 3 hours after the start of reperfusion. To induce ischemia, the normal carotid artery was exposed and left and right occlusion for 7 minutes. The Gerbil core temperature was carefully controlled at 38 ° C. using a constant temperature controlled heating lamp. Reperfusion was initiated by the release of arterial occlusion, so anesthesia was terminated and Gerville began to breathe indoor air. The neck incisions were sealed and Gerbil was returned to the incubator for 1 hour to maintain their core temperature. At 1 hour of reperfusion, CO ₂ was aspirated to induce anesthesia and sacrificed gerville. The CA1 hippocampal sector was incised using a hole punch (0.3 mm), and spectrin degradation products (BDP) were measured by western blotting. Spectrin digests were measured by image analysis, and inhibition was calculated by integrated optical density. Calpine activity and elevated levels of spectrin degradation products have been associated with several neurodegenerative conditions, including those due to ischemia. The detection of calpine activity by the detection of calpine activated spectrin digests is described in detail in US Pat. No. 5,536,639, which is incorporated herein by reference in its entirety.
To quantify histopathological damage, gerbils were returned to their home cages after 1 hour reperfusion in the incubator and sacrificed as described above after 4 days. The brain was quickly removed, frozen on dry ice and then incised using a cryostat. Sections of 20μ were stained with thionine and neurons surviving in the hippocampus CA1 sector were counted using a computer assisted image analyzer.
To facilitate solvation and administration, compound 40 is formulated for use as an emulsion. The emulsion contains 1,2-dimyristoyl-sn-glycero-3-phosphocholine (Sygena, Inc., Cambridge, Mass.), Cholesterol (Genzyme Corp., Cambridge, Mass.) And Compound 40. It was prepared by mixing in a 4: 2: 1 weight part ratio. Chloroform (1 mL) and ethanol (0.5 mL) were added and the contents mixed until all the solute was dissolved in the organic phase. The volatile solvent was then evaporated to a nitrogen stream. Phosphate buffered saline (50 ° C.) was added to the remaining mixture in an amount to yield a compound 40 concentration of 6 mg / ml. The components of the residue were mixed using a Pasteur pipette to give a crude emulsion, and a fine emulsion was obtained using a high pressure emulsifier.
Spectral degradation analysis in the CA1 hippocampal sector of vehicle-treated control gerbils and gerbils treated with compound 40 showed statistically significant inhibition of spectrin degradation in gerbils treated with compound 40 (p <0.0001 1).
FIG. 2 shows the statistical significance (p <0.01) that Compound 40 was neuroprotective 4 days after ischemic injury, which is the time when most hippocampal CA1 neurons denatured in vehicle-treated Gerville. Intact hippocampal CA1 neurons were counted and expressed as% of the number of intact neurons found in the control gerbil at the level of spinal hippocampus described above.
3 shows the neuroprotective effect of administration of Compound 40 at 3 hours post ischemia with statistical significance (p <0.02).
As shown in FIG. 1, compound 40 reduced spectrin degradation by about 50%. Compound 40 also doubled the number of viable hippocampal CA1 neurons relative to the control, as shown in FIG. 2.
The patents, applications, and printed publications mentioned in these patent documents are each intended to be incorporated by reference herein in their entirety.
As will be apparent to those skilled in the art, numerous modifications and variations of the preferred embodiments of the invention can be made without departing from the spirit thereof. All such modifications are intended to be included within the scope of this invention.

权利要求:
Claims (43)
[1" claim-type="Currently amended] Compound of formula (I)
<Formula I>

Where
C ^* is a carbon atom having a D- configuration;
The structure of Q is GB- (CHR ²⁰ ) _q- ;
R ²⁰ is independently H or C _1-4 alkyl;
q is 0, 1 or 2;
B is selected from the group consisting of C (= 0), S (= 0), S (= 0) ₂ , S, CH ₂ , a bond, NH and O;
G is aryl having about 6 to about 14 carbon atoms, heteroaryl having about 5 to about 14 ring atoms, aralkyl having about 7 to about 15 carbon atoms, alkyl having 1 to about 10 carbon atoms, heteroalkyl having 2 to about 7 carbon atoms, Carbohydrate moieties optionally containing alkoxy, arylsulfonyl, alkylsulfonyl, alkylsulfonyl, aralkyloxy, amino, and one or more alkylated hydroxyl groups of 1 to about 10 carbon atoms, wherein aryl, Heteroaryl, aralkyl, alkyl and amino groups are optionally substituted with one or more K groups);
K is halogen, CN, NO ₂ , lower alkyl, aryl, heteroaryl, aralkyl, aralkyloxy, guanidino, alkoxycarbonyl, alkoxy, hydroxy, carboxy and amino, wherein the amino group is an acyl group or 1 To optionally substituted with 3 aryl or lower alkyl groups;
R ¹ is H, alkyl having 1 to about 14 carbon atoms, cycloalkyl having 3 to about 10 carbon atoms, aralkyl having about 7 to about 15 carbon atoms, heteroarylalkyl having about 5 to about 14 ring atoms, and D- Or a natural side chain of L-amino acid, and a synthetic side chain of D- or L-amino acid, wherein alkyl, cycloalkyl, aralkyl and heteroarylalkyl groups are optionally substituted by one or more K groups, and ;
R ² is selected from the group consisting of C (═O) R ⁶ , S (═O) ₂ R ⁶ and a protecting group;
R ⁶ is aryl having about 6 to about 14 carbon atoms, heteroaryl having about 5 to about 14 ring atoms, aralkyl having about 7 to about 15 carbon atoms, alkyl having 1 to about 10 carbon atoms, wherein aryl, heteroaryl, Aralkyl and alkyl group optionally substituted by one or more K groups), heteroalkyl having 2 to about 7 carbon atoms, alkoxy having 1 to about 10 carbon atoms, and amino optionally substituted by one or more alkyl groups, and ;
R ³ is selected from the group consisting of H, lower alkyl, aralkyl and a group of the formula —CO ₂ —R ²¹ , wherein R ²¹ is a lower alkyl group; or
R ³ may form a phthalimido group with R ² ; or
Q and R ^{3 together} with -C ^* and -N (R ² )- Can form groups;
R ⁷ optionally contains a carbon-carbon double bond, wherein the aryl, azide, CN, protected amino group and OSO ₂ -aryl, wherein the aryl group is optionally substituted by one or more K groups, said OSO ₂ -aryl group The aryl moiety of is C _2-5 alkylene optionally substituted by a group selected from the group consisting of one or more K groups; or
R ⁷ is a general formula Can be;
p and y are independently 0 or 1,
R ²² , R ²³ , R ²⁴ and R ²⁵ are independently H or K groups;
R ⁴ and R ⁵ are each independently selected from the group consisting of H and lower alkyl;
W ¹ and W ² are selected such that W ¹ is H and W ² is OC (═O) NH—R ²⁶ , wherein R ²⁶ is alkyl, or W ¹ and W ² are both alkoxy, or W ¹ is OH and W ² is aralkyl, aralkyloxy, aryloxy, heteroaryloxy, heteroaralkyloxy and SO ₃ Z ¹ , wherein Z ¹ is a Group I or II to ions One selected from the group consisting of; or
W ¹ and W ² together are = O, = NR ⁸ , = N (→ O) R ⁹ , -S (CH ₂ ) ₂ O- and -N (R ¹² ) (CH ₂ ) ₂ N (R ¹² )- Can form a group selected from the group consisting of;
R ⁸ is selected from the group consisting of NH (C═O) NH ₂ , hydroxyl and lower alkoxy;
R ⁹ is selected from the group consisting of alkyl and aralkyl;
R ¹² is selected from the group consisting of C _1-4 alkyl and phenyl;
Y is selected from the group consisting of H, C (= 0) NR ¹⁰ R ¹¹ , C (= 0) OR ¹⁰ , CH = N ₂ and CH ₂ R ¹³ ; or
Y and R ¹ may together form — (CH ₂ ) ₄ N (Pr) —, where Pr is H or a protecting group, provided that Y and R ¹ together form — (CH ₂ ) ₄ N (Pr When forming)-, W ¹ and W ² together form ═O;
R ¹⁰ and R ¹¹ are each independently H, alkyl having 1 to about 10 carbon atoms, wherein the alkyl group is optionally substituted by one or more K groups, aryl having about 6 to about 14 carbon atoms, and about 7 to about 15 carbon atoms. Aralkyl is selected from the group consisting of;
R ¹³ is selected from the group consisting of L, lower alkyl, aralkyl, halogen and the group OM;
M is a general formula ego;
Z is selected from the group consisting of N and CR ¹⁴ ;
W is selected from the group consisting of double bonds and single bonds;
D is selected from the group consisting of C═O and a single bond;
E and F are independently selected from the group consisting of R ¹⁴ , R ¹⁵ and J; or
E and F together represent a C _5-7 aliphatic carbocyclic ring, a C _5-7 aromatic carbocyclic ring, an aliphatic heterocyclic ring having 5 to 7 atoms and 1 to 4 heteroatoms, and 5 to 7 atoms And aromatic heterocyclic rings having 1 to 4 heteroatoms, wherein aliphatic carbocyclic rings, aromatic carbocyclic rings, aliphatic heterocyclic rings, and aromatic heterocyclic rings are each optionally substituted by J. To form a linked residue selected from the group;
R ¹⁴ and R ¹⁵ are independently H, C _1-10 alkyl, C _1-10 heteroaryl, C _1-10 alkanoyl and aroyl, wherein the alkyl, heteroaryl, alkanoyl and aroyl groups are Optionally substituted);
J is halogen, C (= 0) OR ¹⁶ , R ¹⁶ OC (= 0), R ¹⁶ OC (= 0) NH, OH, CN, NO ₂ , NR ¹⁶ R ¹⁷ , N = C (R ¹⁶ ) R ¹⁷ , N = C (NR ¹⁶ R ¹⁷ ) ₂ , SR ¹⁶ , OR ¹⁶ , phenyl, naphthyl, heteroaryl and C _3-8 cycloalkyl group;
R ¹⁶ and R ¹⁷ are independently H, C _1-10 alkyl, aryl or heteroaryl, wherein the alkyl, aryl and heteroaryl groups are optionally substituted by K;
L is a phosphorus-containing enzyme reactor.
[2" claim-type="Currently amended] The method of claim 1,
R ¹ is benzyl, p-benzyloxybenzyl,-(CH ₂ ) ₄ -NHC (= O) -O-CH ₂ -C ₆ H ₅ ,-(CH ₂ ) ₄ -NHC (= O) -OtC ₄ H ₉ and-(CH ₂ ) ₄ -NHSO ₂ -C ₆ H ₅ ;
R ³ , R ⁴ and R ⁵ are each H;
W ¹ and W ² together form —C (═O) —;
Y is H or CH ₂ F;
B is CO, O, S, SO ₂ or a bond;
R ² is —C (═O) CH ₃ or —S (═O) ₂ R ⁶ ;
R ⁶ is methyl, p-fluorophenyl, dimethylamino, ethyl, 2-thienyl, 2-isoxazolyl, phenyl, p-methylphenyl, 4-N-methylimidazolyl or 2-naphthyl;
G is tetrahydroisoquinolinyl, benzyl, 3-indolyl, phenyl, N-methylbenzylamino, p-benzyloxyphenyl or 2-thienyl; or
Q and R ³ together form-(CH ₂ ) _3- .
[3" claim-type="Currently amended] The compound of claim 1, wherein q is 0; B is a bond; G is benzyl or 2-thienyl; Y is H; R ¹ is benzyl; R ² is -S (= 0) ₂ R ⁶ ; R ⁶ is methyl, phenyl or 2-thienyl.
[4" claim-type="Currently amended] The compound of claim 1, wherein q is 1; G is tetrahydroisoquinolinyl, benzyl, 3-indolyl, phenyl, N-methylbenzylamino or p-benzyloxyphenyl; R ² is —C (═O) CH ₃ or —S (═O) ₂ R ⁶ ; R ⁶ is methyl, p-fluorophenyl, dimethylamino, ethyl, 2-thienyl, 2-isoxazolyl, p-methylphenyl, 4-N-methylimidazolyl or 2-naphthyl.
[5" claim-type="Currently amended] The compound of claim 4, wherein G is benzyl; R ² is —C (═O) CH ₃ or —S (═O) ₂ R ⁶ ; R ⁶ is methyl, p-fluorophenyl, dimethylamino, ethyl, 2-isoxazolyl, p-methylphenyl, 4-N-methylimidazolyl or 2-naphthyl.
[6" claim-type="Currently amended] The compound of claim 5, wherein R ² is —S (═O) ₂ CH ₃ .
[7" claim-type="Currently amended] The compound of claim 1, wherein q is 2; B is S; G is benzyl; Y is H; R ¹ is benzyl; R ² is -S (= 0) ₂ CH ₃ .
[8" claim-type="Currently amended] The compound of claim 1, wherein G is alkyl, benzyl, tetrahydroisoquinolyl, 3-indolyl, phenyl, N-methylbenzylamino, substituted benzyl, 2-thienyl or p-benzyloxyphenyl.
[9" claim-type="Currently amended] The compound of claim 1, wherein Q and R ³ together are — (CH ₂ ) ₃ —, —CH ₂ —CH (OSO ₂ C ₆ H ₅ ) —CH ₂ —, —CH ₂ —CH (OSO ₂ C ₆ H ₄ CH ₃ ) -CH _2- , -CH ₂ -CH (N ₃ ) -CH _2- , -CH ₂ -CH (CN) -CH _2- , -CH ₂ -CH = CH- and Compound having a formula selected from the group consisting of.
[10" claim-type="Currently amended] The compound of claim 1, wherein B is selected from the group consisting of —C (═O) —, —O—, —S—, —S (═O) ₂ — and a bond.
[11" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is selected from the group consisting of benzyl, substituted benzyl, lysyl side chains and substituted lysyl side chains.
[12" claim-type="Currently amended] The compound of claim 1, wherein R ¹ is alkyl, benzyl, p-benzyloxybenzyl, 2-pyridylmethyl, — (CH ₂ ) ₄ —NHC (═O) —O—CH ₂ —C ₆ H ₅ , — ( CH ₂ ) ₄ -NHC (= O) -OtC ₄ H ₉ and-(CH ₂ ) ₄ -NHSO ₂ -C ₆ H ₅ .
[13" claim-type="Currently amended] 13. The compound of claim 12, wherein said alkyl group is selected from the group consisting of ethyl, isobutyl and tertiary butyl.
[14" claim-type="Currently amended] The compound of claim 1, wherein W ¹ and W ² together form —C (═O); R ¹ and Y together form — (CH ₂ ) ₄ —N (Pr) —; Pr is selected from the group consisting of H and tert-butoxycarbonyl.
[15" claim-type="Currently amended] The compound of claim 1, wherein R ² is selected from the group consisting of tertiary butyloxycarbonyl, —S (═O) ₂ R ^6, and —C (═O) CH ₃ .
[16" claim-type="Currently amended] The compound of claim 15, wherein R ² is —S (═O) ₂ R ⁶ ; And R ⁶ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.
[17" claim-type="Currently amended] The compound of claim 16, wherein R ² is —S (═O) ₂ CH ₃ , —S (═O) ₂ CH ₂ CH ₃ , p-fluorophenylsulfonyl, 2-thienylsulfonyl, 2-isoxazolesulphate A compound selected from the group consisting of fonyl, phenylsulfonyl, p-methylphenylsulfonyl, 4- (N-methylimidazole) sulfonyl and 2-naphthylsulfonyl.
[18" claim-type="Currently amended] The compound of claim 1, wherein Y is selected from the group consisting of H and CH ₂ F.
[19" claim-type="Currently amended] The compound of claim 1, wherein W ¹ and W ² together form —C (═O).
[20" claim-type="Currently amended] The compound of claim 1, wherein W ¹ is OH and W ² is SO ₃ Z ¹ ; Z ¹ is Na.
[21" claim-type="Currently amended] The compound of claim 1, wherein W ¹ is H and W ² is OC (═O) NH—R ²⁶ ; R ²⁶ is alkyl.
[22" claim-type="Currently amended] The compound of claim 1, wherein W ¹ is OH and W ² is aralkyl.
[23" claim-type="Currently amended] The compound of claim 1, wherein W ¹ is OH and W ² is aralkyloxy.
[24" claim-type="Currently amended] The compound of claim 1, wherein W ¹ is OH and W ² is aryloxy.
[25" claim-type="Currently amended] The compound of claim 1, wherein W ¹ is OH and W ² is heteroaryloxy.
[26" claim-type="Currently amended] The compound of claim 1, wherein W ¹ is OH and W ² is heteroaralkyloxy.
[27" claim-type="Currently amended] The compound of claim 1, wherein W ¹ and W ² are both alkoxy.
[28" claim-type="Currently amended] The compound of claim 1, wherein W ¹ and W ² together represent = NR ⁸ , = N (→ O) R ⁹ , —S (CH ₂ ) ₂ O— and —N (R ¹² ) (CH ₂ ) ₂ N (R ¹² )-a compound which forms a group selected from the group consisting of.
[29" claim-type="Currently amended] The compound of claim 11, wherein B is selected from the group consisting of — (C═O) —, —O—, a bond, SO ₂ and —S—; Y is selected from the group consisting of H and CH ₂ F; R ¹ is selected from the group consisting of benzyl, substituted benzyl, lysyl side chains and substituted lysyl side chains; R ² is selected from the group consisting of tertiary butyloxycarbonyl, -C (= 0) CH ₃ and -S (= 0) ₂ R ⁶ .
[30" claim-type="Currently amended] The compound of claim 23, wherein R ⁶ is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
[31" claim-type="Currently amended] The compound of claim 1, wherein Q is benzyloxymethyl; R ¹ is benzyl; R ² is —SO ₂ CH ₃ ; R ³ , R ⁴ , R ⁵ and Y are each H; W ¹ and W ² together form —C (═O) —.
[32" claim-type="Currently amended] A composition for inhibiting protease selected from the group consisting of a serine protease and a cysteine protease comprising the compound of claim 1.
[33" claim-type="Currently amended] A composition for inhibiting protease selected from the group consisting of a serine protease and a cysteine protease comprising the compound of claim 1 in an enantiomerically rich amount.
[34" claim-type="Currently amended] 34. The composition of claim 33, wherein the enantiomerically rich amount of the compound of claim 1 is greater than about 75%.
[35" claim-type="Currently amended] 34. The composition of claim 33, wherein the enantiomerically rich amount of the compound of claim 1 is greater than about 90%.
[36" claim-type="Currently amended] 34. The composition of claim 33, wherein the enantiomerically rich amount of the compound of claim 1 is about 100%.
[37" claim-type="Currently amended] A composition for inhibiting protease selected from the group consisting of a serine protease and a cysteine protease consisting essentially of the compound of claim 1.
[38" claim-type="Currently amended] A protease inhibition method comprising contacting a protease selected from the group consisting of a serine protease and a cysteine protease with an inhibitory amount of the compound of claim 1.
[39" claim-type="Currently amended] A protease inhibition method comprising contacting a protease selected from the group consisting of a serine protease and a cysteine protease with an inhibitory amount of a composition comprising the compound of claim 1 in an enantiomerically rich amount.
[40" claim-type="Currently amended] The method of claim 38, wherein the enantiomerically rich amount of the compound of claim 1 is greater than about 75%.
[41" claim-type="Currently amended] The method of claim 38, wherein the enantiomerically rich amount of the compound of claim 1 is greater than about 90%.
[42" claim-type="Currently amended] The method of claim 38, wherein the enantiomerically rich amount of the compound of claim 1 is about 100%.
[43" claim-type="Currently amended] A protease inhibition method comprising contacting a protease selected from the group consisting of a serine protease and a cysteine protease with an inhibitory amount of the composition consisting essentially of the compound of claim 1.

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RU2108322C1|1998-04-10|Derivatives of cycloalkyl-substituted glutaric acid amide and pharmaceutical composition based on thereof

---

US6683648B2|2004-01-27|α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors

---

KR100432602B1|2004-09-21|Matrix Metalloprotease Inhibitors

---

AU650458B2|1994-06-23|Guanidines

---

US5196438A|1993-03-23|Amino acid derivatives

---

DE60012137T2|2005-01-27|Acetylenic alpha-amino acids based on sulphonamide hydroxamic acids as tace inhibitors

---

JP4091653B2|2008-05-28|N- | sulfonamides useful as retroviral protease inhibitors

---

US6531612B2|2003-03-11|Nitrile derivatives that inhibit cathepsin K

---

AU740263B2|2001-11-01|Thiol sulfonamide metalloprotease inhibitors

---

US6825354B2|2004-11-30|Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and TACE inhibitors

---

US6569855B2|2003-05-27|Substituted cyclic amine metalloprotease inhibitors

---

US6656965B2|2003-12-02|HIV protease inhibitors based on amino acid derivatives

同族专利:

---

公开号 | 公开日

---

EP0910564A1|1999-04-28|

---

AU1025397A|1997-07-03|

---

KR100490807B1|2005-10-14|

---

MX9804262A|1998-09-30|

---

WO1997021690A1|1997-06-19|

---

AT377006T|2007-11-15|

---

DE69637307D1|2007-12-13|

---

US5852007A|1998-12-22|

---

EP0910564A4|1999-04-28|

---

JP2002515860A|2002-05-28|

---

DE69637307T2|2008-02-28|

---

EP0910564B1|2007-10-31|

---

CA2238175A1|1997-06-19|

---

AU714324B2|2000-01-06|

---

ES2293651T3|2008-03-16|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1995-11-28|Priority to US765195P

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1995-11-28|Priority to US60/007,651

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1996-11-26|Priority to US8/755,839

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1996-11-26|Priority to US75583996A

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1996-11-26|Priority to US08/755,839

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1996-11-27|Application filed by 바바라 에스. 쉴버그, 세파론, 인크.

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1999-09-27|Publication of KR19990071683A

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2005-10-14|Application granted

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2005-10-14|Publication of KR100490807B1

优先权:

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申请号 | 申请日 | 专利标题

---

US765195P| true| 1995-11-28|1995-11-28|

---

US60/007,651|1995-11-28|

---

US75583996A| true| 1996-11-26|1996-11-26|

---

US08/755,839|1996-11-26|

---

US8/755,839|1996-11-26|