Bitronectin receptor antagonist

专利摘要:
A compound of formula I-V, which is a betronectin receptor antagonist and useful in the treatment of osteoporosis. (I) ≪ (III) (IV) (V)
公开号:KR19990076878A
申请号:KR1019980705005
申请日:1996-12-20
公开日:1999-10-25
发明作者:윌리엄 헨리 밀러；윌리엄 에드워드 본디넬；토마스 웬-푸 쿠；리차드 맥쿨로치 키난；제임스 마틴 새머넨；쳇 퀀；패디아 엘-페하일 알리；마리아 에이. 라고
申请人:스티븐 베네티아너；스미스클라인 비참 코포레이션；
IPC主号:

专利说明:

Bitronectin receptor antagonist
Integrin is a cell adhesion receptor that is a transmembrane glycoprotein expressed on various cells. These cell surface adhesion receptors include gpIIb / IIIa, a fibrinogen receptor, and _{V 3} , a vitronectin receptor. The fibrinogen receptor gpIIb / IIIa is expressed on the platelet surface, which mediates the formation of platelet aggregation and hemostatic clot at the bleeding site (Philips et al., Blood., 1988, 71, 831). The vitronectin receptor _{V 3} has various functions because it expresses on many cells including endothelial cells, smooth muscle, osteoclasts, and tumor cells. The α _v β ₃ receptor expressed on the membrane of osteoclasts mediates bone resorption processes and contributes to the development of osteoporosis (Ross et al., J. Biol. Chem., 1987, 262, 703). [Alpha] _{v [} beta] ₃ receptors expressed on human venous smooth muscle cells stimulate the migration into the intrenal membranes, resulting in the development of post-angiogenic arteriosclerosis and stenosis (Brown et al., Cardiovascular Res., 1994, 28, 1815 ] Reference). In addition, recent studies have demonstrated that [alpha] _{v [} beta] ₃ antagonists can enhance tumor companies by inducing apoptosis of blood vessel-derived blood vessels (Brooks et al., Cell, 1994, 79, 1157). Thus, agents that block the vitronectin receptor will be useful in the treatment of diseases mediated by this receptor, such as osteoporosis, atherosclerosis, stenosis, and cancer.
The vitronectin receptor is known to bind to a bone matrix protein containing three peptides Arg-Gly-Asp (or RGD), such as osteopontin, bone sarcomatoprotein and trombopodin. Thus, see Horton et al., Exp. Cell Res. 1991, 195, 368) discloses that RGD-containing peptides and anti-vitronectin receptor antibodies (23C6) inhibit dendritic reabsorption and cell division by osteoclasts. In addition, as described in Sato et al., J. Cell Biol. 1990, 111, 1713) discloses that echistatin, a snake venom peptide containing the RGD sequence, is an effective inhibitor of bone resorption in tissue culture and inhibits osteoclast attachment to bone. In [Fisher et al., Endocrinology 1993, 132, 1411], it has also been demonstrated that epstatin inhibits in vivo bone resorption in rats. Bertolini et al., J. Bone Min. Res., 6, Sup. 1, S146, 252], it has been demonstrated that cyclo-S, SN ^[alpha ] -acetyl-cysteine-N ^[alpha] -methyl-arginyl-glycyl-aspartyl-phenylsilamine inhibits osteoclast adhesion to bone. EP 528 587 and EP 528 586 report substituted phenol derivatives that inhibit osteoclast-mediated bone resorption.
EP 0 381 033 of Alig et al., EP 0 540 334 of Hartman et al., WO 93/08714 of Blackburn et al., Bondinell EP 0 478 328 such as Egbertson et al., EP 529,858 by Sugihara et al., WO 93/00095 by Blackburn et al., WO 95/04057 by Blackburn et al. Porter et al., EP 0542 363, and Fisher et al. EP 635 492, disclose certain compounds useful for inhibiting fibrinogen receptors. Certain compounds that have been appropriately substituted in the present invention have been found to be potent inhibitors of the vitronectin receptor. Specifically, it has been found that these compounds are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor, and that the compound contains a fibrinogen receptor antagonist template.
SUMMARY OF THE INVENTION [
The present invention relates to compounds of formula I-V and < RTI ID = 0.0 > XXI, < / RTI > which are useful for the treatment of diseases which have pharmacological activity for inhibiting vitronectin receptor and are a factor in bone resorption such as inflammation, tumor and arteriosclerosis and stenosis, - XXII. ≪ / RTI >
The present invention also relates to a pharmaceutical composition comprising a compound according to formula I-V and XXI-XXII and a pharmaceutical carrier.
The invention is also a method of treating a disease mediated by the vitronectin receptor. In particular aspects, the compounds of the present invention are useful for the treatment of diseases such as osteoporosis, a factor of arteriosclerosis, stenosis, inflammation, cancer and bone resorption.
The present invention relates to pharmaceutical active compounds which inhibit the vitronectin receptor and are useful in the treatment of diseases in which bone resorption is a factor, such as cardiovascular disorders such as inflammation, cancer and arteriosclerosis and stenosis, and osteoporosis.
The present invention includes novel compounds that are more potent inhibitors of the bitronectin receptor than fibrinogen receptors. The compounds of the present invention comprise a fibrin receptor antagonist template attached to a nitrogen-containing 5-membered ring which may optionally be fused to an aromatic 6-membered ring. The fibrinogen receptor antagonist template is substituted by an aliphatic substituent containing an acidic moiety. It is preferred that about 14 mediator covalent bonds are present between the shortest intermolecular pathways between the acidic group of the fibrinogen receptor antagonist template and the nitrogen of the optionally fused 5-membered ring.
As used herein, the term " fibrinogen receptor antagonist template " refers to the core structure of a fibrinogen receptor antagonist, wherein the shim is substituted by an acid group and is attached to an organic group substituted by a basic nitrogen moiety. Fibrinogen receptor antagonists are agents that inhibit fibrinogen binding to platelet-binding fibrinogen receptor GPIIb-IIIa. It is an object of the present invention to provide a method for the preparation of a fibrinogen receptor antagonist by replacing an organic group substituted with a basic nitrogen moiety in a fibrinogen receptor antagonist with an optionally fused nitrogen-containing 5-membered ring, preferably an imidazole ring and most preferably a benzimidazole ring. To a bitronectin receptor antagonist.
The present invention includes a compound of formula (I-V), or a pharmaceutically acceptable salt thereof.

Wherein,
W is - (CHR ^g ) _b -V'- or Ar;
A is a fibrinogen receptor antagonist template;
V 'is CONR ²¹ or NR ²¹ CO;
G is NR ^e , S or O;
R ^g is H, C _1-6 alkyl, Het-C _0-6 alkyl, C _3-7 cycloalkyl, -C _0-6 alkyl or Ar-C _0-6 alkyl;
R²¹Het-C_0-6Alkyl-U'-C_1-6Alkyl-, C_3-7Cycloalkyl-C_0-6Alkyl-U'-C_1-6 Alkyl- or Ar-C_0-6Alkyl-U'-C_1-6Alkyl-;
U 'is CONR ^f or NR ^f CO;
R ^f is H, C _1-6 alkyl or Ar-C _1-6 alkyl;
R ^e is H, C _1-6 alkyl, Ar-C _1-6 alkyl, Het-C _1-6 alkyl, C _3-7 cycloalkyl, -C _1-6 alkyl, (CH _{2) q} OH or (CH ₂ ) _k CO ₂ R ^g, and;
k is 0, 1 or 2;
q is 1 or 2;
b is 0, 1 or 2;
R ^b and R ^c are each H, C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, or C _3-6 cycloalkyl, -C _0-6 alkyl, halogen, CF _{3, ^{oR f, S (O) k}} R f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2 N (R f) selected from the _second or, or R ^b and R ^c is We are bound together, optionally halogen, CF _3, C _1-4 alkyl, OR ^f, S (O) _k R ^f, COR ^f, CO ₂ R ^f OH, NO _2, N (R ^f) _2, CO (NR ^f ) to form a _2, and CH ₂ N (R ^f) ₂ by any of the three substituents selected from the below-substituted 5-membered or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring, or methylenedioxy .
The present invention also includes a compound of the formula (XXI-XXII) or a pharmaceutically acceptable salt thereof.
Wherein,
B is - (CHR ^g ) _a -U- (CHR ^g ) _b -V-;
A is a fibrinogen receptor antagonist template;
G is NR ^e , S or O;
R ^g is H, C _1-6 alkyl, Het-C _0-6 alkyl, C _3-7 cycloalkyl, -C _0-6 alkyl or Ar-C _0-6 alkyl;
R ^k is R ^g , -C (O) R ^g, or -C (O) OR ^f ;
R ⁱ is H, C _1-6 alkyl, Het-C _0-6 alkyl, C _3-7 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl -U ' -C _1-6 alkyl-, C _3-7 cycloalkyl-C _0-6 alkyl-U'-C _1-6 alkyl- or Ar-C _0-6 alkyl-U'-C _1-6 alkyl- or C _≪ / RTI >
R ^f is H, C _1-6 alkyl or Ar-C _1-6 alkyl;
R ^e is H, C _1-6 alkyl, Ar-C _1-6 alkyl, Het-C _1-6 alkyl, C _3-7 cycloalkyl, -C _1-6 alkyl, (CH _{2) q} OH or (CH ₂ ) _k CO ₂ R ^g, and;
U, U 'and V are each absent or CO, CR^g ₂, C (= CR^g ₂), S (O)_k, O, NR^g, CR^gOR^g, CR^g(OR^k) CR^g ₂, CR^g ₂CR^g(OR^k), C (O) CR^g ₂, CR^g ₂C (O), CONRⁱ, NRⁱC (O), C (O) O, C (S) O, OC (S)^g, NR^gC (S), S (O)₂NR^g, NR^gS (O)₂, N = N, NR^gNR^g, NR^gCR^g ₂, NR^gCR^g ₂, CR^g ₂O, OCR^g ₂, C C, CR^g= CR^g, Ar or Het;
k is 0, 1 or 2;
q is 1 or 2;
a is 0, 1 or 2;
b is 0, 1 or 2;
R ^b and R ^c are each H, C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, or C _3-6 cycloalkyl, -C _0-6 alkyl, halogen, CF _{3, ^{oR f, S (O) k}} R f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2 N (R f) selected from the _second or, or R ^b and R ^c is We are bound together, optionally halogen, CF _3, C _1-4 alkyl, OR ^f, S (O) _k R ^f, COR ^f, CO ₂ R ^f OH, NO _2, N (R ^f) _2, CO (NR ^f ) to form a _2, and CH ₂ N (R ^f) ₂ by any of the three substituents selected from the below-substituted 5-membered or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring, or methylenedioxy .
The invention also encompasses pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds of the invention. A prodrug refers to any covalently bonded carrier that in vivo releases an active moiety according to formula (I). Unless otherwise indicated where the compounds of the present invention have one or more chiral centers, the present invention includes each unique non-racemic compound that can be synthesized and fractionated by conventional techniques. When the compound has an unsaturated carbon-carbon double bond, both the cis (Z) and trans (E) isomers are within the scope of the present invention. If the compound is a keto-enol tautomer, for example , Each tautomeric form, whether existing in equilibrium or fixed in one form by appropriate substitution by R ', is included in the present invention.
The compounds of formulas I-V and XXI-XXII inhibit the binding of bitronectin and other RGD-containing peptides to the vitronectin ([alpha] _{v [} beta] ₃ ) receptor. Inhibition of osteoclast bone resorption due to inhibition of vitronectin receptors on osteoclasts is inhibited and this is useful for the treatment of diseases such as osteoporosis associated with bone turnover. In addition, since the compounds of the present invention inhibit betronectin receptors on a number of different types of cells, they are useful for the treatment of cardiovascular diseases and inflammation such as arteriosclerosis and stenosis, and are useful as anti-convulsants and antineoplastic agents something to do.
In certain embodiments, the compounds of the present invention are those compounds of formula II wherein R < ^b & gt ^; and R < ^c > are joined to form an aromatic ring containing up to two nitrogen atoms. In a preferred embodiment, R ^b and R ^c combine to form an optionally substituted phenyl ring of formula (IIa).
Wherein,
G is NR ^e , S, CH or O;
Suitably W is - (CHR ^g ) _a NR ⁱ CO- or Or when G is CH, W is suitably -CH ₂ CH ₂ NR ⁱ CO- wherein R ⁱ is a methylene group bonded to G.
Preferably W is -CHR ^g NR ⁱ CO-.
Suitably, R ⁱ is H, C _1-6 alkyl, C _3-7 cycloalkyl, Ar or; _{^{Halogen, CN, NR g 2, OR}} g, SR g, CO 2 R g, and _{^{CON (R g) 2, Ar}} , Het or C _1- substituted by one to three groups selected from C _3-7 cycloalkyl, _{Lt; /} RTI > In particular, R ⁱ is H, methyl, butyl, cyano-methyl, carboxymethyl, phenylethyl or benzimidazolyl-methyl.
Suitably, R ^x , R ^y and R ^z are each selected from C _1-6 alkyl, methoxy, nitro, trifluoromethyl, fluoro, chloro, amino, or wherein R ^x and R ^y are adjacent to each other, To form a methylenedioxy group.
Preferably G is NR ^e .
Suitably, R ^e is H, C _1-4 alkyl, Ar, Het or C _1-4 alkyl substituted by Ar or Het. More suitably, R ^e is H, methyl or benzimidazolylmethyl.
In another particular embodiment, R < ^b & gt ^; and R < ^c > form a 6-membered aromatic ring containing one or two nitrogen atoms according to the formula IIb-d.
Wherein,
G, R ^z and R ^y are the same as in the above formula (IIa).
In particular, the compounds of the present invention comprise a nitrogen-containing 5-membered ring optionally fused, a linking group W and a fibrinogen receptor antagonist template A. Specifically, the fibrinogen receptor antagonist template A is as defined in WO 93/00095, Bondinell et al., Published January 7, 1993, as sub-formula VI and its pharmaceutically acceptable salts .
A ¹ through A ⁵ optionally form a saturated or unsaturated, optionally substituted 7-membered ring containing up to two heteroatoms selected from the group of O, S and N, wherein S and N may optionally be oxidized ;
D ¹ to D ^{4 form} optionally substituted six-membered rings optionally containing up to two nitrogen atoms;
R is R ^7, or = O, R ¹¹ or R ⁷ by at least one optionally substituted QC _1-4 alkyl, QC _2-4 alkenyl, wherein is one or more substituents selected from the group of QC _2-4 alkynyl ;
R ^* is H, QC _1-6 alkyl, QC _1-6 alkyl, oxo, QC _2-6 alkenyl, QC _3-4 oxo alkenyl, QC _3-4 alkynyl, oxo, QC _2-4 alkynyl, C _{3 6} cycloalkyl, Ar or Het, which is optionally substituted by one or more R < ^{11 &} gt ;;
Q is H, C _3-6 cycloalkyl, Het or Ar;
R ⁷ is selected from the group consisting of -COR ⁸ , -COCR ' ₂ R ⁹ , -C (S) R ⁸ , -S (O) m OR', -S (O) mNR'R " _{OR ') 2, -B (OR} ') 2, -NO 2 and Tet gt;
R ⁸ is -OR ', -NR'R ", -NR'SO ₂ R', -NR'OR ', -OCR' ₂ C (O) OR ', -OCR' ₂ OC (O) _{-OCR '2 C (O) NR} ' 2, CF 3 or AA'1 gt;
R ⁹ is OR ', -CN, -S (O ) r R', S (O) mNR '2, -C (O) R'C (O) NR' 2 or -CO ₂ R ', and;
R ¹¹ is H, ^{halo, -OR 12, -CN, -NR'R 12} , -NO 2, -CF 3, CF 3 S (O) r, -CO 2 R ', -CONR' 2, QC 0- ₆ alkyl-, QC _1-6 oxo alkyl-, QC _2-6 alkenyl -, QC _2-6 alkynyl -, QC _0-6 alkyloxy -, QC _0-6 alkylamino-or QC _0-6 alkyl- S (O) r-;
R ¹² is R ', -C (O) R ', -C (O) NR '2, -C (O) OR 15, -S (O) mR' or S (O) mNR _'2 and;
R ¹³ is R ', -CF ₃ , -SR' or -OR ';
R ¹⁴ is R ', C (O) R', CN, NO ₂ , SO ₂ R 'or C (O) OR ¹⁵ ;
R ¹⁵ is H, C _1-6 alkyl or Ar-C _0-4 alkyl;
R 'is H, C _1-6 alkyl, C _3-7 cycloalkyl, -C _0-4 alkyl or Ar-C _0-4 alkyl;
R "is R ', -C (O) R', or -C (O) OR ¹⁵ ;
R "'is R" or AA2;
AA1 is an amino acid attached through an amino group and the carboxyl group is optionally protected, AA2 is an amino acid attached through a carboxyl group and the amino group is optionally protected;
m is 1 or 2;
n is from 0 to 3;
p is 0 or 1;
t is from 0 to 2;
For the formula (VI), suitably
A ¹ is CR ¹ R ^{1 '} , CR ¹ , NR ¹ , N, O or S (O) _x ;
A ² is CR ² R ^{2 '} , CR ² , NR ² ;
A ³ is CR ³ R ^{3 '} , CR ³ , NR ³ , N, O or S (O) _x ;
A ⁴ is CR ⁴ R ^{4 '} , CR ⁴ , NR ⁴ , or N;
A ⁵ is CR ⁵ R ^{5 '} , CR ⁵ , NR ⁵ , N, O or S (O) _x ;
D ¹ -D ⁴ is CR ¹¹ , CR ⁶ or N;
R ¹ and R ^{1 '} are R ^* or R, or together are = O;
R ² and R ^{2 '} are R ^* , R or = O;
R ³ and R ^{3 '} are R ^* , R or = O;
R ⁴ and R ^{4 '} are R ^* , R or = O;
R ⁵ and R ^{5 '} are R ^* , R or = O;
x is from 0 to 2;
More suitably, A ¹ is CR ¹ R ^{1 '} , CR ¹ , NR ¹ , N, O or S; A ² is CR ² R ^{2 '} , NR ² or CR ² ; A ³ is CR ³ R ^{3 '} ; A ⁴ is CR ⁴ R ^{4 '} , CR ⁴ , NR ⁴ or N; A ⁵ is CR ⁵ R ^{5 '} , CR ⁵ , NR ⁵ , N, O; D ¹ -D ⁴ is CH; R ² or R ⁴ is R; R ³ , R ^{3 '} and R ⁵ , R ^5' are ═O or R ^* , H.
Preferably, A ¹ is CHR ¹ , CR ¹ , NR ", N or S, A ² is CR ² or CR ² R ^{2 '} , A ³ is CR ³ R ^3' , A ⁴ is CR ⁴ R ^{4 '} , or NR ⁴ ; A ⁵ is CR ⁵ R ^5' ; D ¹ -D ⁴ is CH.
In one embodiment, A ¹ is CR ¹ , A ² is CR ² , A ³ is C═O, A ⁴ is NR ^4, and A ⁵ is CHR ⁵ .
In another embodiment, A ¹ is NR ¹ , A ² is CHCR ² , A ³ is CR ³ R ^{3 '} , A ⁴ is NR ⁴ and A ⁵ is C═O.
In another embodiment, A ¹ and A ⁴ are C = O, A ² is NR ² , A ³ is CHR ^{3 '} and A ⁵ is NR ⁵ .
In a preferred embodiment, A ¹ is NR ¹ , A ² is CHR ² , A ³ is C═O, A ⁴ is NR 'and A ⁵ is CHR ⁵ .
Representative sub-formulas of formula VI are each of the following formula VIa-VIi:


Certain embodiments of the invention in which fibrinogen receptor antagonist template A is sub-formula (VI) are named in the Examples.
Preferred compounds of the present invention are:
5 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -1H-benzimidazole-2-aminoacetic acid;
Methyl] amino] carbonyl] -4- (3,3-dimethylbutyl) - (2-methylbenzyl) 3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7 - [[[(5-trifluoromethylbenzimidazol- ≪ / RTI > 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4,7-dimethoxybenzimidazol-2- yl) methyl] - methylamino] carbonyl] -Oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(3,3-dimethylbutyl) -3, 3, 4-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -4- -Oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-methylbenzimidazol-2-yl) methyl] methylamino] carbonyl] -4-methyl- -1,4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol-2-yl) methyl] -N- (4-aminobutyl) amino] carbonyl] -4- Methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol-2-yl) methyl] -N- (2- cyanomethyl) amino] carbonyl] -Methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -1H-l, 4-benzodiazepin-2-acetic acid;
4 - [[[3- (benzimidazol-2-yl) propyl] amino] carbonyl] piperidine-1-acetic acid;
4 - [[[3- (benzimidazol-2-yl) propyl] amino] carbonyl] phenylacetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5,7-dimethylbenzimidazol-2- yl) methyl] methylamino] carbonyl] -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
Methyl] amino] carbonyl] -4- [2- (3,4-methylenedioxy) benzyl] Oxyphenyl) ethyl] -3-oxo-1H-1, 4-benzodiazepin-2-acetic acid;
Methyl] amino] carbonyl] -4- (2-methoxyethyl) -3-oxo < RTI ID = 0.0 & -1H-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] 4-benzodiazepin-2-acetamide;
Yl] methyl] amino] carbonyl] -2-methyl-1H-pyrazolo [3,4-d] pyrimidin- -4-methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -3-oxo-1H-1,4-benzodiazepin- 2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[bis [(benzimidazol-2-yl) methyl] amino] carbonyl] -4- 4-benzodiazepin-2-acetic acid;
Methyl] methylamino] carbonyl] -4- (3,3-dimethylbutyl) -2,3,4,5-tetrahydro-7 - [[[ ) -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
Methyl) amino] carbonyl] -3-oxo-4- (2,2,2 < RTI ID = 0.0 & -Trifluoroethyl) -lH-l, 4-benzodiazepin-2-acetic acid;
(2-phenylethyl) -lH-indol-2-yl) acetyl] amino] -5-oxo-4- 1,4-benzodiazepin-2-acetic acid;
Methyl] amino] carbonyl] -3-oxo-4- (2,2,2-trifluoroethyl) Trifluoroethyl) -1H-1,4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(5,6-difluorobenzimidazol-2-yl) methyl] methylamino] carbonyl] -Oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(2-phenylethyl) -2,3,4,5-tetrahydro-7 - [[bis [(benzimidazol-2-yl) methyl] amino] carbonyl] -1H-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] amino] carbonyl] Oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-4-methyl-7- [[[(4-nitrobenzimidazol-2-yl) methyl] methylamino] carbonyl] -1,4-benzodiazepin-2-acetic acid;
Methyl] amino] carbonyl] -3-oxo-4- (2-methylbenzyl) (2,2,2-trifluoroethyl) -1H-1,4-benzodiazepin-2-acetic acid;
() -4- [4 - [[[(1H-benzimidazol-2-yl) methyl] methylamino] carbonyl] phenyl] -3-phenylbutanoic acid;
(±) -3 - [[[4- (4-azabenzimidazol-2-yl) butanoyl] glycyl] amino] -4-pentenoic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[[1- (2-hydroxyethyl) benzimidazol-2- yl] methyl] amino] carbonyl] 3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
Methyl] amino] carbonyl] -4- (2-methoxybenzyl) -2,3,4,5-tetrahydro-7 - [[[ Ethoxyethyl) -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aminobenzimidazol-2-yl) methyl] methylamino] carbonyl] -4-methyl- -1,4-benzodiazepin-2-acetic acid;
Methyl (3-methyl-3-oxo-1H-1 , 4-benzodiazepine-2-acetate;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] 4-benzodiazepin-2-acetic acid, [(2,2-dimethyl-2-methoxyacetyl) oxy] methyl ester;
Ethyl] methylamino] carbonyl] -4-methyl-3-oxo-1 H-1, 2-benzothiazol- 4-Benzodiazepine- (2S) -acetic acid;
(±) -N- [2- (aminomethyl) -4 - [[[(4-aza-5-methylbenzimidazol-2-yl) methyl] methylamino] carbonyl] phenyl] aspartic acid;
(Methyl) amino] carbonyl] -1H-1, 2-dihydroxy- 4-benzodiazepin-2-acetic acid;
Yl) phenyl] -4-methyl-3-oxo-1H-1,4-benzodiazepin-2- Acetic acid;
() -4- [4 - [[[(Benzimidazol-2-yl) methyl] methylamino] carbonyl] phenyl] -3- (dimethylaminocarbonyl) butanoic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -3-oxo-4- [2- Yl) ethyl] -1H-1,4-benzodiazepine-2-acetate;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2-yl) methyl] methylamino] carbonyl] -1,4-benzodiazepin-2-acetic acid;
(2-hydroxybenzoyl) amino] < RTI ID = 0.0 > butyl] Amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepin-2-acetic acid;
(-) - 2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol- Benzoyl) amino] butyl] amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] amino] carbonyl] -Oxo-lH-l, 4-benzodiazepine-2-acetate;
Methyl] -N - [[[(+) - biotin oil] amino] butyl] amino] carbonyl ] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine- (2RS) -acetic acid;
Ethyl] methylamino] carbonyl] -4-methyl-3-oxo-1 H-1, 2-benzothiazol- 4-Benzodiazepine- (2S) -acetic acid;
Yl) methyl] methylamino] carbonyl] -4-methyl-3- (4-methoxyphenyl) Oxo-lH-l, 4-benzodiazepine-2S-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -3-oxo-1H-1,4-benzodiazepine- 2S) -acetic acid;
(3-oxo-4- (2-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin- ) -1H-1,4-benzodiazepin-2-yl] methyl] tetrazole;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2-yl) methyl] amino] carbonyl] 1,4-benzodiazepin-2-acetic acid;
Methyl-3-oxo-1H-1, 4-benzodiazepin-2-yl) propyl] Acetic acid;
(4-aminobutyl) amino] carbonyl] -3- (4-fluorobenzyl) Oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-2-acetic acid;
(Methyl) amino] carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine -Benzodiazepin-2- (N-hydroxy) acetamide;
Ethyl (±) -3 - [[[2- (benzimidazol-2-yl) ethyl] amino] succinol] amino-4-pentenoate;
() -3 - [[[2- (Benzimidazol-2-yl) ethyl] amino] succinol] amino-4-pentenoic acid;
(-) - 2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol- -2-hydroxybenzoyl) amino] butyl] amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepin-2-acetic acid;
Ethyl] amino] carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine - benzodiazepine- (2S) -acetic acid;
Ethyl] amino] carbonyl] -4-methyl-3-oxo-1H-1,4-benzoimidazo [ - benzodiazepine- (2S) -acetic acid; And
Methyl] methylamino] carbonyl] -2,3,4,5-tetrahydro-4-methyl-3 (1H) -imidazo [ -Oxo-lH-l, 4-benzodiazepin-2-acetic acid;
Or a pharmaceutically acceptable salt thereof.
The most preferred fibrinogen receptor antagonist template is a sub-formula VIa wherein CR ² CR ^{2 '} is CHCH ₂ CO ₂ H, CR ³ CR ^{3 '} is C═O and CR ⁵ CR ^{5 '} is CH ₂ . The vitronectin fibrinogen receptor antagonism is particularly pronounced when the AW-substituent is attached to the 7-position of the 3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine ring system.
The definitions of the substituents below are as defined in the formulas I-IV and XX-XXI, unless otherwise specified.
Another embodiment of the preferred fibrinogen receptor template A is represented by the sub-formula (VII) 1,4-benzodiazepine 2,5-dione.
Wherein,
Y is H, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxycarbonyl, F, Cl, Br, I , CF 3, OR f, S (O) k R f, COR f, NO ^{_{2, N (R f) 2}} , CO (NR f) 2, CH 2 N (R f) 2, ^{_{methylenedioxy, CN, CO 2 R f,}} OC (O) R f, or NHC (O) R ^f ego; And
R ^h is (CH ₂ ) _q CO ₂ R ^f .
The preparation and use of the sub-structures in the preparation of the subunits of the sub-formulas is described in WO 93/00095, Bondinel et al., Published Jan. 7, 1993, and Blackburn, et al. Lt; / RTI > WO 93/08174.
Table I below summarizes other preferred fibrinogen receptor templates included within the scope of the present invention. In EP 0 381 033, published by Alleg, et al., August 8, 1990, the template is as follows:
<Table I>
Wherein,
R ²¹ and R ²² are H or -Z-CO ₂ R ^f or Z-CON (R ^f) _2, and one of the end A ¹ or A ² is -Z-CO ₂ R ^f or Z-CON (R ^f each ) ₂ ;
Z is _{-CH 2 -, -O (CH 2} ) q -, -NR f (CH 2) q -, -S (CH 2) q, -CH 2 CH 2 -, -CH (CH 3) CH 2 - , - (CH ₂ ) ₃ -, -CH = CH-, -C (CH ₃ ) = CH-, CH ₂ -CH = CH or CH = CHCH ₂ ;
Y is H, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxycarbonyl, F, Cl, Br, I , CF 3, OR f, S (O) k R f, COR f, NO ₂ , N (R ^f ) ₂ , CO (NR ^f ) ₂ , CH ₂ N (R ^f ) ₂ , methylenedioxy or Z-CO-R ^f .
EP 0 478 328 to Egbertson et al., Published April 1, 1992, discloses compounds of the formula IX:
Wherein,
R ⁶ is selected from the group consisting of aryl, C _1-10 alkyl, C _3-6 cycloalkyl, C _4-10 aralkyl, C _1-10 alkoxyalkyl, C _1-10 alkaryl, C _1-10 alkylthioalkyl, C _{1 -10} alkoxy thioalkyl, C _1-10 alkylamino, C _4-10 aralkyl-amino, C _1-10 alkanoyl amino, C _4-10 ahreu alkanoyl amino, C _1-10 alkanoyl, C _4-10 ahreu Alkane oil, or C _1-10 carboxyalkyl;
Y is H, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxycarbonyl, F, Cl, Br, I CF 3, OR f, S (O) k R f, COR f, NO 2 (R ^f ) ₂ , CO (NR ^f ) ₂ , CH ₂ N (R ^f ) ₂ , methylenedioxy, CN, CO ₂ R ^f , OC (O) R ^f or NHC (O) R ^f .
EP 0542 363 of Eldred et al., Published May 19, 1993, discloses compounds of formula X,
Wherein,
M ¹ is CH or N;
M ² is CH or N, with the proviso that when M ¹ is CH, M ² is N;
G 'is N or N ⁺ R &quot;.
EP 0 537 980 of Porter et al., Published April 21, 1993, discloses compounds of formula (XI)
Wherein,
M ¹ is CH or N;
M ² is CH or N, provided that M ¹ is CH and M ² is N.
EP 0 635 492 to Klinnick et al., Published January 25, 1995 discloses compounds of the formula XII,
Wherein,
M ¹ is CH or N;
Y is H, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxycarbonyl, F, Cl, Br, I CF 3, OR f, S (O) k R f, COR f, NO 2 , N (R ^f ) ₂ , CO (NR ^f ) ₂ , CH ₂ N (R ^f ) ₂ , methylenedioxy, CN, CO ₂ R ^f , OC (O) R ^f or NHC (O) R ^f ;
M ³ is CH ₂ or C = O; And
R ^h is (CH ₂ ) _q CO ₂ R ^f .
WO 95/04057 to Blackburn et al., Published February 9, 1995, discloses compounds of the formula XIII,
Wherein,
Y is H, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxycarbonyl, F, Cl, Br, I CF 3, OR f, S (O) k R f, COR f, NO 2 , N (R ^f ) ₂ , CO (NR ^f ) ₂ , CH ₂ N (R ^f ) ₂ , methylenedioxy, CN, CO ₂ R ^f , OC (O) R ^f or NHC (O) R ^f ;
R ^h is (CH ₂ ) _n CO ₂ R ^f ;
B is to be.
In EP 0540 331 of Hartmann et al., Published May 5, 1993, compounds of the formula XIV are disclosed.
L ^* is ^{-C (O) NR g - (} CH 2) -, -C (O) - (CH 2) q -, NR g - (CH 2) q -, -O- (CH 2) q -, or _{S (O) k - (CH} 2) q - is.
EP 0 529,858 of Sugihara et al., Published March 3, 1993, discloses the formula of the formula XV.
EP 0 483 667 of Himmeisbach et al., Published May 6, 1992, discloses the formula of formula XVI.
Wherein,
Y is H, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxycarbonyl, F, Cl, Br, I CF 3, OR f, S (O) k R f, COR f1, NO 2 (R ^f ) ₂ , CO (NR ^f ) ₂ , CH ₂ N (R ^f ) ₂ , methylenedioxy, CN, CO ₂ R ^f , OC (O) R ^f or NHC (O) R ^f .
EP 0 567 968 to Linz et al., Published November 3, 1993, discloses the formula of formula XVII.
EP 0 539 343 of Bovy et al., Published April 28, 1993, discloses the formula of formula XVIII.
Wherein,
R ^d is Het-C _0-6 alkyl;
Z "and Z"'are each hydrogen, C _1-4 alkyl, halo, OR ^f , CN, S (O) _k R ^f , CO ₂ R ^f or OH.
Compounds of the invention comprising a particular fibrinogen template are named in the Examples. These examples are provided for illustrating the present invention and do not limit the scope of the present invention.
The above description of the fibrinogen receptor template used in the present invention is taken from the pending public patent application. Reference should be made to the above patent application with respect to the entire contents of the process, including the method of making the template and the specific compound using the template, and the entire specification of the patent application is incorporated herein by reference.
Table II below describes other fibrinogen receptor antagonists with cardiac structures useful for carrying out the present invention. Reference should be made to the above patent application with respect to the entire contents of the process, including the method of making the template and the specific compound using the template, and the entire specification of the patent application is incorporated herein by reference. Any of the fibrinogen receptor antagonists conjugated to the optionally fused nitrogen-containing 5-membered ring is also contemplated to have the novel utility described herein, so the following list is not intended to limit the invention.
<Table II>
Adir et Compagnie
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Asahi Breweries, Ltd.
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Asahi Glass
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DuPont Merck (DuPont Merck)
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Ellem Ind Farma Spa
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Farmitalia Erba SRL Carlo
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Fuji Photo Film
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Hoffmann-La Roche
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Kogyo Gijutsuin High School
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Kyowa Hakko Kogyo KK (Kyowa Hakko Kogyo KK)
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Laboratoire Chauvin,
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La Jolla Cancer Res. Fndn
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Lilly / COR
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Merck
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When the compounds of the present invention have one or more chiral centers, the present invention includes each unique non-racemic compound that can be synthesized and decomposed by conventional techniques, unless otherwise specified. When the compound has an unsaturated carbon-carbon double bond, both the cis (Z) and trans (E) isomers fall within the scope of the present invention. The meaning of a particular substituent at a particular position is independent of its meaning or meaning of another substituent unless otherwise specified.
Abbreviations and symbols commonly used in the art of peptide and chemical technology are used herein to describe the present invention. In general, amino acid abbreviations are defined by the IUPAC-IUB association committee, Eur. J. Biochem., 158, 9 (1984)].
As used herein, C _1-4 alkyl means an optionally substituted alkyl group of 1 to 4 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl. C _1-6 alkyl also includes pentyl, n-pentyl, isopentyl, neopentyl, and hexyl and the simple aliphatic isomers thereof. C _0-4 alkyl and C _0-6 alkyl also indicate that the presence of an alkyl group is not essential (e.g., the presence of a covalent bond).
C _1-4 alkyl or C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _1-6 alkyl and oxo be optionally substituted by a substituent R ^x, R ^x is present in the on-carbon Resulting in a stable structure and can be obtained by conventional synthetic techniques. Suitable groups for R ^x include C _1-4 alkyl, OR ¹ , SR ¹ , C _1-4 alkyl, C _1-4 alkylsulfonyl, C _1-4 alkylsulfoxy, -CN, N (R ¹ ) _{2 ^{, CH 2 N (R 1)}} 2, -NO 2, -CF 3, -CO 2 R 1 -CON (R 1) 2, -COR 1, -NR 1 C (O) R 1, OH, F, Cl , Br, I, N ₃ or CF ₃ S (O) r- is the (r is from 0 to 2).
Ar or aryl as used herein refers to phenyl or naphthyl, or phenyl substituted with one to three substituents as defined above for alkyl, especially C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, means _{alkyl, N 3, OH, CO 2} H, F, Cl, Br or phenyl or naphthyl substituted by naphthyl I-trifluoromethyl.
Het or heterocycle is stable and usable by conventional chemical synthesis and is an optionally substituted 5- or 6-membered monocyclic ring containing 1-3 heteroatoms selected from the group of nitrogen, oxygen and sulfur, or 9 or 10 Quot; refers to a cyclic non-cyclic ring. Examples of heterocycles include benzofuryl, benzimidazole, benzopyran, benzothiophene, biotin, furan, imidazole, indolin, morpholine, piperidine, piperazine, pyrrole, pyrrolidine, pyridine, tetrahydropyridine , Pyridine, thiazole, thiophene, quinoline, isoquinoline and tetra- and perhydro-quinoline and isoquinoline. Any possible combination of up to three substituents on the Het ring, as defined above for an alkyl group, which is available and stable by chemical synthesis, is within the scope of the present invention.
C _3-7 cycloalkyl refers to an optionally substituted carbocyclic ring system having from 3 to 7 carbon atoms, which may contain up to two unsaturated carbon-carbon bonds. Typical examples of C _3-7 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cycloheptyl. Any combination of up to three substituents on the cycloalkyl ring, as defined above for alkyl groups, which are available and stable by chemical synthesis are within the scope of the invention.
R ^b and R ^c are taken together to form a 5-or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic ring fused to a ring to which R ^b and R ^c are attached, Or a 5 or 6 membered heterocycle selected from those described above for Het, or a phenyl, cyclohexyl or cyclopentyl ring. Preferably, R ^b and R ^c are D 1 = D 2 -D 3 = D 4, wherein D 1 -D 4 are each CH, N or CR _x with the proviso that not more than two of D 1 -D 4 are N. Most preferably, when R &lt; ^b & gt ^; and R &lt; ^c &gt; are bonded together, they form a -CH = CH-CH = CH- group.
Certain radical groups are abbreviated herein. t-Bu refers to tertiary butyl lacqual, Boc refers to t-butyloxycarbonyl radical, Fmoc refers to fluorenylmethoxycarbonyl radical, Ph refers to phenyl radical, Cbz refers to benzyloxycarbonyl radical BrZ refers to an o-bromobenzyloxycarbonyl radical, ClZ refers to an o-chlorobenzyloxycarbonyl radical, Bzl refers to a benzyl radical, 4-MBzl refers to a 4-methylbenzyl radical, Methyl refers to ethyl, Et refers to ethyl, Ac refers to acetyl, Alk refers to C _1-4 alkyl, Nph refers to 1- or 2-naphthyl, and cHex refers to cyclohexyl. Tet refers to 5-tetrazolyl.
Certain reagents are abbreviated herein. DCC refers to dicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, DIEA refers to diisopropylethylamine, EDC refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, hydrochloride . HOBt is 1-hydroxybenzotriazole, THF is tetrahydrofuran, DIEA is diisopropylethylamine, DME is dimethoxyethanol, DMF is dimethylformamide, NBS is N-bromo-succinic acid Propanephosphonic acid cyclic anhydride; DPPA is diphenylphosphoryl azide; BOP is benzotriazol-1-yloxy-tris (dimethyl- Amino) phosphonium hexafluorophosphate, HF refers to hydrofluoric acid, TEA refers to triethylamine, TFA refers to trifluoroacetic acid, and PCC refers to pyridinium chlorochromate.
Compounds of formula I-V are prepared, for example, by reacting compounds of formula (XIX) with compounds of formula (XX) by methods generally known in the art.

(Wherein L &lt; ^{1 &gt;} and L &lt; ² &gt; are groups capable of reacting to form a covalent bond in the W part)
Typical methods include coupling to form amide bonds, nucleophilic substitution reactions, and palladium catalyzed coupling. For example, when W contains an ether or an amine linkage, this bond may be formed by a displacement reaction, one of L ¹ and L ² will contain an amino or hydroxy group and the remainder is a displaceable group, For example, chloro, bromo or iodo groups. When W contains an amide bond, typically one of L &lt; ^{1 &gt;} and L &lt; ² &gt; will contain an amino group and the remainder will contain a carboxy group. In another approach, L &lt; ¹ &gt; may be an aryl or heteroaryl bromide, iodide or trifluoromethylsulfonyloxy derivative, L &lt; ² &gt; contains an amino group and the amide bond is carbon monoxide And palladium-catalyzed aminocarbonylation.
It is clear that the exact identity of L ¹ and L ² will depend on the bond forming site. The general method of preparation of the linkage- (CHR ") _r -U- (CHR") _s -V- is for example described in EP-A 0 372 486 and EP-A 0 381 033 and EP- 363, the disclosures of which are incorporated herein by reference.
For example, if V is CONH, L ¹ will be -NH ₂ , L ² will be OH (in acid) or Cl (in acid chloride) and R ^{6 "} is W- (CR ' ₂ ) _q -Z - (- amidino benzyloxycarbonyl). R ^{6 "is} (CR'R ¹⁰⁾ _r can be a _{-U- (CR '2) s -C} (O), the functional group may be optionally protected, for example, Benzoyl- or (N ^alpha -Boc, N ^guan- Toos) arginyl-. When L &lt; ² &gt; is OH, a coupling agent is used.
Similarly, when V is NHCO, L ¹ can be -CO ₂ H or CO-Cl, L ² can be -NH ₂ , and R ^{6 "} is W- (CR ' ² ) _q -Z- (CR _{^{'R 10) r -U- (CR}} ' 2) s -. may be, for example, R ^{6 "is} (benzyloxycarbonyl-amidino) phenyl, (benzyloxycarbonylamino) methyl benzyl-or 6 - (benzyloxycarbonylamino) hexyl-. &Lt; / RTI &gt;
When V is NHSO ₂ , L ¹ may be SO ₂ Cl, L ² may be -NH ₂ , and R ^{6 "} may be as above. When V is SO ₂ NH, L ¹ is -NH ₂ L ² can be SO ₂ Cl. The method for preparing the sulfonyl chloride is described, for example, in J. Org. Chem., 23, 1257 (1958).
If V is CH = CH, L ¹ will be -CHO, L ² is P = CH-Ph ₃ days ^{will, R 6 "W- (CR '} 2) q -Z- (CR'R 10) r -U - (CR ' ² ) - Alternatively, L ¹ is CH = P-Ph ₃ and L ² is CHO, for example R ^{6 "} is W- (CR' ² ) _q -Z- ( CR'R ¹⁰ ) _r -U- (CR ' ² ) _s-1 -CHO.
When V is CH ₂ CH ₂ , it is obtained by reduction of an appropriate protected compound wherein V is CH = CH.
When V is CH ₂ O, CH ₂ N or C≡C, L ¹ can each be -OH, -NH or -C≡CH; L ² can be -Br; R ^{6 "'} may be W- (CR ^' ₂ ) _q -Z- (CR'R ¹⁰ ) _r -U- (CR ^' ₂ ) _s - For example, R ^6" Amino) -methylbenzyl- or 2- (N-benzyl-4-piperidinyl) -ethyl. Similarly, U or V may be OCH ₂ , NR'CH ₂ or C≡C, L ¹ may be -CH ₂ Br, and L ² may be -OH, -NH or -C≡CH. Alternatively, when U or V is C C, L ¹ may be Br, I or CF ₃ SO ₃ , L ² may be C≡CH, and the coupling may be catalyzed by palladium and a base.
V is CHOHCH ₂ the compound may be V is prepared by the procedures described in the literature [J.Org.Chem., 54, 1354 ( 1988)] from a suitably protected compound is CH = CH.
Compounds wherein V is CH ₂ CHOH can be prepared from an appropriately protected compound wherein V is CH = CH in Tet. Lett., 31, 231 (1990), by basic hydrolysis and basic oxidation.
The central 6-7 fused ring system of formula VI is prepared by methods well known in the art (see, for example, Hynes et al., J. Het. Chem., 1988, 25, 1173; Muller et al., Helv. Chim. Acta., 1982, 65, 2118; Mori et al., Heterocylces, 1981, 16, 1491). Similarly, processes for preparing benzazepines, 1,4-benzothiazepines, 1,4-benzoxazepines and 1,4-benzodiazepines are described, for example, in WO 93/00095 to Bondinel et al.
The preparation of the compounds of the present invention is described in detail in the following reaction schemes.
a) EtOAc / LiN (TMS) ₂ , THF; b) Et ₃ SiH, BF ₃ OEt ₂ , CH ₂ Cl ₂ ; c) H ₂ , 10% Pd / C, EtOH; _{d) EtSH, AlCl 3, CH} 2 Cl 2; e) Tf ₂ O, 2,6-lutidine, CH ₂ Cl ₂ ; f) CO, KOAc, Pd (OAc) ₂ , dppf, DMSO; g) 2- (methylaminomethyl) benzenimidazole dihydrochloride, EDC, HOBt.H ₂ O, (i-Pr) ₂ NEt, CH ₃ CN; h) 1.0 N NaOH, EtOH.
Suitably substituted deoxybenzoin such as 2- (4-methoxyphenyl) -1-phenylethanone (Chem, Ber. 1958, 91, 755-759) I-2 is obtained by aldol reaction with an enolate of ethyl acetate, which may be produced from ethyl acetate, in contact with propyl amide (LDA) or lithium bis (trimethylsilyl) amide (LiN (TMS) ₂ ). Though THF is mainly used in the presence of various additives such as HMPA or TMEDA, THF is generally a selected solvent for the aldol reaction. According to a general experimental scheme for the reduction of tertiary benzyl alcohol (Orphanopoulos and Smonu, Synth. Commun. 1988, 833), I-2 and triethylsilane in the presence of boron trifluoride etherate (BF ₃ .OEt ₂ ) (Et ₃ SiH), I-3 is obtained with the olefinic product derived from the -Removalion reaction of the alcohol. The olefinic product can be readily converted to I-3 by hydrogenation over a palladium catalyst such as palladium metal (Pd / C) on activated carbon in a suitable inert solvent such as, for example, methanol, ethanol or ethyl acetate. Removal of the methyl ether of I-3 to obtain I-4 can be carried out in the presence of a Lewis acid catalyst, preferably anhydrous trichloride (AlCl ₃ ), in an inert solvent such as CH ₂ Cl ₂ , ). &Lt; / RTI &gt; Other useful methods for the removal of methyl ether are described in Greene, &quot; Protective Groups in Organic Synthesis " (Wiley-Interscience). Alcohols I-4 can be obtained by reaction with trifluoromethanesulfonic anhydride (Tf ₂ O) in the presence of a suitable non-nucleophilic amine base such as 2,6-lutidine in an inert solvent, generally CH ₂ Cl ₂ , Is converted to its trifluoromethanesulfonate ester I-5. I-5 is prepared according to the general method for the carboxylation of the aryl trifluoromethanesulfonic acid salt (Cacchi and Lupi (Tet. Lett. 1992, 33, 3939)) in a suitable solvent, preferably DMSO, , 1.1'- bis (diphenylphosphino) in the presence of ferrocene (dppf), and a palladium catalyst, for instance lithium acetate palladium (Pd (OAc) _2), reacts with carbon monoxide (CO). The resulting benzoic acid derivative I-6 is converted to the active form of the carboxylic acid using, for example, EDC and HOBt, or SOCl ₂ , and the active form is then converted to the active form, such as DMF, CH ₂ Cl ₂ , or CH ₃ CN For example, 2- (methylaminomethyl) methylbenzimidazole dihydrochloride in a solvent to obtain I-7. Depending on the need for acid neutralization, diisopropylethylamine ((i-Pr) ₂ NEt) or an additional base such as pyridine may be used. A number of additional methods for converting carboxylic acids to amides are known and described in " Compendium of Organic Synthetic Methods &quot;, Vol. I-VI. (Wiley-Interscience publication) or Bodansky, &quot; The Practice of Peptide Synthesis &quot;, (Springer-Verlag Publ.). The ethyl ester of I-7 is hydrolyzed using aqueous bases, such as LiOH in aqueous THF or aqueous methanol or NaOH in ethanol, and the intermediate carboxylate salt is oxidized with a suitable acid, such as TFA or HCl Whereby a carboxylic acid I-8 is obtained. Alternatively, the intermediate carboxylate salt may be isolated or, if desired, the carboxylate salt of the free carboxylic acid may be prepared by methods known in the art.
a) isobutylene, TfOH, CH ₂ Cl ₂ ; b) methyl acrylate, Pd (OAc) ₂ , P (tol) ₃ , (i-Pr) ₂ NEt, propionitrile; c) H ₂ , 10% Pd / C, MeOH, EtOAc; d) 1.0 N LiOH, THF, H 2 O; e) Dimethylamine hydrochloride, EDC, HOBt.H ₂ O, (i-Pr) ₂ NEt, CH ₃ CN; _{f) LiN (TMS) 2,} THF, then BrCH ₂ CO ₂ Et; _{g) TFA, CH 2 Cl 2} ; h) 2- (methylaminomethyl) benzimidazole dihydrochloride, EDC, HOBt.H ₂ O, (i-Pr) ₂ NEt, CH ₃ CN; I) 1.0 N LiOH, THF, H 2 O.
The commercially available 4-bromobenzoic acid (II-1) can be obtained by reacting isobutylene with isobutylene in the presence of an acid catalyst such as trifluoromethanesulfonic acid (TfOH) or sulfuric acid in an inert solvent, typically CH ₂ Cl ₂ or diethyl ether. Butyl ester &lt; RTI ID = 0.0 &gt; II2 &lt; / RTI &gt; Other methods for the production of tert-butyl esters are described in "Protective Groups in Organic Synthesis," (Wiley-Interscience). Other esters can be used as long as they are used with subsequent chemistry, and can be selectively removed as needed. The II-3 is obtained by a Heck-type reaction between II-2 and methyl acrylate. General conditions for the Hek reaction have been elucidated by Hek (Org. Reactions 1982, 27, 345). In the presence of palladium (II) acetate (Pd (OAc) ₂ ) and tri-ortho-tolylphosphine (P (tol) ₃ ) in an inert solvent such as CH ₃ CN, propionitrile or toluene. In the presence of a suitable acid scavenger such as ethylamine ((i-Pr) ₂ NEt), II-2 and methyl acrylate react to give II-3. The reaction to obtain the saturated compound II-4 by reduction of an alpha, beta -unsaturated ester of II-3 is carried out in a standard hydrogenation environment, for example in an inert solvent, generally methanol, ethanol, ethyl acetate, Is carried out by reaction with hydrogen, in the presence of a catalyst, preferably palladium metal (Pd / C) on a slippery carbon. The methyl ester of II-4 is hydrolyzed using aqueous bases, such as LiOH in aqueous THF or aqueous methanol or NaOH in ethanol, and the intermediate carboxylate salt is acidified by a suitable acid, such as TFA or HCl Whereby a carboxylic acid II-5 is obtained. This compound is converted to the active form of the carboxylic acid using, for example, EDC and HOBt, or SOCl ₂ , and the activated form is then reacted with a suitable amine in a suitable solvent such as DMF, CH ₂ C ₂ or CH ₃ CN, For example, II-6 is obtained by reacting with dimethylamine hydrochloride. Depending on the need for acid neutralization, diisopropylethylamine ((i-Pr) ₂ NEt) or an additional base such as pyridine may be used. A number of additional methods for converting carboxylic acids to amides are known and described in " Compendium of Organic Synthetic Methods &quot;, Vol. I-VI. (Wiley-Interscience publication) or Bodansky, &quot; The Practice of Peptide Synthesis &quot;, (Springer-Verlag Publ.). (II) is reacted with II-6 and an amide base such as lithium bis (trimethylsilyl) amide (LiN (TMS) ₂ ), sodium bis (trimethylsilyl) amide (NaN (TMS) ₂ ), potassium bis (trimethylsilyl) amide (KN (TMS) ₂ ), or lithium diisopropylamide (LDA). This compound is generally reacted with a nucleophile, e. G. Ethyl bromoacetate, in situ, rather than isolated, to give the alkylated product II-7. Various additives known in the art such as HMPA, tetramethylethylenediamine (TMEDA) or 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU ) Is used to improve the efficiency of the alkylation reaction. The tert-butyl ester group of II-7 is removed under acidic conditions in an inert solvent, generally CH ₂ Cl ₂ , 1,4-dioxane, or a mixture thereof, generally with TFA or HCl to give the acid II-8 Loses. Other useful methods for removing tert-butyl esters are described in Greene, &quot; Protective Groups in Organic Synthesis &quot; (Wiley-Interscience). II-8 is converted to II-9 under the general conditions described in Scheme I where I-6 is converted to I-7, II-9 is converted to II-9 under the general conditions described in Scheme I where I- 0.0 &gt; II-10. &Lt; / RTI &gt;
a) 3- carboxylic bome ethoxy propionyl _{chloride, (i-Pr) 2 NEt} , CH 2 Cl 2; b) 0.1 N NaOH, MeOH; c) ethyl 3-amino-4-pentenoate, EDC, HOBt.H ₂ O, (i-Pr) ₂ NEt, CH ₃ CN, DMF; d) 1.0 N LiOH, THF, H 2 O, CH 3 CN.
Under this membrane is manufactured of 2- (2-aminoethyl) benzimidazole, neutral solvent, generally in the presence of a suitable acid scavenger such as triethylamine, diisopropylethylamine, or pyridine in CH ₂ Cl _2, 3- Carbomethoxypropionyl chloride to give III-2. The methyl ester of III-2 is hydrolyzed under the general conditions described in Scheme I where I-7 is converted to I-8 to give III-3. Alternatively, III-1 can be reacted with succinic anhydride in the presence of a suitable base such as triethylamine, diisopropylethylamine, or pyridine, generally in CH ₂ Cl ₂ , in a neutral solvent. III-3 is converted to III-4 by reaction with the known ethyl 3-amino-4-pentynoate under the general conditions described in Scheme I in which I-6 is converted to I-7 (WO93 / 07867). Hydrolysis of the ethyl ester of III-4 to III-5 is carried out under the general conditions described in Scheme I where I-7 is converted to I-8.
a) Methyl 4- (chloro-formyl) butyrate, Et ₃ N, THF; b) AcOH; c) 1.0 N NaOH, MeOH; d) Boc-Gly, EDC, HOBt.H ₂ O, (i-Pr) ₂ NEt, CH ₃ CN; _{e) TFA, CH 2 Cl 2} ; f) 3, EDC, HOBt · H 2 O, (i-Pr) 2 NEt, CH 3 CN ;, g) 1.0 N LiOH, THF, H 2 O.
The synthesis of IV-8 is carried out by the reaction of two respective prepared intermediates, IV-3 and IV-6. Synthesis of Intermediate IV-3 is initiated by a commercially available 2,3-diaminopyridine (IV-1). According to this scheme, IV-1 is prepared by reacting methyl 4- (chloropyridine) in the presence of a suitable acid scavenger such as triethylamine, diisopropylethylamine, or pyridine in a neutral solvent, typically CH ₂ Cl ₂ or THF Methyl) butyrate to obtain an intermediate monoacylated derivative. This derivative is then cyclized using, for example, refluxing acetic acid to give IV-2. IV-2 is hydrolyzed under the general conditions described in Scheme I in which I-7 is converted to I-8 to give IV-3. Preparation of intermediate IV-6 was carried out in the same manner as in Example 1, except that tert-butoxycarbonylglycine (Boc-Gly) commercially available under standard peptide bond formation conditions described in Scheme 1 in which I-6 was converted to I-7 and the reference Bodansky publication ) And the known ethyl 3-amino-4-phenytoate (WO 93/07867). The product IV-5 of this reaction is deprotected to IV-6 under known acidic conditions to effect Boc protecting group removal. Such conditions are described in Bodansky and Greene. The two intermediates IV-3 and IV-6 are coupled under the standard peptide coupling conditions as described, to give IV-7, which is converted to I-7 according to the general method described in Scheme I, -8. &Lt; / RTI &gt;
_{a) (Boc) 2 O,} DMAP, CH 3 CN; b) isobutyl chloroformate, Et ₃ N, THF, and then 1,2-phenylenediamine, then AcOH; c) (n-Bu ₃ Sn) ₂ , (PPh ₃ ) ₂ PdCl ₂ , DMF; _{d) CuI, (PPh) 3} PdCl 2, DMF; e) 4M HCl / dioxane; f) 1.0 N NaOH, MeOH.
Synthesis of V-7 is accomplished by the reaction of two respective prepared intermediates, V-2 and V-5. V-2 can be prepared by reacting a compound of formula (I) in the presence of an acylation catalyst, preferably 4-dimethylaminopyridine (DMPA) or 4-pyrrolidinopyridine, in a neutral solvent such as CH ₃ CN, THF or CH ₂ Cl ₂ (D-tert-butyl dicarbonate ((Boc) ₂ O). Preparation of intermediate V-5 is initiated by commercially available 3-iodobenzoic acid (V-3) and is converted to the benzimidazole derivative V-4. According to this scheme, V-3 is reacted with isobutyl chloroformate in the presence of a suitable amine base, such as triethylamine, diisopropylethylamine, or 4-methylmorpholine, in a neutral solvent, typically CH ₂ Cl or THF And reacted with the mormite to obtain an intermediate mixed anhydride derivative. Without isolation, the derivative reacts with the appropriate phenylenediamine to give the mono-N-acylated phenylenediamine intermediate. This intermediate is then cyclized to V-4 using acetic acid. (Triphenylphosphine) palladium (II) chloride ((PPh ₃ ) ₂ PdCl ₂ ) in an inert solvent, generally DMF, in the reaction of V-4 with bis (tributyltin) &Lt; / RTI &gt; under a palladium catalyst. The Stille type coupling of V-2 and V-5 from which V-6 is obtained can be carried out in the presence of copper (I) iodide (CuI) in a suitable neutral solvent, generally DMF, Phenylphosphine) palladium (II) chloride ((PPh ₃ ) ₂ PdCl ₂ ). To obtain V-7, the protecting group of V-6 is removed by a well-established method as described in the literature [Greene publication] which is known and cited in the art. That is, the Boc protecting group is removed in an acidic environment such as 4M HCl in dioxane or TFA in CH ₂ Cl ₂ , and the methyl ester is hydrolyzed under the general conditions described in Scheme I where I-7 is converted to I-8.
a) 3- _{butylene-1-ol, (PPh 3) 2 PdCl 2} , PPh 3, CuI, Et 3 N; b) H ₂ , 10% Pd / C, EtOH; c) 2,2,6,6-tetramethyl-oxopiperidinium chloride, CH ₂ Cl ₂ followed by NaClO ₂ , Na ₂ HPO ₃ , 2-methyl-2-butene, H ₂ O; d) isobutyl chloroformate, Et ₃ N, followed by 1,2-phenylenediamine, then AcOH; e) 1.0 N LiOH, THF, H2O; f) TFA, CH ₂ Cl ₂
Preparation of the compounds described in Scheme V VI-1 was triethylamine (Et ₃ N) In general, bis (triphenyl from such an amine solvent, the amount of catalyst with copper iodide (I) (CuI) a catalytic amount of a palladium catalyst, and the alkylene phosphine) palladium (II) chloride ((PPh _{3) 2} in the presence of PdCl _2, 3- butylene-1-ol and the reaction to the VI-2 can be obtained. triphenylphosphine (PPh ₃₎ and a phosphine such as The reduction of the acetylenic unit VI-2 is carried out under standard hydrogenation conditions known in the art. The resulting compound, VI-3, can be prepared according to the procedure described in Wovkulich, J. Org. Chem 1993, 58, 832-839. A number of other processes for the oxidation of primary alcohols to the corresponding carboxylic acid have been described, (See " Compendium of Organic Synthetic Methods &quot;, Wiley-Interscience, The conversion of the carboxylic acid of VI-4 to the benzimidazole derivative VI-5 follows the procedure described in the above scheme. The methyl ester of VI-5 is removed as described in the above scheme and the Boc The protecting group is removed under acidic conditions such as 4M HCl in dioxane or TFA in CH ₂ Cl ₂ to give VI-6.
a) 1,2- _{phenylenediamine, DCC, DMF, CH 2 Cl} 2; b) AcOH, THF; c) TsCl, NaH, THF; d) O ₃ , CH ₂ Cl ₂ , MeOH, then DMS; _{e) NH 2 OH · HCl,} NaOAc, MeOH; f) NCS, DMF; g) tert- butyl-3-pentenoate unit, Et ₂ N; h) 4M HCl / dioxane, CH ₂ Cl _2; i) ethyl 3-aminobutyrate, EDC, HOBt.H ₂ O, (i-Pr) ₂ NEt, CH ₃ CN; j) 1.0 N LiOH, THF, H 2 O.
Commercially available 4-pentenoic acid (VII-1) is converted to the benzimidazole derivative VII-2 using the general method described above. The protection of one of the nitrogen elements of the benzamidazole residue in VII-2 is carried out in the presence of a suitable base, usually sodium hydride or aqueous alkali metal hydroxide, in an inert solvent, preferably THF, in the presence of a sulfonyl chloride, for example p- Is carried out by reaction with sulfonyl chloride to give VII-3. Other protecting groups known in the art can be used and removed as needed, as long as they are compatible with subsequent chemistry. These protecting groups are described in Greene, " Protective Groups in Organic Synthesis " (Wiley-Interscience). The oxidative decomposition of the olefin of VII-3, in which the aldehyde VII-4 is obtained, can be carried out by saponification in an inert solvent, typically a mixture of CH ₂ Cl ₂ or CH ₂ Cl ₂ and MeOH, followed by a suitable reducing agent, (DMS) or triphenylphosphine by the same reduction of ozone. Other methods for oxidative decomposition such as the Lemieux-Johnson reaction (J. Org. Chem. 1956, 21, 487) may also be used. The aldehyde is converted to aldocin (VII-5) by standard procedures known in the art and the aldocin is converted to the oxycinnamoyl chloride derivative (VII-5) by the method described in WO 95/14682 and WO 95/14683 VII-6. For example, in the presence of a suitable base such as triethylamine or diisopropylethylamine in an inert solvent such as benzene or toluene according to the experimental protocol described in WO 95/14682 and WO 95/14683, The cyclization product I-7 is obtained by the reaction of VII-6 with olefins such as butenes (Tet. Lett. 1985, 26, 381-384). The tert-butyl ester VII-7 is removed under standard acidic conditions, typically TFA in CH ₂ Cl ₂ or HCl in dioxane to give the carboxylic acid VII-8. The carboxylic acid is activated, for example using EDC and HOBt, or SOCl ₂ , and the activated form is then reacted with a suitable amine such as DMF, CH ₂ Cl ₂ or CH ₃ CN in a neutral solvent, VII-9 is obtained by reacting with a suitable derivative. Depending on the need for acid neutralization, diisopropylethylamine ((i-Pr) ₂ NEt) or an additional base such as pyridine may be used. A number of additional methods for converting carboxylic acids to amides are known and described in "Compendium of Organic Synthetic Methods", Vol. I-VI. (Wiley-Interscience publication) or Bodansky, " The Practice of Peptide Synthesis " (Springer-Verlag publication). Derivatives of [beta] -alanine are readily available in racemic or optically pure forms by a variety of methods known in the art. Representative methods are described in WO 93/07867. The ethyl ester and sulfonyl protecting group of VII-9 are removed using aqueous bases, for example LiOH in THF or aqueous methanol or NaOH in ethanol. The intermediate carboxylate salt is oxidized with a suitable acid, such as TFA or HCl, to give the carboxylic acid VII-10. Alternatively, the intermediate carboxylate salt can be isolated if desired, or the carboxylate salt of the free carboxylic acid can be prepared by methods known in the art.
a) COCl ₂ in toluene, Na ₂ CO ₃ , H ₂ O; b) -alanine benzyl ester tosylate, DMAP, pyridine; c) CH ₃ I, 2,6- flow tidin, DMF; d) BrCH ₂ COBr, Et ₃ N, CH ₂ Cl ₂ ; e) NaH, DMF; f) CO, (Ph ₃ P) ₂ PdCl ₂ , DIEA, 2- (methylaminomethyl) benzimidazole dichloride, NMP; g) H ₂ , Pd / C, EtOH.
Compound VIII-5 was synthesized according to the procedures of US 5,403,363 and WO 950457 except that 2-amino-4-iodobenzoic acid was used instead of 2-amino-5-iodobenzoic acid (VIII- . In the presence of a palladium catalyst, preferably (Ph ₃ P) ₂ PdCl ₂ , in an inert solvent, optionally 1-methyl-2-pyrrolidinone (NMP) Methyl) benzimidazole with VIII-5 gives amide VIII-6. Depending on the need for acid neutralization, diisopropylethylamine (DIEA) or an additional base such as pyridine may be used. The benzyl ester of VIII-6 is removed under standard hydrolysis conditions known in the art to give VIII-7. Alternatively, the benzyl ester can be saponified using an aqueous base, for example LiOH in aqueous THF, or aqueous methanol or NaOH in ethanol. The intermediate carboxylate salt is oxidized by a suitable, for example TFA or HCl, to obtain the carboxylic acid. If necessary, the intermediate carboxylate salt of VIII-7 may be isolated, or a suitable salt of the carboxylic acid may be prepared by methods known in the art.
a) -alanine ethyl ester hydrochloride, DMAP, pyridine; b) BrCH ₂ COBr, Et ₃ N, CH ₂ Cl ₂ ; c) NaH, DMF; d) Lawesson's reagent, THF, 50 &lt; 0 &gt;C; e) CH ₃ I, (n-Bu) ₄ NHSO ₄ , NaOH, CH ₂ Cl ₂ , H ₂ O; f) propargylamine, pyridine.HCl, toluene; g) CO, (Ph ₃ P) ₂ PdCl ₂ , DIEA, 2- (methylaminomethyl) benzimidazole dichloride, NMP; _{h) LiOH, THF, H 2} O.
Compound IX-6 was prepared according to the procedures of US 5,403,836 and WO 950457 except that 4-iodo iso-anhydride (IX-1, see Scheme I), which was not 5-iodo iso-anhydride, . IX-6 is converted to IX-7 according to the procedure described in Scheme XIII, where XIII-5 is converted to XIII-7.
a) 1-Boc- _{piperazine, NaBH 3 CN, HCl, MeOH} ; b) 4M HCl / dioxane, CH ₂ Cl _2; c) SOCl ₂ , CH ₂ Cl ₂ ; d) 3, DIEA, DMF; e) 1.0 N NaOH, MeOH.
The readily available 1- (ethoxycarbonylmethyl) -4-piperidone (X-1, EPA 0 542 363 A2) is reacted with commercially available 1-Boc-piperazine and a suitable reducing agent, preferably sodium cyanoboron Amine X-2 is obtained by reductive amination with hydride. This reaction is generally carried out with HCl in an acidic solvent, such as methanol or ethanol, generally under an acidic catalyst. The Boc protecting group is removed under acidic conditions, preferably HCl / dioxane or TFA in a suitable solvent such as CH ₂ Cl ₂ to give amine X-3. This can be done by reacting with 2- (2-chloroethyl) benzimidazole (X-5) in the presence of a suitable acid scavenger in a polar solvent, preferably DMF, for example diisopropylethylamine (DIEA) Product X-6 is obtained. 2- (2-chloroethyl) imidazole-benzamide is an inert solvent, for example in CH ₂ Cl _2, the presence of triphenylphosphine, by reaction with a suitable halogenation reagent such as thionyl chloride or carbon tetrachloride, 2- ( 2-hydroxyethyl) benzimidazole. The ethyl ester of X-6 is removed using an aqueous base, for example LiOH in aqueous THF or aqueous methanol or NaOH in ethanol. The intermediate carboxylate salt is oxidized by a suitable acid, such as TFA or HCl, to give the carboxylic acid X-7. Alternatively, if necessary, the intermediate carboxylate salt may be isolated, or the carboxylate salt of the free carboxylic acid may be prepared by methods known in the art.
a) 2- (3-bromopropyl) benzimidazole, DIEA, DMF; b) 4 M HCl / dioxane, CH ₂ Cl _2.
The readily available piperazine derivative XI-1 (EPA 0 537 980 A1) can be readily obtained in a polar solvent, preferably DMF, in the presence of a suitable acid scavenger such as diisopropylethylamine (DIEA) The coupled product XI-2 is obtained by reacting with 2- (3-bromopropyl) benzamidazole (J. Org. Chem. 1962, 27, 2165) available. The tert-butyl ester protecting group is removed under standard acidic conditions, preferably HCl / dioxane or TFA in a suitable solvent such as CH ₂ Cl ₂ to give the carboxylic acid XI-3. If desired, suitable salts of carboxylic acids may be prepared by methods known in the art.
a) 2- (benzimidazolyl) propionic acid, BOP-Cl, NMM, CH 2 Cl 2; _{b) LiOH, THF, H 2} O; c) benzyl -alaninate, EDC, HOBt.H ₂ O, NMM, CH ₂ Cl ₂ ; _{d) H 2, 10% Pd} / C, AcOH, THF, H 2 O.
WO 95/25091 of Beavers et al., The procedure of Example 1, except that N -Boc-D-lys (Cbz) -OH was replaced with 2- (benzimidazolyl) Followed by XII-4.
a) 2- (aminomethyl) benzimidazole, Et ₃ N, benzene; b) 1.0 N LiOH, MeOH, H 2 O; c) β-alanine ethyl ester, BOP, Et ₃ N, CH ₃ CN.
1-H-isoindole-5-carboxamide, for the preparation of 2,3-dihydro-N- (2-carboxy-ethyl) -2- [2- (piperidinyl) ethyl] Under the general conditions described (Processes 1-12 of EPA 0 540 334 A1), a suitably functionalized amine such as 2- (aminomethyl) benzoimidazole is reacted with dimethyl 4-bromomethylbenzene-1,3-dicarboxylate (XIII-1; synthesized in EP 0540334A1) to give XIII-2. The methyl ester of XIII-2 is hydrolyzed in a suitable base such as LiOH or aqueous methanol in aqueous THF or NaOH in ethanol, and the intermediate carboxylate salt is oxidized with a suitable acid, such as TFA or HCl Carboxylic acid XIII-3 is obtained. The carboxylic acid of XIII-3 is converted to the active form of the carboxylic acid using, for example, EDC and HOBt, SOCl ₂ , or BOP reagent, and the active form is then converted to the activated form of DMF, CH ₂ Cl ₂ , or CH ₃ CN In a suitable solvent, XIII-4 is obtained by reaction with a suitable amine, for example, beta -alanine ethyl ester. Depending on the need for acid neutralization, diisopropylethylamine ((i-Pr) ₂ NEt) or the necessary additional base such as pyridine may be used. A number of additional methods for converting carboxylic acids to amides are known and described in "Compendium of Organic Synthetic Methods", Vol. I-VI. (Wiley-Interscience publication) or Bodansky, " The Practice of Peptide Synthesis &quot;, (Springer-Verlag Publ.). Then, XIII-5 is obtained by the above-mentioned ester hydrolysis in which XIII-2 is converted to XIII-3. Alternatively, if necessary, the intermediate carboxylate salt of XIII-5 can be isolated, or the carboxylate salt of the free carboxylic acid can be prepared according to methods known in the art.
a) (Boc) ₂ O, NaOH, 1.4-dioxane, H ₂ O; b) BrCH ₂ CO ₂ Bn, K ₂ CO ₃ , acetone; c) 4 M HCl / dioxane; d) 2- (Benzimidazolyl) acetic acid, EDC, DIEA, DMF; e) H ₂ , 5% Pd / C, MeOH.
XIV-1 is treated with di-tert-butyl bicarbonate and sodium hydroxide in aqueous dioxane to afford XIV-2 and alkylated on oxygen with benzyl bromoacetate and potassium carbonate in acetone. The Boc group in XIV-3 is removed by hydrogen chloride in dioxane and the resulting XIV-4 is alkylated on nitrogen with (benzimidazolyl) acetic acid, EDC and DIEA in DMF. The benzyl ester in XIV-5 is treated with hydrogen and palladium on carbon in methanol to give XIV-6.
a) 2- (benzimidazolyl) acetic acid, EDC, DIEA, DMF; _{b) NaOH, H 2 O,} CH 3 OH.
XI-1, prepared as described in EP-A-0372486, such as Alig et al, is reacted with (2-benzimidazole) acetic acid in the presence of EDC and DIEA and in a suitable solvent such as DMF or acetonitrile Lt; RTI ID = 0.0 &gt; substituted &lt; / RTI &gt; carboxylic acid. A number of additional methods for converting carboxylic acids to amides are known and described in &quot; Compendium of Organic Synthesis &quot;, Vol. I-VI. (Springer-Verlag Publishing). The hydrolysis of the ester is carried out by saponification with a suitable reagent, for example sodium oxide, in a suitable solvent, such as aqueous methanol. Alternatively, the benzyl ester can be converted to the acid by treatment with a suitable catalyst, such as Pd / C and hydrogen, in a suitable solvent such as methanol, ethanol or acetic acid.
a) 2- (benzimidazolyl) acetic acid, EDC, DIEA, DMF; b) TFA
XVI-1 as described in EP 0505868, such as Alig et al., Is suitably substituted with a suitable substituent such as (2-benzimidazole) acetic acid in the presence of EDC and DIEA in a suitable solvent such as DMF or acetonitrile Lt; / RTI &gt; carboxylic acid. A number of additional methods for converting carboxylic acids to amides are known and described in " Compendium of Organic Synthesis &quot;, Vol. I-VI. (Springer-Verlag Publishing). Hydrolysis of the ester in XVI-2 is carried out by trifluoroacetic acid or hydrogen chloride to give XVI-3. Alternatively, the esters in XVI-2 can be saponified with a suitable reagent, such as 1N NaOH, in a suitable solvent, e.g. methanol.
a) 2- (benzimidazolyl) acetic acid, EDC, DIEA, DMF; b) TFA, CH ₂ Cl ₂
XVII-1 prepared as described in EP 0529858 by Sugihara et al. Is condensed with a suitably substituted carboxylic acid such as (2-benzimidazolyl) acetic acid and the tert-butyl ester is condensed According to the general procedure of Example 59 of the above patent application, such as XVII-3. Other additional methods for converting carboxylic acids to amides are known and described in " Compendium of Organic Synthesis ", Vol. I-VI. (Springer-Verlag Publishing).
a) 4- [2- (benzimidazolyl) methyl] phenol, Cs ₂ CO _3, DMF; b) TFA
Compound XVIII-1, prepared as disclosed in Austrian patent application AU-A-86926/91, such as Himmelsbach, is described in Wahlgren and Addison, J. Heterocycl. Such as 4- [2- (benzimidazolyl) methyl] phenol prepared by the general procedure described in the literature, Chem., 1989, 26, 541-3, Is treated according to the general method of Patent Document 3 (51) to obtain XVIII-2. Tert- butyl ester in XVIII-2 is according to the general procedure of the patent document, in Example 7 (3) of the power MEL Bark hydrolyzed by 1N NaOH in CH ₃ OH the XVIII-3 are obtained. Alternatively, the tert-butyl ester can be cleaved by TFA or HCl.
a) HO ₂ CCH ₂ Ph-4-CH ₂ CH ₂ CO ₂ CH ₃ , Ph ₂ POCl, Et ₃ N, DMAP, THF; _{b) NaH, DMF, BrCH 2} CO 2 CH 3; c) KOt-Bu is THF, DMF; _{d) KOt-Bu, CH 3} I, DMF; _{e) LiOH, THF, H 2} O.
XIX-5 is prepared using the procedure of Linz et al. EP 0567968 except that (2-benzimidazolyl) methanamine is used instead of 4-cyanoaniline.
a) ClCH ₂ CO ₂ Et, Et ₃ N, DMF; b) BBr _3; c) (CF ₃ SO) ₂ O; d) CO, Pd (OAc) 2, PPh 3, DIEA, NMP, NH 4 HCO 3, H 2 O; _{e) H 2 NR, EDC /} HOBt, DIEA, DMF; f) H ₂ NR, CO, Pd (OAc) ₂ , PPh ₃ , DIEA, NMP, NH ₄ HCO ₃ , H ₂ O; g) 1N NaOH, HOEt.
Scheme XX is a method for preparing a 1,2,3,4-tetrahydroisoquinoline compound, a typical fibrinogen receptor antagonist, as described in MJ Fisher et al. EP 0635492, filed January 25, 1995 . Thus, 6-methoxy-3,4-dihydroisoquinoline, such as compound XX-1, can be prepared as described in DJSall and GLGrunewald, J. Med. Chem. 1987, 30, 2208-2216. The isoquinoline is treated with a haloacetic ester in the presence of a tertiary amine to obtain the 2-acetic acid ester represented by the formula (XX-2). The 6-methoxy compound is converted to the corresponding 6-hydroxy compound by, for example, BBr ₃ , by a method known in the art, and is converted to triflate by trifluorosulfonic acid anhydride. Carboxy compounds such as XX-5 are obtained by palladium-catalyzed carbonylation and then condensed with amines exemplified by (2-benzimidazolyl) acetic acid using standard amide coupling reagents to give compounds of formula XX- Preferred amides such as 6 are obtained. Alternatively, the palladium-catalyzed carbonylation reaction with the triflate exemplified by compound XX-4 is trapped with the aminomethyl compound and after saponification the corresponding 6- (2-benzimidazolyl) methylaminocarboxylic acid A benzyl compound, XX-7 is obtained.
a) 1. LiN (TMS) ₂ , 2. ClCH ₂ CO ₂ Et, DMF; b) BBr _{3; c) (CF 3 SO 2)} 2 O; d) CO, Pd (OAc) 2, PPh 3, DIEA, NMP, NH 4 HCO 3, H 2 O; _{e) H 2 NR, EDC /} HOBt, DIEA, DMF; f) H ₂ N-RCO, Pd (OAc) ₂ , PPh ₃ , DIEA, NMP, NH ₄ HCO ₃ , H ₂ O; g) 1N NaOH, HOEt.
Scheme XXI illustrates the preparation of a typical fibrinogen receptor antagonist 3,4-dihydroisoquinolin-1-one compound, as described in MJ Fisher et al. EP 0635492, filed January 25, &Lt; / RTI &gt; That is to say, D. J.Sall and G. L. Grunewald, J. Med. Chem. The 1-oxo compound XXI-1 prepared by the method described in &lt; RTI ID = 0.0 &gt; 1987,₂ And a haloacetic acid ester to give the 2-acetic acid ester exemplified by XXI-2. The 1-oxo compound is then used in a similar series of reactions listed in Scheme XX to yield XXI-7 by substituting the corresponding 1-oxo analog as shown in Scheme XXI. Alternatively, in Scheme XX, a palladium-catalyzed carbonylation reaction with a triflate exemplified by compound XXI-4 is trapped with an amine to give the amide XXI-7 after saponification.
a) RCO-X; b) TFA / CH ₂ Cl ₂
Scheme XXII provides a method for preparing a 6-acylaminotetralin compound, a typical fibrinogen receptor antagonist, as described in M. J. Fisher et al. EP 0635492, filed January 25, Namely, 6-amino-2-tert-butyloxycarbonyl-tetra (2-tert-butyloxycarbonyl) -propylamine represented by the formula XXII-1 prepared by the method described in EP 0635492 by MJ Fisher et al., Filed on January 25, -1-one is condensed with an activated derivative of a carboxylic acid, such as an activated derivative of (2-benzimidazolyl) acetic acid, to obtain the amide, XXII-2, after de-esterification.
a) CF ₃ SO ₂ O; b) CO, Pd (OAc) 2, PPh 3, DIEA, NMP, NH 4 HCO 3, H 2 O; _{c) H 2 NR, EDC /} HOBt, DIEA, DMF; d) H ₂ NR, CO, Pd (OAc) ₂ , PPh ₃ , DIEA, NMP, NH ₄ HCO ₃ , H ₂ O; e) 1N NaOH, HOEt.
Scheme XXIII provides a method for preparing a 6-aminoacyltetralin compound, a typical fibrinogen receptor antagonist, as described in M. J. Fisher et al. EP 0635492, filed January 25, 1995. That is to say, the ethyloxycarbonylmethyl-6-hydroxy-tetral-thiophene-2-carboxaldehyde compound, exemplified by Compound XXIII-1, prepared by the method described in EP 0635492 by MJ Fisher et al., Filed on January 25, 1995, 1-one is treated with triflic anhydride to give the triplet of formula XXIII-2, which is used in a palladium-catalyzed carbonylation reaction to give the carboxylic acid as compound XXIII-3, followed by condensation with an amine And after the esterification, a 6-aminoacyl compound, XXIII-5, is obtained. Alternatively, the palladium-catalyzed carbonylation reaction with the triflate exemplified by compound XXIII-2 is trapped with the amine compound and after saponification the corresponding 6-aminoacyl compound, XXIII-5, is obtained.
a) BrCH ₂ CO ₂ Et, K ₂ CO ₃ , NaI; b) 1. DBU, EtOH, 2. HCl, EtOH; c) DiBAL, -78 &lt; 0 &gt;C; d) NaH, THF; e) H ₂ , 10% Pd-C; f) R ₂ CO-X; g) 1N NaOH, MeOH
Reaction Scheme XXIV is prepared by reacting 5-acylaminobenzofuran and 5-acylamino dihydrobenzofuran, a typical fibrinogen receptor antagonist, as described in EP 0655439 by ML Denney et al., Filed May 31, 1995 Of the present invention. Namely, the 4-nitrosalicylaldehyde represented by the compound XXIV-1 is treated with a haloacetic acid ester to obtain the phenoxyacetic acid ester represented by the compound XXIV-2. The 2-alkoxycarbonylfuran exemplified by the compound XXIV-3 is obtained by treating an aldehyde with a base, for example DBU. The 2-alkoxycarbonyl group is reduced to aldehyde by, for example, DiBAL. The Wittig reaction gives the 2-acrylate esters exemplified by compound XXIV-4, and the benzofuran-2-propionic acid ester exemplified by compound XXIV-5 and the dihydrobenzofuran represented by compound XXIV-6 -2-propionic acid ester. The amine XXIV-5 is then condensed with an activated derivative of the carboxylic acid to give amides 5, XXIV-8 after esterification. Alternatively, the amine XXIV-6 is condensed with an activated derivative of the carboxylic acid to give the esterified amide, XXIV-7.
a) 1. TBDMS-Cl, amidazole; b) DiBA1-H, -78 [deg.] C, d) NaH, THF; e) H ₂ , 5% Pd-C; f) Et ₂ N + F-
_{a) (CF 3 SO 2)} 2 O; b) CO, Pd (OAc) 2, PPh 3, DIEA, NMP, NH 4 HCO 3, H 2 O; _{c) H 2 NR, EDC /} HOBt, DIEA, DMF; d) H ₂ NR, CO, Pd (OAc) ₂ , PPh ₂ , DIEA, NMP, NH ₄ HCO ₃ , H ₂ O; e) 1N NaOH, EtOH.
_{a) (CF 3 SO 2)} 2 O; b) CO, Pd (OAc) 2, PPh 3, DIEA, NMP, NH 4 HCO 3, H 2 O; _{c) H 2 NR, EDC /} HOBt, DIEA, DMF; d) H ₂ NR, CO, Pd (OAc) ₂ , PPh ₂ , DIEA, NMP, NH ₄ HCO ₃ , H ₂ O; e) 1N NaOH, EtOH
Scheme XXV is prepared by reaction of 5-acylaminobenzofuran and 5-aminoacyl dihydrobenzofuran, a typical fibrinogen receptor antagonist, as described in EP 0655439 by ML Denney et al., Filed May 31, 1995 Of the present invention. Namely, 5-hydroxybenzofuran-2-carboxylic acid esters such as compound XXIVa-1, prepared as described in EP 0655439, such as ML Denney et al., Filed May 31, 1995, Cl &lt; / RTI &gt; to give the TBDMS derivative, XXVa-2, of the ester. The ester is reduced to an aldehyde such as compound XXVa-3. The acrylic acid ester, XXVa-4, is obtained by the Wittig reaction. By catalytic reduction, benzofuran-2-acetic acid ester and dihydrobenzofuran-2-acetic acid ester are obtained. The benzofuran-2-acetic acid ester, XXVa-5, or dihydrobenzofuran-2-acetic acid ester, XXVa-6, is obtained by decomposition of the silyl ether group of each ester by a method known in the art.
As shown in Schemes XXVb and XXVc, each alcohol can then be converted to the carboxylic acid by palladium-catalyzed carbonylation, such as compound XXVb-2 or XXVc-2, by palladium catalysed carbonylation, And amide XXVb-4 or XXVc-4 is obtained after de-esterification. Alternatively, the palladium-catalyzed carbonylation reaction with the triflate exemplified by compound XXVb-1 or XXVc-1 is trapped with the aminomethyl compound and, after de-esterification, the corresponding 6-aminoacyl compound, XXVb -4 or XXVc-4 is obtained.
Amide coupling reagent as used herein means a reagent capable of forming a peptide bond. Typical coupling methods use carbodiimides, activated anhydrides and esters, and acyl halides. Reagents such as EDC, DCC, DPPA, PPA, BOP reagents, HOBt, N-hydroxysuccinimide and oxalyl chloride are typical.
Coupling methods to form peptide bonds are generally known in the prior art. Peptide synthesis methods are generally described in Bodansky et al., The PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984, Ali et al., J. Med. Chem., 29, 984 (1986) and J. Med. , 2291 (1987)) and are generally described in the art and incorporated herein by reference
Typically, an amine or an aniline is reacted with a suitable carbodiimide coupling agent, such as N, N'-dicyclohexylcarbodiimide (DCC), via its free amino group, optionally in the presence of 1-hydroxybenzotriazole (HOBt) and dimethylaminopyridine (DMAP) in the presence of a suitable carboxylic acid substrate. Other methods are also suitable, such as the formation of an activated ester, anhydride or acid halide of the free carboxyl of an appropriately protected acid substrate, and subsequent reaction with the free amine of a suitably protected amine optionally in the presence of a base. For example, the protected Boc-amino acid or Cbz-amidinobenzoic acid can be reacted with an iso-propanediol in the presence of a base such as N-methylmorpholine, DMAP or trialkylamine in an anhydrous solvent such as methylene chloride or tetrahydrofuran (THF) Is treated with butyl chloroformate to form the " activated anhydride ", which is subsequently reacted with the free amine of the second protected amino acid or aniline.
Compounds of formulas XIX and XX may be prepared by methods known in the art, such as those described in standard or reference references and exemplified herein (Wiley-Interscience, COMENDIUN OF ORGANIC SYNTHETIC METHODS, Vol. ). Typical routes for benzimidazole are described in Nestor et al., J. Med. Chem. 1984, 27, 320). Representative methods for the preparation of compounds of formula XX are also known in the art and are described, for example, in EP-A 0 381 033.
The acid addition salts of the present compounds may be prepared from the parent compound and an excess of an acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacid, maleic acid, succinic acid or methanesulfonic acid in a suitable solvent do. Most compounds form acceptable internal salts or amphoteric ions. With an excess of an alkaline reagent such as a hydroxide, carbonate or alkoxide containing a suitable cation; Or by treating the parent compound with a suitable organic amine. Specific examples of cations present in pharmaceutically acceptable salt is a ^{Li +, Na +, K +} , Ca ++, and Mg ⁺⁺ cations, such as NH ₄ ^+.
The present invention provides a pharmaceutical composition comprising a compound according to Formulas I to V and Formulas XXI to XXII and a pharmaceutically acceptable carrier. Accordingly, the compounds of formulas (I) to (V) and (XXI) to (XXII) can be used for the preparation of medicaments. The pharmaceutical compositions of formulas (I) through (V) and (XXI through XXII) prepared as described above may be formulated as liquid or lyophilized powders for parenteral administration. Powders may be formulated prior to use by addition of a suitable diluent or other pharmaceutically acceptable carrier. The liquid formulation may be an isotonic buffered aqueous solution. Examples of suitable diluents are conventional isotonic saline, standard 5% dextrose in water or sodium or ammonium acetate buffer. Such formulations are particularly suitable for parenteral administration, but may be used for oral administration or may be contained in a metered dose inhaler or inhaler for inhalation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy-cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
Alternatively, these compounds may be formulated as encapsulated, tableted or emulsions or syrups for oral administration. A pharmaceutically acceptable solid or liquid carrier may be added to improve or stabilize the composition or to facilitate the preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, brine and water. The carrier may also contain a sustained release material, such as glyceryl monostearate or glyceryl distearate, either alone or in combination with the wax. The amount of solid carrier is varied, but is preferably from about 20 mg to about 1 g per dosage unit. The pharmaceutical preparation may be pulverized, mixed, granulated and compressed in the case of tablet form, if necessary; Or in the case of hard gelatine capsules, may be prepared according to conventional pharmaceutical techniques, including grinding, mixing and filling. When a liquid carrier is used, the preparation may be in the form of a syrup, an elixir, an emulsion or an aqueous or non-aqueous suspending agent. Such liquid formulations may be administered orally or directly in soft gelatine capsules.
For rectal administration, the compounds of the present invention may also be mixed with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycol to form suppositories.
The compounds described herein are antagonists of the vitronectin receptor and are useful for the treatment of diseases caused by ligands or cells in which the following pathologies interact with the bitronectin receptor. For example, these compounds are useful in the treatment of diseases that cause pathologies due to the loss of bone matrix. Thus, the present compounds are useful for the treatment of bone loss due to osteoporosis, hyperparathyroidism, Paget's disease, hypercalcemia of malignant lesions, keel lesions produced by bone metastases, fixed or sex hormone deficiency. The compounds of the present invention have utility as antitumor agents, antiangen agents, anti-inflammatory agents and anti-convulsants and are useful for the treatment of atherosclerosis and stenosis.
The present compounds are administered orally or parenterally to the patient in such a manner that the concentration of the drug is sufficient to inhibit aggregate uptake or other applications. The pharmaceutical compositions containing the peptides are administered in an oral dosage of about 0.1 to about 50 mg / kg in a manner consistent with the condition of the patient. Oral administration is preferably about 0.5 to about 20 mg / kg. In the case of acute treatment, parenteral administration is preferred. Intramuscular bolus injection may be sufficient, but intravenous injection of 5% dextrose in water or a peptide in normal saline or similar formulations is most effective. Typically, parenteral administration will range from about 0.01 to about 100 mg / kg; Preferably 0.1 to 20 mhg / kg. The compound is administered one to four times daily at a level that achieves a total daily dose of from about 0.4 to about 400 mg / kg / day. The exact level and method of administration of the compound can be readily determined by those skilled in the art by comparing the blood level of the preparation with the concentration required to have a therapeutic effect.
The present compounds can be tested with one of several biological assays to determine the concentration of a compound required to have a certain predetermined pharmacological effect.
Bitronectin binding inhibition
α _ν β ₃ that bind to the solid-phase ^{[3 H] -SK & F-} 107260: human placenta or human platelet buffer T in ₍₂ mM CaCl 2 and 1% octyl glucoside _{containing) α ν β 3 (0.1-0.3 mg} / mL) was diluted with a buffer T containing 1 mM CaCl ₂ , 1 mM MnCl ₂ , 1 mM MgCl ₂ (buffer A) and 0.05% NaN ₃ , and then diluted with a 96-well ELISA plate (Corning, New York, NY). 0.1 to 0.2 μg of _{v 3} was added per well. Plates were incubated overnight at 4 ° C. In the experiment, the wells were washed once with Buffer A and incubated with 0.1 mL of 3.5% bovine serum albumin in the buffer for 1 hour at room temperature. After incubation, the wells were completely inhaled and washed twice with 0.2 mL buffer A.
The compound was dissolved in 100% DMSO to obtain a 2 mM stock solution, which was diluted with binding buffer (15 mL Tris-HCl (pH 7.4), 100 mM NaCl, 1 mM CaCl ₂ , 1 mM MnCl ₂ , 1 mM MgCl ₂ ) &Lt; / RTI &gt; concentration of the final compound. This solution was diluted to the desired final compound concentration. Various concentrations of unlabeled antagonist (0.001-100 μM) were added to the wells of three sets and then 50 nM [ ³ H] -SK & F-107260 (65-86 Ci / mmol) was added.
Plates were incubated at room temperature for 1 hour. After incubation, the wells were inhaled completely and washed once with 0.2 mL of ice-cold buffer A in a well-to-well manner. The receptor was dissolved in 0.1 mL of 1% SDS and [ ³ H] -SK & F-107260 bound by liquid scintillation count was determined by adding 3 mL Ready-Safe with a Beckman LS liquid scintillation counter at 40% efficiency. Non-specific binding of [ ³ H] -SK & F-107260 was measured in the presence of 2 μM SK & F-107260 and the binding was constantly below 1% of the total radioligand flux. IC ₅₀ (antagonist concentration that inhibits binding of [ ³ H] -SK & F-107260 by 50%) was measured by a modified nonlinear least squares curve-adjusted procedure from the LUNDON-2 program. Ki (dissociation constant of antagonist) was calculated according to the equation: Ki = IC ₅₀ / (1 + L / Kd) where L and Kd were the concentration and dissociation constant of [ ³ H] -SK & F-107260, respectively.
The compounds of the present invention inhibit vitronectin binding to SK & F-107260 at a concentration range of about 0.001 to 50 micromolar.
The compounds of the invention also undergo in vitro and in vivo bone resorption assays in accordance with standard art-of-the-art assays for the evaluation of inhibition of bone formation, such as the pit formation assays described in EP 528 587, Human osteoclasts instead of osteoclasts, and human osteoclasts as described by Wronski et al., Cells and Materials 1991, Sup. 1, 69-74. &Lt; / RTI &gt;
Vascular smooth muscle cell migration assay
Rat or human aortic smooth muscle cells were used. Cell migration was monitored in a Transwell cell culture chamber using a polycarbonate membrane (Costar) with 8 um pore. The bottom surface of the filter was covered with bitronectin. The cells were suspended in DMEM supplemented with 0.2% bovine serum albumin at a concentration of 2.5-5.0x10 ⁶ cells / mL and pretreated with various concentrations of the test compound at 20 ° C for 20 minutes. Only the solvent was used as a control standard. 0.2 mL of the cell suspension was placed in the upper compartment of the chamber. The lower compartment contained 0.6 mL of DMEM supplemented with 0.2% bovine serum albumin. Under an atmosphere of 95% air / 5% CO ₂ for 24 hours to perform incubation at 37 ℃. After incubation, non-migrating cells on the upper surface of the filter were removed by gentle scraping. The filter was fixed in methanol and stained with 10% Giemsa stain. a) Counting the number of cells transferred to the bottom surface of the filter, or b) extracting cells stained with 10% acetic acid and measuring the absorbance at 600 nM.
Parathyroid Surgical Incision Rat Model
Each experimental group is composed of 5-6 male Sprague-Dawley rats. The parathyroid glands were incised 7 days before using the rats (provided by Taconic Farms). Twenty-four hours prior to use, the calculated ionized calcium was measured in whole blood immediately after the blood was recovered by the tail vein puncture into the heparinized tube. If the ionized Ca concentration is 1.2 mM / L (as measured by a Ciba-Corning Model 634 Calcium pH Analyzer), the rat is included. The rats were then fed with no-calcium food and deionized water. At the start of the experiment, the rat weight is about 100 g. Baseline Ca levels were measured and rats were immediately administered a compound of the human parathyroid hormone 1-34 peptide (hPTH1-34 (saline) or saline (saline)) as a single intravenous (tail vein) , Dose 0.2 mg / kg salt solution / 0.1% bovine serum albumin, Bachem, Ca) or PTH vehicle. The calcium response to PTH (and other effects of the compound on this reaction) is measured 2 hours after compound / PTH administration.
Rat ulnar drift model
Each experimental group consists of 8-10 male Sprague-Dawley or Wistar rats weighing approximately 30-40 g at the beginning of the experiment. The test agent is administered once a day or several times a day for a period of 7 days by an appropriate route. Prior to the first administration, rats are dosed with a single dose of a fluorescent marker (tetracycline 25 mg / kg, or calcine 10 mg / kg) that marks the osteogenic surface location at the appropriate time. After administration of the compound is complete, the mice are killed and the two paws are removed from the elbow and the leg is removed from the knee and the skin is removed. The sample is frozen and fixed vertically on a microtome chuck. The transverse section of the medial axis region of the ulna is cut in the cryostat. The bone resorption rate is measured according to the shape of the middle part of the cortical bone. Measurements are carried out as follows: The amount of bone resorption on the periosteal surface is the same as the distance developed on the fluorescence label inserted on the surface of the endosteal bone at the 0th day of the periosteum surface; This distance is calculated by subtracting the bone width between the label and the cortical surface at day 7 from the width at day 0; The reabsorption rate per unit of a day is calculated by dividing the result by 7.
Human osteoclast reabsorption analysis (" pit analysis ")
* Partial samples of osteoclast-derived cell suspensions were transferred from a liquid nitrogen store, rapidly warmed to 37 ° C and washed once in RPMI-1640 medium by centrifugation (1000 rpm, 4 ° C for 5 min).
The medium is inhaled and replaced with a rat anti-HLA-DR antibody and diluted 1: 3 in RPMI-1640 medium. Incubate on ice for 30 minutes and mix the cell suspension frequently.
* Cells are washed twice with cold RPMI-1640 by centrifugation (1000 rpm, 5 min at 4 ° C) and cells are transferred to a sterile 15 ml centrifuge tube. The number of nucleated cells is counted in an improved Neubauer coefficient chamber.
Sufficient magnetic beads (5 / mononuclear cells) coated with goat anti-mouse IgG are removed from the storage bottle and placed in 5 ml of fresh medium (this will wash the toxic amide preservative). Fix the beads on the magnet to remove the medium and replace it with fresh medium.
Mix the beads with the cells and incubate the suspension on ice for 30 minutes. Mix the suspension frequently.
* Fix the bead-coated cells on a magnet and follow the remaining cells (osteoclast-rich fraction) by tilting them in a sterile 50 ml centrifuge tube.
Add new medium to bead-coated cells to push trapped osteoclasts. This washing process is repeated 10 times. Discard the bead-coated cells.
* Count the osteoclasts within the counting chamber by filling the chamber with a large-pore disposable plastic Pasteur chamber.
Cells are pelleted by centrifugation and the density of osteoclasts is adjusted to 1.5 x 10 ⁴ / ml in EMEM medium supplemented with 10% fetal bovine serum and 1.7 g / l sodium bicarbonate.
* (For each treatment) Follow a 3 ml aliquot of the cell suspension into a 15 ml centrifuge tube. Cells are pelleted by centrifugation.
Add appropriate treatments to each 3 ml tube (dilute to 50 uM in EMEM medium). Also included are appropriate vehicle control standards, positive control standards (87 MEMl diluted to 100 ug / ml) and analogous control standards (IgG2a diluted to 100 ug / ml). Incubate at 37 占 폚 for 30 minutes.
* 0.5 ml aliquots of cells are seeded on a sterile dentin slice in a 48-well plate and incubated for 30 minutes at 37 ° C. Each treatment is screened four times.
* Wash slices with warm PBS 6 times (10 ml / well on 6-well plate) and treat them freshly or as a control standard. Incubate at 37 ° C for 30 minutes.
Tartrate resistant acid phosphate (TRAP) procedure (selective staining for osteoclast-associated cells)
The slices were washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2 M sodium chocodilate) for 5 minutes.
* It was washed in water and incubated in TRAP buffer at 37 ° C for 5 minutes.
* After washing in cold water, incubate for 5 minutes at 4 ° C in cold acetate buffer / magenta garnet.
• Inhale excess buffer, wash slice in water and air dry.
* TRAP positive osteoclasts are counted by blight-field microscopy and then removed from the dentin surface by sonication.
* The pit volume is measured using a Nikon / Larseytech ILN21W confocal microscope.
Resorption and attachment analysis of osteoclasts in humans
Pit resorption and attachment assays were developed and standardized using normal human osteoclasts derived from osteoclastoma tissue. The osteoclast group is negatively screened from the osteoclast cell suspension using magnetic beads (Dynal Inc., New York, USA). This bead is coated with a murine monoclonal antibody that recognizes human Group II major histocompatibility antigens present in many mononuclear cells within the cell suspension. The magnet is used to express the antigen and ultimately the cells that bind the beads are separated from the cell mixture. An osteoclast-rich suspension is prepared for use in the assay detailed below.
Reabsorption analysis (simultaneous ELISA readout)
The osteoclast-enriched preparation is preincubated with the test compound (4 doses) or the control chart at 37 째 C for 30 minutes. They are then seeded into bovine cortical bone pieces in a 48-well tissue culture plate and incubated for an additional 2 hours at 37 &lt; 0 &gt; C. Wet phosphate buffered saline (PBS) 6 times to wash the bone slices to remove non-adherent cells and then back into the wells of a 48-well plate containing the new compound or control chart. In each well, the supernatant is aspirated into individual tubes and screened with competitive ELISA to detect collagen released during the resorption process. As a commercially available ELISA (Osteometer, Denmark), the 8 amino acid sequences (Glu-Lys-Ala-His-Asp-Gly-Gly-Arg) present in the carboxy terminal telopeptide of the α1 chain of type I collagen Lt; RTI ID = 0.0 &gt; rabbit &lt; / RTI &gt; antigen.
Adhesion analysis
Osteoclast-derived osteoclasts are preincubated with compound (4 doses) or a control chart at 37 째 C for 30 minutes. The cells are then seeded with osteopontin (2.5 μg / ml of osteopontin in human or rat) coated slides and incubated for 2 hours at 37 ° C. Rinse the slides well in PBS to remove unattached cells and fix the remaining cells on the slide in acetone. The osteoclasts are stained with tartrate-resistant acid phosphatase (TRAP), an optional marker for phenotype cells, and the number is counted with an optical microscope. The results are expressed as percent adhesion inhibition for the vehicle chart.
Inhibition of RGD-mediated GPIIb-IIIa binding
Purification of GPIIb-IIIa
10 units of old, washed human platelets (obtained from the Red Cross) were dissolved in 3% octylglucoside, 20 mM Tris-HCl, pH 7.4, 140 mM NaCl, 2 mM CaCl ₂ by gentle stirring for 2 hours at 4 ° C Respectively. The lysate was centrifuged at 100,000 g for 1 hour. The resulting supernatant was transferred to a 5 mL Lentyl lectin Sepharose 4B column (EY Labs) previously equilibrated with 20 mM Tris-HCl, pH 7.4, 140 mM NaCl, 2 mM CaCl _2, 1% octylglucoside (Buffer A) . After 2 hours of incubation, the column was washed with 50 mL cold buffer A. Lectin-retaining GPIIb-IIIa was eluted with buffer A containing 10% dextrose. All procedures were carried out at 4 ° C. The obtained GPIIb-IIa was purified to> 95% as evidenced by SDS polyacrylamide gel electrophoresis.
Insertion of GPIIb-IIIa in liposomes
A mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polaripi) was inhaled into the wall of a glass tube under a stream of nitrogen. Purified GPIIb-IIIa was diluted to a final concentration of 0.5 mg / mL and mixed with the phospholipid at a protein: phospholipid concentration of 1: 3 (w: w). The mixture was resuspended and sonicated for 5 minutes with a sonar device. The mixture was dialyzed overnight using 12,000-14,000 molecular weight exclusion dialysis tubing for a 1000 fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaCl ₂ (with two modifications). GPIIb-IIIa-containing liposomes were centrifuged at 12,000 g for 15 minutes and resuspended in dialysis buffer to a final protein concentration of approximately 1 mg / mL. Liposomes were stored at -70 ° C until needed.
Competitive binding to GPIIb-IIIa
Binding of the fibrinogen receptor (GPIIb-IIIa) was erotic and analyzed by an indirect competitive binding method using ^{[3 H] -SK & F-} 107260 as an RGD- type ligand. Binding assays were performed using a 0.22 um hydrophilic Durafor membrane in a 96-well filter plate assembly (Millipore Corporation, Bedford, Mass.). Nonspecific binding was masked by pre-application of wells at room temperature for 1 hour with 0.2 mL of 10 [mu] g / ml polylysine (Sigma Chemical Co., St. Louis, Mo.). Various concentrations of unlabeled benzodiazepine were added in 5 wells. [ ³ H] -SK & F-107260 was applied to each well to a final concentration of 4.5 nM followed by addition of 1 μg of purified platelet GPIIb-IIIa-containing liposome. The mixture was incubated at room temperature for 1 hour. Filtration using a Millipore filtration manifold followed by separation of the GPIIb-IIIa- linkage [ ³ H] -SK & F-107260 from unbound by washing with ice-cold buffer (two times, 0.2 mL each). The bound radioactive activity remaining on the filter was counted in a 1.5 mL Redisolve (Beckman Instruments, Fullerton, CA) in a Beckman liquid scintillation counter (Model LS6800) with 40% efficiency. Non-specific binding was measured in the presence of 2 μM unlabeled SK & F-107260 and the total radioactivity added to the sample was constantly less than 0.14%. All data points are the average of four measurements.
Competitive binding data were analyzed by nonlinear least squares curve-fitting procedure. This method provides the IC50 (in equilibrium with ^{[3 H] -SK & F-} 107260 specific binding the antagonist concentration that inhibit 50%) of the antagonist. IC50 relates to the equilibrium dissociation constant (Ki) of the antagonist based on the Cheng and Prusoff equation: Ki = IC50 / (1 + L / Kd), where L is the [ ³ H] -SK & F-107260 (4.5 nM) and Kd is the dissociation constant of [ ³ H] -SK & F-107260 of 4.5 nM as determined by Scatchard analysis.
The compounds of the present invention inhibit bitonectin binding to SK & F-107260 with a Ki in the bitronectin receptor approximately 10-fold greater than for the fibrinogen receptor. Preferred compounds have a Ki at the neurotransmitter that is 30 times greater than the fibrinogen receptor. The most preferred compounds have a Ki at the neurotransmitter that is 100 times greater than the fibrinogen receptor.
The following examples are intended to illustrate, but not to limit, the scope of the invention in any way, but also to the preparation of the compounds of the invention. Numerous other embodiments are readily apparent to those skilled in the art.
Example Overview
Nuclear magnetic resonance spectra were recorded at 250 or 400 MHz using a Bruker AM 250 or Bruker AC 400 spectrometer, respectively. CDCl ₃ is Diteriochloroform, DMSO-d ₆ is hexadecyldimethylsulfoxide and CD ₃ OD is tetraditer methanol. The chemical potentials are reported in ppm (δ) in the lower region from the internal reference tetramethylsilane. The abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = polyline, dd = doublet, dt = triplet, app = = Broad. J represents the NMR coupling constant as measured by Hertz. Continuous wave infrared (IR) spectra were recorded on a Perkin-Elma 683 infrared spectrometer and Fourier Transform Infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. The IR and FTIR spectra were recorded in a transitional manner and the band positions reported in inverse wavelet (cm ^-1 ). Mass spectra were obtained on a VG 70 FE, PE Syx API III, or VG ZAB HF device using fast atom bombardment (FAB) and electrospray (ES) ionization techniques. Elemental analysis was obtained using a Perkin-Elma 240C atomic analyzer. Melting points are obtained on the Thomas-Hover melting point device and are not calibrated. All temperatures are recorded in degrees Celsius.
Anal Tech Silica Gel GF and this. Merck silica gel 60 F-254 thin film plates were used for thin-layer chromatography. Both flash and gravity chromatography were performed. Merck-Keygel gel 60 (230-400 mesh) silica gel. Analysis and preparative HPLC were performed on lane-in or Beckmann chromatography. ODS refers to an octadecylsilyl derived silica gel chromatographic support. 5 [mu] Apex-ODS refers to a silica gel chromatographic support derived from octadecylsilyl having a nominal particle size of 5 mu, prepared in Jones chromatography, Littleton, Colo. YMC ODS-AQ (registered trademark) is an ODS chromatographic support and a registered trademark of YMC of Kyoto, Japan. PRP-1 (registered trademark) is a polymer (styrene divinylbenzene) chromatographic support and is a registered trademark of Hamilton, Inc. of Reno, Nev. Celite (R) is a filter aid consisting of acid-washed diatomaceous silica and is a registered trademark of Mannville, Inc. of Denver, Colorado.
Methyl (2S) -7-carboxy-4-methyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- Methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate, methyl (2R) , 4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate, methyl (±) -7-carboxy-4-isopropyl-3-oxo-2,3,4,5-tetrahydro-1H -1,4-benzodiazepine-2-acetate, methyl (±) -7-carboxy-3- (±) -8-carboxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2- benzazepine- -7-amino-5-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-2-acetic acid and tert- butyl-4-fluoro-3-methylbenzoate were prepared according to Bondinell, et al. Lt; RTI ID = 0.0 &gt; WO 93/00095. &Lt; / RTI &gt; Methyl (±) -7-carboxy-4- (2-methoxyethyl) -3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- -7-carboxy-4- [2- (3,4-methylenedioxyphenyl) ethyl] -3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- Methyl (±) -7-carboxy-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- Methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate, (S) -2, Methyl] -3-oxo-1H-1, 4-benzodiazepin-2-yl) methyl] Acetic acid, 2- (methylaminomethyl) benzimidazole dihydrochloride and 4-aza-5-methyl- (methylamino) methylbenzimidazole were prepared according to P50256-1.
Production Example 1
Preparation of 2- (aminomethyl) -4-aza-5-methylbenzimidazole dihydrochloride
a) 2,3-Diamino-6-methylpyridine
10% Pd / C (3.2 g , 3 mmol) in anhydrous EtOH 2- amino-6-methyl-3-nitropyridine at room temperature for H was added and the mixture (2.30 g, 15 mmol) solution of ₂ (150 ml) ( 50 psi). After 1.5 h, the mixture was filtered through Celite (R) and the filtrate was concentrated in vacuo to give the title compound as a yellow oil. This was used without further purification. ¹ H NMR (250 MHz, CD ₃ OD) 6.82 (d, 1H), 6.36 (d, 1H), 2.25 (s, 3H).
b) 2-Amino-3 - [(benzyloxycarbonyl) glycyl] amino-6-methylpyridine
DCC (3.09 g, 15 mmol) was added dropwise to a solution of 2,3-diamino-6-methylpyridine (15 mmol) and Cbz-glycine (3.14 g) in DMF (19 ml) and CH ₂ Cl ₂ g, 15 mmol). When the DCC was dissolved, the slightly cloudy solution was warmed to room temperature. After 18.5 hours, the mixture was filtered through Celite (R) and the filtrate was concentrated to dryness by rotary evaporation. The residue was reconcentrated from xylene (DMF removal) to give a yellow solid. To give the title compound (2.24 g, 48%) by silica gel chromatography (10% MeOH / CHCl ₃₎ as a yellow _{solid: TLC R f (10% MeOH} / CHCl 3) 0.57: 1 H NMR (250 MHz, DMSO- _{d 6) δ9.11 (br s,} 1H), 7.48-7.60 (br t, 1H), 7.20-7.48 (m, 6H), 6.40 (d, 1H), 5.69 (br s, 2H), 5.06 (s , 2H), 3.82 (d, 2H), 2.23 (s, 3H).
c) Preparation of 4-aza-2- (benzyloxycarbonyl) aminomethyl-5-methylbenzimidazole
A solution of 2-amino-3 - [(benzyloxycarbonyl) glycyl] amino-6-methylpyridine (2.24 g, 7.13 mmol) in glacial acetic acid (70 ml) was heated under reflux under argon. After 17 h, the solution was concentrated (rotary evaporation, high vacuum) and the residue was reconcentrated from toluene (acetic acid removal). The resulting yellow oil was treated with hot EtOAc (20 ml) and the mixture was cooled to room temperature. Collected by suction filtration The solids were washed with EtOAc to give the title compound (1.72 g, 81%) as an off-white _{solid: TLC R f (15% MeOH} / CHCl 3) 0.63; MS (ES) m / e 297.4 (M + H) &lt; ⁺ & gt ^; .
d) 2- (Aminomethyl) -4-aza-5-methylbenzimidazole dihydrochloride
(Benzyloxycarbonyl) aminomethyl-5-methylbenzimidazole (213.4 mg, 0.72 mmol) and 1.0 (4-fluorophenyl) Was added to a solution of N HCl (1.44 ml, 1.44 mmol). On the mixture with H ₂ purge (purge), H ₂ (balloon; balloon) and stirred vigorously at room temperature in the state. After 2 h, the reaction was filtered through celite and the filtrate was concentrated by rotary evaporation to give the title compound as an off-white solid. MS (ES) m / e 163.2 (M + H) <^+> .
Production Example 2
Preparation of methyl (±) -2,3,4,5-tetrahydro-7-carboxy-4- (3,3-dimethylbutyl) -3-oxo-1H-1,4-benzodiazepine-
a) tert-Butyl-3 - [(3,3-dimethylbutyl) amino] methyl-4-nitrobenzoate
(17.9 g, 74.7 mmol), NBS (19.9 g, 112.0 mmol), benzoyl peroxide (1.81 g, 7.47 mmol) and CCl ₄ (370 ml ) Was heated while refluxing. After 17.5 hours, the reaction was cooled thoroughly with ice and filtered to remove the precipitated succinimide. The filtrate was concentrated to give a tan oil.
This oil (4.2 g, 13.29 mmol) was dissolved in dry THF (50 ml) and 3,3-dimethylbutylamine (3.0 g, 29.64 mmol) was added in one portion. The orange-yellow solution was stirred at room temperature for 80 minutes and then concentrated to remove the THF. The residue was diluted with Et ₂ O (150 ml) and subsequently washed with 1.0 N NaOH (25 ml) and H ₂ O (25 ml). The aqueous layers were combined, back extracted with Et ₂ O (50 ml), and the combined organic layers were washed with brine (25 ml) and dried (MgSO ₄ ). Concentration afforded the title compound as a light brown oil: MS (ES) m / e 337.2 (M + H) &lt; ⁺ & gt ^; .
b) Preparation of tert-butyl 3 - [[N- (3,3-dimethylbutyl) -N- (tert- butoxycarbonyl)] amino] methyl-4-nitrobenzoate
Di -tert- butyl dicarbonate (4.0 g, 18.39 mmol) of tert- butyl 3 in CHCl ₃ (80 ml) at room temperature - [(3,3-dimethylbutyl) amino] methyl-4-nitro benzoate (4.12 g, 12.26 mmol). After 18 h, the reaction was concentrated and reconcentrated from hexane (CHCl ₃ removal). (ES) m / e, 437.2 (M + H) &lt; ⁺ & gt ^; , 459.2 (M + H) &lt; ⁺ &gt;. [ Na) ⁺ .
c) Preparation of tert-butyl 4-amino-3 - [[N- (3,3-dimethylbutyl) -N- (tert-butoxycarbonyl)] amino] methyl benzoate
10% Pd / C (1.0 g, 0.94 mmol) was added to a solution of tert-butyl 3 - [[N- (3,3- dimethylbutyl) -N- (tert- butoxycarbonyl)] amino] Methyl-4-nitrobenzoate (4.95 g, 11.35 mmol) and the mixture was shaken under Parr apparatus under H ₂ (55 psi) at room temperature. After 4 hours, the reaction was filtered through Celite (R) and the filtrate was concentrated to give the title compound (4.3 g, 93%) as a reddish brown oil: MS (ES) m / e 407.4 (M ⁺ .
d) Synthesis of tert-butyl (±) -4- [2- (1,4-dimethoxy-1,4-dioxobutyl) amino] -3 - [[N- (3,3-dimethylbutyl) (tert-butoxycarbonyl)] amino] methyl benzoate
To a solution of tert-butyl-4-amino-3 - [[N- (3,3-dimethylbutyl) -N- (tert- butoxycarbonyl)] amino] methylbenzoate (5.6 g, 13.79 mmol) and dimethylacetylene dicarboxylate (1.86 ml, 15.17 mmol) was heated under reflux for 1 hour, and then cooled to room temperature. The resulting solution was combined with MeOH (80 ml) and 10% Pd / C (2.9 g, 2.76 mmol) and the mixture was shaken under Parr apparatus under H ₂ (50 psi) at room temperature. After 22 h, the reaction was filtered through Celite (R) and the filtrate was concentrated by rotary evaporation. Residue was re-concentrated from CHCl ₃ sikyeotgo the chromatography was performed with (MeOH removed), and then silica gel (25% EtOAc / hexane). The title compound (2.64 g, 42%) was obtained as a pale yellow oil: MS (ES) m / e 551.2 (M + H) <^+> .
e) Methyl (±) -2,3,4,5-tetrahydro-7-carboxy-4- (3,3-dimethylbutyl) -3-oxo-1H-1,4-benzodiazepine-
Tert- butyl (±) in TFA (25 ㎖) at 0 ℃ of anhydrous _{CH 2 Cl 2 (25 ㎖)} -4- [2- (1,4- dimethoxy-1,4-oxobutyl) amino] - Was added all at once to a solution of 3 - [[N- (3,3-dimethylbutyl) -N- (tert-butoxycarbonyl) amino] methylbenzoate (12.64 g, 4.8 mmol), and the pale yellow solution was warmed to room temperature Respectively. After 1 h, the solution was concentrated by rotary evaporation and the residue was reconcentrated from toluene (residual TFA removal). The resulting oil in toluene (50 ml) and _{Et 3 N (3.34 ml, 24} mmol) were combined and heated at reflux the mixture. A pale yellow homogeneous solution was produced. After 16 h, the reaction was concentrated by rotary evaporation to give a solid residue. It was dissolved in minimal MeOH (~ 10 ml), diluted with H ₂ O (10 ml), and adjusted to pH 4.5 with glacial acetic acid. The mixture was filtered and the precipitate was washed sequentially with MeOH and Et ₂ O and then vacuum dried to give the title compound (1.88 g, 93%) as a nearly colorless powder: MS (ES) m / e 363.2 (M + ⁺ .
Production Example 3
Preparation of bis [(benzimidazol-2-yl) methyl] amine tris (trifluoroacetate)
a) Synthesis of bis [1-N- (tert-butoxycarbonyl) benzimidazol-2-yl] methyl-N- (tert-butoxycarbonyl) amine
To a stirred solution of 2-aminomethylbenzimidazole dihydrochloride hydrate (6.26 g, 28.4 mmol) and triethylamine (4.0 ml, 28.4 mmol) in dry THF (50 ml) 2- (bromomethyl) benzimidazole (P50256-1; 2.00 g, 9.48 mmol). After 8 h, a solution of di-tert-butyl dicarbonate (10.0 g, 45.84 mmol) in CHCl ₃ (50 ml) was slowly added. The resulting mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in CH ₂ Cl ₂ (150 ml) and washed successively with water (60 ml), 5% NaHCO ₃ (60 ml) and brine (60 ml). Dried (MgSO _4), and subjected to concentration and silica gel chromatography _{(6% MeOH / CH 2 Cl} 2) to give the title compound (0.46 g, 8%) as a light yellow oil: MS (ES) m / e 578.4 (M + H) ⁺ .
b) Bis [(benzimidazol-2-yl) methyl] amine tris (trifluoroacetate)
The bis TFA (3 ml) and CH ₂ Cl ₂ (9 ml) solution at room temperature [[1-N- (tert- butoxycarbonyl) benzimidazol-2-yl] methyl -N- (tert- butoxycarbonyl Carbonyl) amine (0.23 g, 0.4 mmol). After 35 min the solution was concentrated by rotary evaporation and the residue was reconcentrated from toluene (residual TFA removal) to give the title compound (0.17 g, 68%) as a white powder: MS (ES) m / e 278.0 M + H) &lt; ⁺ & gt ^; .
Production Example 4
Preparation of 2 - [[1- [benzimidazol-2-yl) methyl] benzimidazole] methyl] amine bis (trifluoroacetate)
a) Synthesis of [[1-N- (tert-butoxycarbonyl) benzimidazol-2-yl] methyl-N- (tert-butoxycarbonyl) amine
To a stirred solution of dry CH ₂ Cl ₂ (50 ml) solution of 2-aminomethyl-benzimidazole dihydrochloride hydrate (3.0 g, 13.63 mmol) and triethylamine (8.44 ml, 61.3 mmol) CH 2 Cl 2 (50 tert-butyl dicarbonate (6.54 g, 30.0 mmol) in dichloromethane (5 ml) at 0 ° C. The reaction was stirred at room temperature for 1 hour and then triethylamine (1.9 ml, 13.8 mmol) and di-tert-butyl dicarbonate (2.97 g, 13.63 mmol) were further added. The resulting mixture was stirred at room temperature for 24 hours and then concentrated. The residue was dissolved in CH ₂ Cl ₂ (50 ml) and washed sequentially with 0.5 N HCl (2 x 40 ml), 5% NaHCO ₃ (50 ml), and brine (50 ml). The crude product was recrystallized from CH ₂ Cl ₂ / ether to give the title compound (2.8 g, 59%) as a white powder: MS (ES) m / e 348.2 (M + H) <^+> .
b) Preparation of 2 - [[1 - [[1- (tert-butoxycarbonyl) benzimidazol-2-yl] methyl] benzimidazole] methyl] -N, N-di- (tert- Butyl) amine
(Tert-butoxycarbonyl) benzimidazol-2-yl] methyl] -N- (di-tert-butoxycarbonyl) benzoate in dry THF (12 ml) and DMF (Tert-butoxycarbonyl) -2- (bromomethyl) benzimidazole (0.6 g, 1.93 mmol) was added to a stirred solution of the title compound (0.6 g, 1.73 mmol) and NaH (0.1 g, 4.17 mmol) . The resulting mixture was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in CH ₂ Cl ₂ (100 ml) and washed successively with water (50 ml), 5% NaHCO ₃ (30 ml) and brine (30 ml). Dried (MgSO _4), concentrated and purified by silica gel chromatography (2: 3 EtOAc / hexanes) over to give the title compound (0.27 g, 27%) as a light yellow oil: MS (ES) m / e 578.2 (M + H) ⁺ .
c) 2 - [[1 - [(benzimidazol-2-yl) methyl] benzimidazole] methyl] amine bis (trifluoroacetate)
_{TFA / CH 2 Cl 2 (30} ml, 25%) solution at room temperature for 2 - [[1 - [[( 1-N-tert- butoxycarbonyl) benzimidazol-2-yl] methyl] benzimidazole ] Methyl] -N, N-di- (tert-butoxycarbonyl) amine (0.25 g, 0.43 mmol). After 25 min, the solution was concentrated by rotary evaporation and the crude product was recrystallized from CH ₂ Cl ₂ / ether to give the title compound (0.17 g, 63%) as an off-white powder: MS (ES) m / e 278.0 + H) ⁺ .
Example 1
Methyl] amino] carbonyl] -4- (2-methoxybenzyl) -2,3,4,5-tetrahydro-7 - [[[ Ethoxyethyl) -3-oxo-1H-1, 4-benzodiazepin-2-acetic acid
a) Methyl (±) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol- Methoxyethyl) -3-oxo-lH-l, 4-benzodiazepin-2-acetate
EDC methyl (±) -7- carboxy-4- (2-methoxyethyl) of (138 mg, 0.72 mmol) in anhydrous CH ₃ CN ₍₃ ml) at room temperature 3-oxo -2,3,4,5 (202 mg, 0.60 mmol), 2- (aminomethyl) -4-aza-5-methylbenzimidazole dihydrochloride (0.72 mmol), HOBt Was added to a solution of H ₂ O (97 mg, 0.72 mmol) and diisopropylethylamine (0.84 ml, 4.8 mmol). After 16 hours, concentrate the reaction was concentrated and the residue material from xylenes / CHCl _3. By silica gel chromatography (15% MeOH / CHCl ₃₎ to give the title compound _{(impure): TLC R f (15%} MeOH / CHCl 3) 0.55; MS (ES) m / e 481.5 (M + H) &lt; ⁺ & gt ^; . This was used without further purification.
b) Preparation of (±) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] amino] carbonyl] -4- -Methoxyethyl) -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid
Methyl] amino] carbonyl] -4- (2-methoxybenzyl) -2,3,4,5-tetrahydro-7 - [[[ (0.60 mmol), 1.0 N LiOH (1.8 ml, 1.8 mmol) and THF (4.2 ml) was stirred at room temperature for 45 min &Lt; / RTI &gt; and concentrated to remove the THF. Washing the aqueous layer with _{Et 2 O (2 x 2 ml} ) , and the Et ₂ O layer was discarded. Dilute the aqueous layer with CH ₃ CN (2 ml) and acidified with TFA (0.23 ml). The resulting solution was concentrated and dried by rotary evaporation and the residue was purified by ODS chromatography (12% CH ₃ CN / H ₂ O with 0.1% TFA; 250 mL, 15% CH ₃ CN / H ₂ O). Concentrated and was obtained (50% of the 199.5 mg, two steps) to yield the title compound through freeze-drying as a pale yellow powder: HPLC (PRP-1 (trademark), 0.1% TFA containing _{15% CH 3 CN / H 2} O) K '= 1.4; : MS (ES) m / e 467 (M + H) &lt; ⁺ & gt ^; . C ₂₃ H ₂₆ N ₆ O ₅揃 1.5 CF ₃ CO ₂ H 揃 1.33H ₂ O; Theoretical values: C, 47.21; H, 4.60; N, 12.70. Found: C, 47.20; H, 4.73; N, 12.79.
Example 2
Methyl] amino] carbonyl] -4- (2-methoxyethyl) -3-oxo &lt; RTI ID = 0.0 & -1H-l, 4-benzodiazepin-2-acetic acid
a) methyl (±) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -4- (2-methoxyethyl) 3-oxo-lH-l, 4-benzodiazepin-2-acetate
EDC (230 mg, 1.2 mmol) was added to a solution of methyl (+) - 7-carboxy-4- (2- methoxyethyl) -3-oxo-2,3,4,5-tetra (336.4 mg, 1.0 mmol), 2- (aminomethyl) benzimidazole dihydrochloride hydrate (264 mg, 1.2 mmol), HOBt.H ₂ O (162 mg, mg, 1.2 mmol) and diisopropylethylamine (0.70 ml, 4.0 mmol). After 17 h, the reaction was concentrated and the residue was reconcentrated from xylene (2 x) to remove DMF. The residue was diluted with H ₂ O (3 ml) and extracted with CHCl ₃ ( ₃ x 5 ml). The combined extracts were treated with MeOH (2 ml) and the precipitate was dissolved, then dried (MgSO ₄ ) and concentrated. Recrystallization from xylene (removal of residual DMF) gave a pale yellow solid. Was dissolved in MeOH / CHCl ₃ and concentrated to give an oil solution. Was obtained a off-white solid by silica gel chromatography _{(10% MeOH / CHCl 3)} , by grinding them together with EtOAc (3 ml) the title compound (397.1 mg, 85%) to give a colorless solid: TLC R _f (10% MeOH / CHCl ₃₎ 0.46; : MS (ES) m / e 466.2 (M + H) &lt; ⁺ & gt ^; .
b) Preparation of (±) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -4- (2-methoxyethyl) -Oxo-lH-l, 4-benzodiazepin-2-acetic acid
1.0 N LiOH (1.0 ml, 1.0 mmol) of methyl (±) -2,3,4,5- tetrahydro -7 at room temperature in THF (4.3 ml) and _{H 2 O (3.3 ml) -} [[[( benz Yl) methyl] amino] carbonyl] -4- (2-methoxyethyl) -3-oxo-1H-l, 4- benzodiazepine-2-acetate (397 mg, 0.85 mmol) . The light yellow mixture was stirred at 40-50 &lt; 0 &gt; C for 1 hour and the resulting homogeneous solution was stirred for 17.5 hours. The reaction was concentrated and the resulting oil was dissolved in H ₂ O (4 ml). The solution was filtered to remove the microparticles, and the filtrate was neutralized with 1.0 N HCl (1.0 ml). Collect the light yellow solid, one of the high temperature: were pulverized well while stirring with _{1 CH 3 CN / H 2 O} . Collect the resulting solid, a sufficient amount of 1: 1 CH ₃ CN / H ₂ O and washed, and dried at high vacuum (40 ℃) to give the title compound (327.9 mg, 85%) as a colorless powder. HPLC (PRP-1 _{(TM), 15% CH 3 CN /} H 2 O containing 0.1% TFA) K '= 4.6 ; : MS (ES) m / e 452.2 (M + H) &lt; ⁺ & gt ^; . C ₂₃ H ₂₅ N ₅ O ₅ ; Theoretical values: C, 61.19; H, 5.58; N, 15.51. Found: C, 61.18; H, 5.58; N, 15.39.
Example 3
Methyl] amino] carbonyl] phenyl] -3-phenylbutanoic acid was prepared in the same manner as in (1)
a) Ethyl 3-hydroxy-4- (4-methoxyphenyl) -3-phenylbutanoate
To a solution of lithium bis (trimethylsilyl) amide (1.0 M in THF, 40 ml, 40 mmol) in dry THF (60 ml) in a flame dried flask at -78 ° C under argon was added anhydrous EtOAc , 44 mmol) was added dropwise. The yellow solution was stirred for 0.5 h at -78 <0> C and then a solution of 2- (4-methoxyphenyl) -1-phenylethanone (Chem. Ber. 1958, 91, 755-759; 4.53 g, 20 mmol) was added dropwise over 12 minutes. Additional THF (2 ml) was used for shipping. After 0.5 h, the reaction was quenched with saturated NH ₄ Cl solution (120 ml) and warmed to room temperature. EtOAc extraction, drying (MgSO _4), to give the concentration and silica gel chromatography (20% EtOAc / hexane) to yield the title compound (6.13 g, 96%) as a light yellow oil: TLC R _f (20% EtOAc / hexanes) 0.34; : MS (ES) m / e 315.2 (M + H) &lt; ⁺ & gt ^; .
b) Ethyl 4- (4-methoxyphenyl) -3-phenylbutanoate
Ethyl 3-hydroxy of the boron trifluoride etherate in anhydrous CH ₂ Cl ₂ (49 ml) of (4.8 ml, 39 mmol) under argon at 0 ℃ -4- (4- methoxy-phenyl) -3-phenyl-butanoate (6.13 g, 19.5 mmol) and triethylsilane (6.2 ml, 39 mmol) over 3 min. After stirring the reaction overnight at room temperature, quenched with _{5% NaHCO 3 (100 ml)} . The mixture was vigorously stirred for 10 minutes and then separated. The aqueous layer was extracted with CH ₂ Cl ₂ (100 ml), the organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated. The material was concentrated and the residue from hexane (CH ₂ Cl ₂ removed) to give a yellow oil. This was dissolved in absolute EtOH (100 ml) and 10% Pd / C (775 mg, 1.95 mmol) was added. The mixture was shaken under H ₂ (50 psi) at room temperature with a Parr apparatus for 2 hours and then filtered through Celite (R). The filtrate was concentrated and the residue was chromatographed on silica gel (15% EtOAc / hexanes). The title compound (5.27 g, 91%) was obtained as a colorless oil: TLC _Rf (15% EtOAc / hexanes) 0.40; : MS (ES) m / e 299.2 (M + H) &lt; ⁺ & gt ^; .
c) Ethyl-4- (4-hydroxyphenyl) -3-phenylbutanoate
Anhydrous ammonium trichloride (4.49 g, 33.7 mmol) was added to a solution of ethyl 4- (4-methoxyphenyl) -3-phenylbutanoate (2.01 g, 6.74 mmol) in anhydrous CH ₂ Cl ₂ ) And ethanethiol (2.5 ml, 33.7 mmol). The yellow solution was allowed to warm to room temperature, stirred for 3 h, then recooled to 0 &lt; 0 &gt; C and quenched with cold 3 N HCl (67 ml). The mixture was stirred for 5 minutes and then separated. The aqueous layer was extracted with CH ₂ Cl ₂ ( ₂ x 100 ml) and the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. Silica gel chromatography (25% EtOAc / hexanes) gave the title compound (1.84 g, 96%) as a colorless oil: TLC _Rf (30% EtOAc / hexanes) 0.47; MS (ES) m / e 285.2 (M + H) &lt; ⁺ & gt ^; .
d) Ethyl 3-phenyl-4- [4- (trifluoromethanesulfonyloxy) phenyl] butanoate
(4-hydroxyphenyl) -3-phenylbutanoate (1.84 g, 6.47 mmol) and 2,6-lutidine (1.5 ml) in anhydrous CH ₂ Cl ₂ , 12.9 mmol) in anhydrous tetrahydrofuran (50 ml) was dropwise added dropwise trifluoromethanesulfonic anhydride (1.4 ml, 8.4 mmol). After 0.5 h, the yellow solution was warmed to room temperature and stirred for 1 h. The reaction was diluted with Et ₂ O (150 ml) and washed sequentially with 1.0 N HCl (15 ml), 5% NaHCO ₃ (15 ml) and saturated brine (15 ml). Dried (MgSO _4), the title compound (2.62 g, 97%) as a concentrated and purified by silica gel chromatography (15% EtOAc / Hexane) was obtained as a nearly colorless _{oil: TLC R f (20% EtOAc} / hexanes) 0.55; : MS (ES) m / e 417.0 (M + H) &lt; ⁺ & gt ^; .
e) Ethyl 4- (4-carboxyphenyl) -3-phenylbutanoate
(2.62 g, 6.29 mmol), anhydrous KOAc (2.47 g, 25.16 mmol), Pd (OAc) ₂ , (70.6 The mixture of dppf (697.4 mg, 1.26 mmol) and anhydrous DMSO (31 ml) was bubbled with carbon monoxide (3 times / carbon monoxide purge cycle, then carbon monoxide in the mixture for 5 minutes) ), And then heated at 70 캜 under a carbon monoxide balloon. After 3.5 h, the reaction was diluted with H ₂ O (31 ml), cooled with ice, and acidified with 1.0 N HCl (25 ml). Extraction with CH ₂ Cl ₂ (2x100 ml), drying (MgSO ₄ ), concentration and re-concentration from toluene gave a red light-orange liquid. The title compound (1.78 g, 91%) was obtained as a cream solid by silica gel chromatography (7: 3 toluene / EtOAc with 1% AcOH): TLC _Rf (7: 3 toluene / EtOAc with 1% AcOH) 0.47; : MS (ES) m / e 313.2 (M + H) &lt; ⁺ & gt ^; .
f) Ethyl (±) -4- [4 - [[[(1H-benzimidazol-2-yl) methyl] methylamino] carbonyl] phenyl] -3-phenylbutanoate
Ethyl 4- (4-carboxyphenyl) in from the EDC (230 mg, 1.2 mmol) at room temperature in anhydrous CH ₃ CN (5 ml) -3- phenyl-butanoate (312.4 mg, 1.0 mmol), 2- ( methylaminomethyl ) Benzimidazole dihydrochloride (281 mg, 1.2 mmol), HOBt.H ₂ O (162 mg, 1.2 mmol) and diisopropylethylamine (0.70 ml, 4.0 mmol). After 18 h, the reaction was concentrated and the brown residue was purified by silica gel chromatography (1: 1 EtOAc / CHCl ₃ with 5% MeOH). The title compound (439.2 mg, 96%) was obtained as a light orange foam: TLC R _f (5% MeOH containing _{1: 1 EtOAc / CHCl 3)} 0.50; MS (ES) m / e 456.2 (M + H) &lt; ⁺ & gt ^; .
g) (짹) -4- [4 - [[[(1H-benzimidazol-2-yl) methyl] methylamino] carbonyl] phenyl]
Methyl] amino] carbonyl] phenyl] -3-phenyl butanoate (439.2 mg, 0.34 mmol) in EtOH (8.4 ml) , 0.96 mmol) and 1.0 N NaOH (1.2 ml, 1.2 mmol) was stirred at 50 &lt; 0 &gt; C. After 24 h, the reaction was concentrated to dryness and the residue was purified by ODS chromatography (35% MeOH / H ₂ O). The title compound via concentration and nonggyeol drying (412.2 mg, 86%) to give a colorless powder: HPLC (PRP-1 (trademark), 0.1% TFA containing _{35% CH 3 CN / H 2} O), K '= 1.4 ; : MS (ES) m / e 428 (M + H) &lt; ⁺ & gt ^; , 450 (M + Na) &lt; ⁺ & gt ^; . C ₂₆ H ₂₄ N ₃ O ₃ Na ₂ .75H ₂ O; Theoretical values: C, 62.58; H, 5.96; N, 8.42. Found: C, 62.34; H, 5.84; N, 8.44.
Example 4
Methyl] amino] carbonyl] phenyl] -3- (dimethylaminocarbonyl) butanoic acid was prepared in the same manner as in (1)
a) tert-Butyl 4-bromobenzoate
A mixture of 4-bromobenzoic acid (20.10 g, 100 mmol), anhydrous CH ₂ Cl ₂ (100 ml) and condensed isobutylene (-78 ° C, 100 ml) was added dropwise to a solution of trifluoromethanesulfonic acid And the resulting mixture was refluxed under a dry ice / acetone condenser. After 40 minutes, isobutylene (30 ml) was further added and further refluxed for 20 minutes. The reaction was poured into Et ₂ O (500 ml) and washed sequentially with 1.0 N KOH ( ₂ x 50 ml), H ₂ O (50 ml) and saturated brine (50 ml). The title compound (15.28 g, 59%) was obtained as a pale yellow oil by drying (MgSO ₄ ), concentration and silica gel chromatography (5% EtOAc / hexane): TLC _Rf (5% EtOAc / hexane) 0.59; : MS (ES) m / e 259/257 (M + H) &lt; ⁺ & gt ^; .
b) Methyl 3- [4- (tert-butoxycarbonyl) phenyl] propanoate
A solution of tert-butyl 4-bromobenzoate (5.14 g, 20 mmol), methyl acrylate (9.1 ml, 100 mmol), Pd (OAc) ₂ (224.5 mg, 1 mmol), tri -o-tolylphosphine (608.8 mg, 2 mmol) and diisopropylethylamine (7.0 ml, 40 mmol) was heated under reflux for 3 hours and then concentrated by rotary evaporation. The residue was diluted with Et ₂ O (200 ml) and washed successively with 1.0 N HCl (2 x 50 ml), 5% NaHCO ₃ (50 ml) and saturated brine (50 ml). Dried (MgSO _4), concentrated and purified by silica gel chromatography with (15% EtOAc / hexane) to give the title compound (3.34 g, 64%) as a pale yellow _{solid: TLC R f (20% EtOAc} / hexanes) 0.51; : MS (ES) m / e 263.0 (M + H) &lt; ⁺ & gt ^; .
c) Methyl 3- [4- (tert-butoxycarbonyl) phenyl] propanoate
10% Pd / C (2.71 g, 2.55 mmol) was added to a solution of methyl 3- [4- (tert-butoxycarbonyl) phenyl] propanoate (3.34 g, 12.73 mmol) in EtOAc (65 ml) ) Solution, and the mixture was shaken with a Parr apparatus at room temperature under H ₂ (50 psi). After 3 h, the reaction was filtered through Celite (R) and the filtrate was concentrated to dryness by rotary evaporation. Recrystallization from hexane afforded the title compound (3.27 g, 97%) as a hazy gray oil: TLC _Rf (20% EtOAc / hexanes) 0.63; : MS (ES) m / e 265.0 (M + H) &lt; ⁺ & gt ^; .
d) 3- [4- (tert-Butoxycarbonyl) phenyl] propanoic acid
(3.27 g, 12.37 mmol), 1.0 N LiOH (14.8 ml, 14.8 mmol), THF (31 ml) and H ₂ O (16 ml ) Was stirred for 1.5 hours at room temperature and then concentrated by rotary evaporation to remove THF. The aqueous solution was washed with Et ₂ O ( ₂ × 30 ml) and the Et ₂ O layer was discarded. Acidifying the aqueous layer with 1.0 N HCl (about 17 ml) and the mixture was extracted with CHCl ₃ (3x50 ml). Drying (Na ₂ SO ₄ ) and concentration gave the title compound (3.04 g, 98%) as a colorless powder: mp 88.5-89.5 ° C; _{: MS (DCI / NH 3)} m / e 268.0 (M + H) +.
e) N, N-Dimethyl 3- [4- (tert-butoxycarbonyl) phenyl] propanamide
EDC (2.09 g, 10.88 mmol) of 3- [4- (tert- butoxycarbonyl) phenyl] propanoic acid (2.27 g, 9.07 mmol) at room temperature in anhydrous CH ₃ CN (45 ml), dimethylamine hydrochloride ( 0.88 g, 10.88 mmol), HOBt.H ₂ O (1.47 g, 10.88 mmol) and diisopropylethylamine (3.2 ml, 18.14 mmol). After 19.5 hours, the reaction was concentrated and the residue was chromatographed on silica gel (EtOAc). The title compound (2.46 g, 98%) was obtained as a colorless oil: TLC _Rf (EtOAc) 0.52; : MS (ES) m / e 278.4 (M + H) &lt; ⁺ & gt ^; .
f) Ethyl 4- [4-tert-butoxycarbonyl) phenyl] -3- (dimethylaminocarbonyl) butanoate
A solution of lithium bis (trimethylsilyl) amide in THF (1.0 M, 5.8 ml, 5.8 mmol) under argon at-78 C was added over 2.5 min to a solution of N, N-dimethyl 3- [4- (tert -Butoxycarbonyl) phenyl] propanamide (1.34 g, 4.83 mmol) in tetrahydrofuran (20 mL). The yellow solution was stirred at -78 [deg.] C for 0.5 h, then ethyl bromoacetate (2.7 ml, 24.15 mmol) was added over the course of 15 seconds (precooling) to the flask wall. After 0.5 h, the reaction was poured into a saturated solution of NH ₄ Cl (50 ml) and the mixture was extracted with EtOAc (2 x 100 ml). Dried (MgSO _4), a light yellow oil was obtained through concentration and reconcentrated from xylenes. The title compound (453.5 mg, 26%) was obtained as a pale yellow oil by silica gel chromatography (1: 1 EtOAc / hexanes): TLC _Rf (1: 1 EtOAc / hexanes) 0.44; MS (ES) m / e 364.2 (M + H) &lt; ⁺ & gt ^; .
g) Ethyl 4- (4-carboxyphenyl) -3- (dimethylaminocarbonyl) butanoate
Ethyl 4- [4- (tert- butoxycarbonyl) phenyl] of the TFA (2.3 ml) at 0 ℃ anhydrous _{CH 2 Cl 2 (2.3 ml)} -3- ( dimethylamino-carbonyl) butanoate (168.6 mg , &Lt; / RTI &gt; 0.46 mmol) in one portion. The solution was stirred at room temperature for 0.5 h and then concentrated to dryness by rotary evaporation. The residue was reconcentrated from toluene to give the title compound as a pale yellow oil: MS (ES) m / e 308.0 (M + H) &lt; ⁺ & gt ^; .
methyl) amino] carbonyl] phenyl] -3- (dimethylaminocarbonyl) butanoate
Ethyl 4- (4-carboxyphenyl) at room temperature in anhydrous _{CH 3 CN (2.3 ml) -3-} ( dimethylamino-carbonyl) butanoate (0.46 mmol), 2- (methylaminomethyl) benzimidazole dihydrochloride EDC (105.8 mg, 0.55 mmol) was added to a solution of the title compound (129.2 mg, 0.55 mmol), HOBt.H ₂ O (74.6 mg, 0.55 mmol) and diisopropylethylamine (0.32 ml, 1.84 mmol) After 22 h, concentrate the reaction and the yellow residue was chromatographed on silica gel (10% MeOH containing _{1: 1 EtOAc / CHCl 3)} . The title compound (191.5 mg, 92%) was obtained as a light yellow oil: TLC R _f (10% MeOH containing _{1: 1 EtOAc / CHCl 3)} 0.44; MS (ES) m / e 451 (M + H) &lt; ⁺ & gt ^; .
I) () -4- [4 - [[[(Benzimidazol-2-yl) methyl] methylamino] carbonyl] phenyl] -3- (dimethylaminocarbonyl)
Ethyl (±) -4- [4 in THF (2.2 ml) and _{H 2 O (1.6 ml) -} [[[( benzimidazol-2-yl) methyl] methylamino] carbonyl] phenyl-3- (dimethyl (191.5 mg, 0.43 mmol) and 1.0 N LiOH (0.52 ml, 0.52 mmol) was stirred at room temperature for 17 hours and then acidified with TFA (0.10 ml, 1.29 mmol). Concentration afforded an aqueous residue which was further chromatographed using ODS chromatography (17% CH ₃ CN / H ₂ O with 0.1% TFA, 15% CH ₃ CN / H ₂ O with 0.1% TFA). Concentration and lyophilization gave the title compound (133.4 mg, 47%) as a colorless powder: HPLC (PRP-1 (registered trademark), 20% CH ₃ CN / H ₂ O with 0.1% TFA) K '= 1.3; MS (ES) m / e 423.2 (M + H) &lt; ⁺ & gt ^; . C ₂₃ H ₂₆ N ₄ O ₄ · 2CF ₃ CO ₂ H · 0.5H ₂ O; Theoretical values: C, 49.17; H, 4.43; N, 8.49. Found: C, 49.13; H, 4.62; N, 8.52.
Example 5
(S) -2,3,4,5-tetrahydro-7 - [[[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -4-methyl- , 4-benzodiazepin-2-acetic acid, [(2,2-dimethyl-2-methoxyacetyl) oxy] methyl ester
yl) methyl] methylamino] carbonyl-4 (3S) -2,3,4,5-tetrahydro-7 - [[[[[1- (tert-butoxycarbonyl) benzimidazol- -Methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetic acid
To a solution of (S) -2,3,4,5-tetrahydro-7- [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl- Tert-butyl dicarbonate (230 mg, 0.36 mmol) in DMF (2 ml) was added to a mixture of tetrahydrofuran-1 H- 1, 4-benzodiazepine-2-acetic acid (444 mg, 1.0 mmol) , 1.05 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours. A partial analysis showed only a 50% conversion rate. Triethylamine and di-tert-butyl dicarbonate were added one more time and further stirring was continued for 18 hours. Some of the material still did not react, a third reagent amount was added and the reaction was stirred for a further 18 hours. The reaction mixture was concentrated to dryness, the residual oil was treated with water, filtered and vacuum dried at 40-50 ° C to give the title compound as a white solid (0.442 g, 85%). : MS (ES) m / e 522.4 (M + H) &lt; ⁺ & gt ^; .
b) Synthesis of (S) -2,3,4,5-tetrahydro-7 - [[[[[1- (tert-butoxycarbonyl) benzimidazol- 2- yl] methyl] methylamino] carbonyl] Methyl-3-oxo-1H-1,4-benzodiazepin-2-acetic acid, [(2,2- dimethyl- 2- methoxyacetyl) oxy] methyl ester
Anhydrous potassium carbonate (0.25 g, 1.8 mmol) was added to a solution of the compound of Example 5a (0.209 g, 0.4 mmol) in dry acetone (10 ml). The reaction mixture was stirred at room temperature under argon for 1 hour. After adding 2-methoxy-2-methylpropanoic acid chloromethyl ester (US Pat. No. 4,602,012, July 22, 1986) (0.334 g 2.0 mmol) tetrabutylammonium iodide (0.03 g, 0.08 mmol ). The reaction was stirred at room temperature under argon for 48 hours. It was filtered and the filtrate was concentrated to give the yellow oil residue of the title compound (0.67 g, quantitative yield). TLC R _f 0.48 (silica gel, 6% methanol in methylene chloride). MS (ES) m / e 652.2 (M + H) &lt; ⁺ & gt ^; .
c) (S) -2,3,4,5-Tetrahydro-7 - [[[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -4-methyl- Benzodiazepine-2-acetic acid, [(2,2-dimethyl-2-methoxyacetyl) oxy] methyl ester
TFA (1 ml) was added to a solution of the compound of Example 5b (0.67 g, 1 mmol) in methylene chloride (5 ml). The reaction was stirred at room temperature under argon for 4 hours. It was concentrated to dryness and the residue was evaporated three times with methylene chloride to remove the TFA completely to give the title compound (0.4 g, 73%). It was purified by flash silica column (step gradient, 2-3% methanol in methylene chloride). The fractions containing the pure compound were collected and concentrated to give the title compound (65 mg) as an off-white solid. MS (ES) m / e 552.2 [M + H] &lt; ⁺ &gt;. ^{1 H NMR (400 MHz, (} CDCl 3) δ 7.6 (br s, 1H), 7.22 (m, 6H), 6.5 (d, 1H), 5.85 (d, 1H), 5.8 (d, 1H), 5.4 ( 3H), 3.15 (s, 3H), 3.05 (s, 3H), 5.05 (m, ., 3H), 3.02 (dd , 1H), 2.7 (dd, 1H), 1.4 (s, 6H) C 28 H 33 N 5 O 7 · 1.25 H 2 O Calcd: C, 58.58; H, 6.23 ; N, Found: C, 58.60, H, 5.94, N, 12.00.
Example 6
(Methyl) amino] carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine -Benzodiazepin-2- (N-hydroxy) acetamide &lt; / RTI &gt;
(a) Synthesis of (±) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methylamino] carbonyl] -4-methyl- , 4-benzodiazepin-2- (N-hydroxy) acetamide
NaOMe (25 wt% solution of MeOH, 2.2 ml, 9.7 mmol, from Aldrich) was added to a solution of hydroxyamine hydrochloride (0.67 g, 9.7 mmol) in MeOH (40 ml) Lt; / RTI &gt; Methyl] amino] carbonyl] -4-methyl-3-oxo-1H-1,2,3,4,5tetrahydro-7 - [[[(benzimidazol- 4-Benzodiazepine-2-acetate (0.82 g, 1.9 mmol) was suspended in MeOH (2 ml) and THF (15 ml) and added dropwise to the solution. Then the reaction was treated with 45 ℃ which then, after the mixture is concentrated in vacuo Keene, 0.1% TFA containing _{10% CH 3 CN / H 2} O (5 ml) was stirred at for 24 hours. After dissolving all the material, a solid precipitated. Half of this material was dissolved in the mobile phase by addition of an excess of TFA, this pre-HPLC (YMC ODS-AQ, 50 x 250 mm, flow rate 80 ml / min, 0.1% TFA containing _{10% CH 3 CN / H 2} O; purification by t _R = 57 min) to give the title compound (91 mg, 22%) as a white solid. MS (ES) m / e 423.1 [M + H] &lt; ⁺ &gt;. ^{1 H NMR (400 MHz, DMSO} -d 6) δ 9.06 (bt, J = 4 Hz, 1H), 7.77 (m, 2H), 7.58 (m, 2H), 7.50 (m, 2H), 6.60 (d, J = 10 Hz, 1H), 6.40 (bs, 1H), 5.52 (d, J = 19 Hz, 1H), 5.18 ), 3.83 (d, J = 19 Hz, 1H), 2.95 (s, 3H), 2.60 (dd, J = 17,9 Hz 1H), 2.28 (dd, J = 15,7 Hz, 1H). C ₂₁ H ₂₂ N ₆ O _{4 ·} 1.5 C ₂ HF ₃ O ₂ · 1.0 H ₂ O) Theoretical: C, 47.14; H, 4.20; N, 13.74. Found: C, 46.95; H, 4.24; N, 13.37.
Example 7
Yl) phenyl] -4-methyl-3-oxo-1H-1,4-benzodiazepin-2- Preparation of acetic acid
a) 2- (3-Iodophenyl) benzimidazole
A THF (50 ml) 3- iodo in Fig acid (5.0 g, 20 mmol) and Et ₃ N isobutyl chloroformate (2.9 ml, 21 mmol) to the cooled solution of (3.7 ml, 26 mmol) was added. This solution was stirred for 1 hour at 10 &lt; 0 &gt; C. All of the solution was slowly added to a solution of 1,2-diaminobenzene (2.2 g, 20 mmol) in THF (50 ml). After 18 h, the reaction was concentrated and the residue was partitioned between EtOAc and 5% Na ₂ CO ₃ . Each layer was separated and the EtOAc layer was washed with water. The organic layer was concentrated and the residue was treated with EtOAc and left for 15 minutes. Filtration gave a solid which was treated with AcOH (50 ml) and heated to 110 &lt; 0 &gt; C. After 18 h, the solution was concentrated. The residue was treated with EtOAc and the solution was filtered to give the title compound (3.14 g, 50%): MS (ES) m / e 321.2 (M + H) <^+> .
b) 2 - [(3-tributylstannyl) phenyl] benzimidazole
2- (3-iodophenyl) benzimidazole (1.0 g, 3.1 mmol), bis tributyltin (3.9 ml, 6.2 mmol) and _{PdCl 2 (PPh 3) 2 (} 100 mg, 0.14 in DMF (10 ml) mmol) &lt; / RTI &gt; was heated to 90 &lt; 0 &gt; C under argon. After 2 h, the solution was concentrated. The residue was treated with hexane and filtered. EtOAc was added and the solution was filtered. The filtrate was concentrated to give the title compound (812 mg, 54%): MS (ES) m / e 485.4 (M + H) <^+> .
c) Methyl (±) -2,3,4,5-tetrahydro-1- (tert-butoxycarbonyl) -7-iodo-4-methyl- 2-acetate
CH ₃ CN (10 ml) methyl-7-iodo-4-methyl-3-oxo -1H-1,4- benzodiazepine-2-acetate (1.6 g, 4.3 mmol) and DMAP (10 mg, 0.08 mmol) of To the solution was added di-tert-butyl dicarbonate (2.0 g, 8.6 mmol) and the solution was stirred at room temperature. Additional di-tert-butyl dicarbonate (total 8 g, 34.4 mmol) was added periodically until the reaction was complete. Concentration and silica gel chromatography gave the title compound (1.8 g, 90%): MS (ES) m / e 497.2 (M + Na) &lt; ⁺ & gt ^; .
d) Methyl (±) -2,3,4,5-tetrahydro-7- [3- (benzimidazol-2- yl) phenyl] -1- (tert-butoxycarbonyl) 3-oxo-lH-l, 4-benzodiazepin-2-acetate
To a solution of 2 - [(3-tributylstannyl) phenyl] benzimidazole (0.24 g, 0.5 mmol), methyl (+ -) - 1- (tert-butoxycarbonyl) (0.2 mg, 0.7 mmol), CuI (10 mg, 0.05 mmol) and PdCl ₂ (PPh ₃ ) ₂ (40 mg, 0.05 mmol ) Was heated to 100 &lt; 0 &gt; C under argon. After 18 hours, the solution was concentrated. The title compound (0.06 g, 22%) was obtained by silica gel chromatography: MS (ES) m / e 541.5 (M + H) <^+> .
e) Synthesis of methyl (±) -2,3,4,5-tetrahydro-7- [3- (benzimidazol-2-yl) phenyl] -4- -2-acetate
To a solution of methyl (±) -2,3,4,5-tetrahydro-7- [3- (benzimidazol-2-yl) phenyl] -1- (tert- Methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (0.06 g, 0.11 mmol) in dichloromethane was stirred at room temperature for 1 hour. This solution was concentrated to give the title compound (0.05 g, 100%): MS (ES) m / e 441.4 (M + H) <^+> .
f) (±) -2,3,4,5-Tetrahydro-7- [3- (benzimidazol-2-yl) phenyl] -4- 2-acetic acid
1.0 N NaOH at room temperature (0.22 ml, 0.22 mmol) of 1: Preparation of methyl (±) of _{1 MeOH / H 2 O (2} ml) -2,3,4,5- tetrahydro-7- [3- (benzimidazole Yl) phenyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine-2- acetate (0.05 g, 0.11 mmol) Lt; / RTI &gt; The residue was dissolved in water and the solution was acidified to pH 4 with AcOH (litmus paper). Filtration gave the title compound (0.05 g, 10%): ¹ H NMR (250 MHz, DMSO-d ₆ ) 2.4-2.9 (m, 2H), 3.0-3.1 (s, 3H), 3.8-4.0 (M, 1H), 5.0-5.1 (m, 1H), 5.5-5.6 (d, 1H), 6.7-6.8 (d, 1H), 7.5-8.5 + H) ⁺ . _{C 25 H 22 N 4 O 3} · 1.5 HCl · 1.0 AcOH · 0.5H 2 O Calcd: C, 58.94; H, 5.22; N, 10.18. Found: C, 59.00; H, 5.15; N, 9.92%.
Example 8
(Methyl) amino] carbonyl] -1H-1, 2-dihydroxy- Preparation of 4-benzodiazepin-2-acetic acid
a) 2 - [[(N-benzyloxycarbonyl) amino] methyl] phenanthrumimidazole
According to the general procedure of Example 7 (a), except that N-Cbz-glycine was used instead of 3-iodobenzoic acid and 9,10-diaminophenanthrene was used instead of 1,2-diaminobenzene, the title compound 0.41 g, 45%): MS (ES) m / e 382.4 (M + H) <^+> .
b) 2- (Aminomethyl) phenanthrylimidazole
A solution of 2 - [[(N-benzyloxycarbonyl) amino] methyl] phenanthrumimidazole (0.2 g, 0.52 mmol) in 30% HBR acetic acid (0.8 ml) was stirred at room temperature for 1 hour. The solution was concentrated and the residue was treated with Et ₂ O. Filtration gave the title compound (0.138 g, 80%) as an oil residue: MS (ES) m / e 248.3 (M + H) <^+> .
c) Methyl (짹) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7 - [[[henanthridimidazol-2- yl) methyl] amino] carbonyl] 1,4-benzodiazepine-2-acetate
To a solution of 2- (aminomethyl) phenanthrumimidazole (0.138, 0.42 mmol), methyl (+) - 7-carboxy-4-methyl- To a solution of tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.123 g, 0.42 mmol), HOBt.H ₂ O (0.063 g, 0.42 mmol) and Et ₃ N (0.14 ml, g, 0.42 mmol). After 18 hours, the reaction was concentrated, and the residue was distributed between EtOAc and 5% NaHCO _3. It separated the layers and washed the organic layer with H ₂ O. Drying (Na ₂ SO ₄₎ and concentrated to give the title compound (0.2 g, 90%): MS (ES) m / e 522.4 (M + H) +.
d) (짹) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7 - [[[(phenanthrimidazol-2-yl) methyl] amino] carbonyl] 1,4-benzodiazepin-2-acetic acid
(±) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7 - [[[(phenanthridimidazol- (ES) m / e &lt; RTI ID = 0.0 &gt; (ES) &lt; / RTI &gt; 508.5 (M + H) &lt; ⁺ & gt ^; . C ₂₉ H ₂₅ N ₅ O ₄ · 1.0 TFA · 3.0 H ₂ O Theoretical: C, 55.11; H, 4.77; N, 10.37. Found: C, 55.38; H, 5.13; N, 10.74.
Example 9
Methyl (+/-) - 7-carboxyl-4- (2,2,2-trifluoroethyl) -3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin- Preparation of acetate
a) tert-Butyl 3 - [(2,2,2-trifluoroethyl) amino] methyl-4-nitrobenzoate
4-nitrobenzoate (2.4 g, 8 mmol) was dissolved in dry THF (50 ml) and 2,2,2-trifluoroethylamine (3 ml, 38 mmol) Was added all at once. The orange-yellow solution was stirred at room temperature for 40 minutes and then concentrated to remove the THF. The residue was diluted with Et ₂ O (100 ml) and washed _{twice with} 10% aqueous Na ₂ CO ₃ (50 ml) and brine (50 ml). The organic layer was dried (MgSO _4). The title compound (1.6 g, 63%) was obtained as a yellow oil: ¹ H NMR (250 MHz, CDCl ₃ ) 8.21 (d, J = 1.3 (D, J = 8.4, 1.3 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 4.20 (s, 2H), 3.24 1.62 (s, 9 H).
b) Synthesis of tert-butyl 3 - [[N- (2,2,2-trifluoroethyl) -N- (tert- butoxycarbonyl) amino] methyl-4-nitrobenzoate
To a solution of tert-butyl 3 - [(2,2,2-trifluoroethyl) amino] methyl-4-nitrobenzoate (1.6 g, 5 mmol) in CH ₂ Cl ₂ (25 ml) at room temperature was added di- -Butyl dicarbonate (2.15 g, 10 mmol) was added in one portion. The reaction was concentrated and heated to 50 &lt; 0 &gt; C for 18 h under vacuum. Silica gel chromatography (2% - 5% EtOAc / hexanes) gave the title compound (2 g, 96%) as a yellow oil. ¹ H NMR (250 MHz, CDCl ₃ ) 7.85-8.15 (m, 3H), 4.75-5.05 (m, 2H), 3.80-4.10 , 9H).
c) Preparation of tert-butyl 4-amino-3 - [[N- (2,2,2-trifluoroethyl) -N- (tert-butoxycarbonyl) amino] methyl benzoate
To a solution of tert-butyl 3 - [[N- (2,2,2-trifluoroethyl) -N- (tert- butoxycarbonyl) amino] methyl-4-nitrobenzoate (2.0 g, , 5 mmol) was added 10% Pd / C (0.4 g, 0.4 mmol) and the mixture was shaken with Parr apparatus at room temperature under H ₂ (55 psi). After 4 hours, the reaction product was filtered through celite (R) and, by concentration of the filtrate the title compound (1.9 g, 99%) was obtained a a colorless ^{oil: 1 H NMR (, 400 MHz} CDCl 3) δ 7.76 (dd, 2H, J = 8.5 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H) 9H), 1.51 (m, 9H).
d) Preparation of tert-butyl (±) -4- [2- (1,4-dimethoxy-1,4-dioxobutyl) amino] -3 - [[N- (2,2,2- ) -N- (tert-butoxycarbonyl) amino] methyl benzoate
To a solution of tert-butyl 3 - [[N- (2,2,2-trifluoroethyl) -N- (tert- butoxycarbonyl) amino] methylbenzoate (1.9 g, 5 mmol) And dimethylacetylene dicarboxylate (0.58 ml, 5.5 mmol) in DMF (5 ml) was heated to reflux for 60 minutes and then cooled to room temperature. The resulting solution was combined with MeOH (20 ml) and 10% Pd / C (0.5 g, 0.5 mmol) and the mixture was shaken with Parr apparatus at room temperature under H ₂ (50 psi). After 3 h, the reaction was filtered through Celite (R) and the filtrate was concentrated by rotary evaporation. The title compound (1.6 g, 62%) to give the a light yellow oil ^{1 H NMR (400 MHz, CDCl} 3) δ 7.85 (dd, J = 8.4, 2.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H) , 6.65 (d, J = 8.4 Hz, 1H), 6.15 (br s, 1H), 4.55-4.70 (m, 2H), 4.40 ), 3.70 (s, 3H), 3.35-3.50 (m, 2H), 2.95 (dd, J = 16.9, 6.8 Hz, 1H), 2.84 (dd, J = 16.9, 6.9 Hz, 1H) 18H).
e) Methyl (±) -7-carboxyl-4- (2,2,2-trifluoroethyl) -3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin- 2-acetate
Tert- in anhydrous CH ₂ Cl ₂ (20 ml) at 0 ℃ butyl (±) -4- [2- (1,4- dimethoxy-1,4-oxobutyl) amino] -3 - [[N- (1.6 g, 3 mmol) in tetrahydrofuran (5 ml) was added TFA (7 ml) at once, and a pale yellow solution Was warmed to room temperature. After 2 h, the solution was concentrated by rotary evaporation and the residue was reconcentrated from toluene (residual TFA removal). The resulting oil in toluene (10 ml) and _{Et 3 N (2 ml, 15} mmol) were combined and heated at reflux the mixture under argon. After 18 hours, the solution was allowed to cool and was concentrated to dryness under vacuum. The residue was dissolved in a minimum amount of MeOH (about 15 ml) at reflux, diluted with water (10 ml) and acidified with glacial acetic acid (4 drops). The mixture was left in the refrigerator overnight and then filtered. The solid was dried in a high vacuum condition, to give the title compound (0.80 g, 76%) as a tan ^{powder: 1 H NMR (400 MHz,} DMSO-d 6) δ 7.61 (2, 1H), 7.57 (dd, J = 8.5 J = 8.5 Hz, 1H), 5.59 (d, J = 16.7 Hz, 1H), 5.25 (m, (Dd, J = 16.8, 5.4 Hz, 1H), 4.28 (m, 2H), 4.15 , 1H).
f) methyl (±) -2,3,4,5-tetrahydro-7 - [[[[(benzimidazol-2-yl) methyl] amino] carbonyl] , 2-trifluoroethyl) -1H-1,4-benzodiazepine-2-acetate
(±) -7-carboxy-4- (2,2,2-trifluoroethyl) -3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (0.20 g, 0.71 mmol), HOBt.H ₂ O (0.12 g, 0.86 mmol), 2-aminomethylbenzimidazole dihydrochloride (0.19 g, 0.86 mmol) and DIEA (0.5 ml, 2.8 mmol ) And acetonitrile (5 ml) was added EDC (0.16 g, 0.86 mmol). The resulting solution was stirred at room temperature overnight and then concentrated. The residue was partitioned between ethyl acetate and water and the layers separated. The organic phase was washed with brine, dried (MgSO _4), and concentrated. With (CH ₂ Cl ₂ containing 1% to 10% of CH ₃ OH) was purified by silica gel chromatography to give the title compound (0.12 g, 44%) as a tan solid: NMR (400 MHz, DMSO- d 6) δ J = 5 Hz, 1 H), 5.53 (m, 2H), 6.57 (d, J = (d, J = 16.8 Hz, 1H), 5.13 (m, 1H), 4.75 (m, 2H), 4.10 1H), 2.69 (dd, J = 16.8,5.4 Hz, 1H).
g) (±) -2,3,4,5-Tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -3- 2-trifluoroethyl) -1H-1,4-benzodiazepine-2-acetic acid
_{THF (10 ml), CH 3} OH (2 ml) and H ₂ O ₍₂ ml) methyl (±) -2,3,4,5- tetrahydro of -7 - [[[(benzimidazol-2- Yl) methyl] amino] carbonyl] -3-oxo-4- (2,2,2-trifluoroethyl) A solution of monohydrate (0.017 g, 0.4 mmol) was stirred overnight at room temperature. It was concentrated and the residue was dissolved in water. The solution was adjusted to pH 4 with 3 N HCl and then refrigerated for 1 hour. The resulting solid was collected by filtration and dried to give the title compound (0.11 g, 90%) as a white solid: MS (ES) m / e 476 (M + H) &lt; ⁺ & gt ^; . C ₂₂ H ₂₀ N ₅ F ₃ O _{4 ·} 1.25 H ₂ O Theoretical: C, 53.07; H, 4.55; N, 14.06. Found: C, 52.85; H, 4.36; N, 13.98.
Example 10
Methyl) amino] carbonyl] -3-oxo-4- (2,2,2 &lt; RTI ID = 0.0 & -Trifluoroethyl) -1H-1,4-benzodiazepin-2-acetic acid
methyl) amino] carbonyl] -3-oxo-4- (2, &lt; / RTI & 2,2-trifluoroethyl) -1H-1,4-benzodiazepine-2-acetate
Following the procedure of Example 9 (f) but substituting 2- (methylaminomethyl) benzimidazole dihydrochloride for 2-aminomethylbenzimidazole dihydrochloride, the title compound was prepared: ¹ H NMR _{(400 MHz, CDCl 3) δ} 7.67 (m, 2H), 7.37 (m, 2H) 6.54 (d, J = 8 Hz, 1H), 5.46 (d, J = 16.7 Hz, 1H), 5.20 (m, 1H ), 5.04 (s, 2H), 4.71 (m, IH), 4.17 (m, IH), 3.94 s, 3H), 2.98 (m, IH), 2.74 (m, IH).
b) (짹) -2,3,4,5-Tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -3-oxo- , 2-trifluoroethyl) -1H-1,4-benzodiazepine-2-acetic acid
Yl) methyl] methylamino] carbonyl] -3 (3H) -quinolinone according to the process of Example 9 (g) (ES) m / e 490.2 [M + H &lt; + &gt; ] ⁺ . C ₂₃ H ₂₂ N ₅ F ₃ O ₄ · 2.25 H ₂ O Theoretical: C, 52.12; H, 5.04; N, 13.21. Found: C, 52.00; H, 5.12; N, 13.09.
Example 11
Methyl] amino] carbonyl] -3-oxo-4- (2-methylbenzyl) (2,2,2-trifluoroethyl) -1H-1,4-benzodiazepine-2-acetic acid
a) Methyl (±) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] amino] carbonyl] -4- (2,2,2-trifluoroethyl) -1H-1,4-benzodiazepine-2-acetate
According to the procedure of Example 9 (f) except that 2- (aminomethyl) -4-aza-5-methylbenzimidazole dihydrochloride was used instead of 2-aminomethylbenzimidazole dihydrochloride, the title compound : MS (ES) m / e 505.2 (M + H) &lt; ⁺ & gt ^; .
b) Preparation of (±) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] amino] carbonyl] -3- 4- (2,2,2-trifluoroethyl) -1H-1,4-benzodiazepine-2-acetic acid
(±) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2-yl) methyl] amino (ES) m / e calcd for &lt; RTI ID = 0.0 &gt; e 491.2 (M + H) &lt; ⁺ & gt ^; . C ₂₂ H ₂₁ N ₆ F ₃ O ₄ .27 _/ 8 H ₂ O Theoretical: C, 48.73; H, 4.97; N, 15.50. Found: C, 48.50; H, 4.59; N, 15.33.
Example 12
Methyl] amino] carbonyl] -4- [2- (3,4-methylenedioxy) benzyl] Oxyphenyl) ethyl] -3-oxo-1H-1,4-benzodiazepin-2-acetic acid
a) Methyl (±) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -4- [2- Methylenedioxyphenyl) ethyl] -3-oxo-1 H-1, 4-benzodiazepine-2-acetate
EDC (0.10 g, 0.55 mmol) was added to a solution of methyl 7-carboxy-4- [2- (3,4-methylenedioxyphenyl) ethyl] 4-benzodiazepine-2-acetate (0.14 g, 0.3 mmol), 2- ( methylaminomethyl) benzimidazole dihydrochloride (0.12 g, 0.51 mmol), HOBt · H 2 O (0.072 g, 0.55 mmol) and DIEA (0.32 ml, 1.84 mmol). The resulting solution was stirred overnight at room temperature and then concentrated. The residue was partitioned between ethyl acetate and water and the layers separated. Water extracted with ethyl acetate, wash the combined organic phases with brine, dried (MgSO ₄₎ and concentrated. The title compound (0.11 g, 59%) was obtained as a colorless foam by silica gel chromatography. _{^{1 H NMR (CDCl 3) δ}} 7.62 (m, 2H), 7.31 (m, 2H), 7.20 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H), 6.65 (d, J = 7.9 Hz, 1H), 6.60 (s, 1H), 6.55 (d, J = 7.9 Hz, 1H), 6.46 (d, J = 8.1 Hz, 1H) J = 16.5 Hz, 1H), 5.02 (m, 1H), 4.93 (d, J = 14.6,1H), 4.83 , 3.74 (s, 3H), 3.71 (m, 1H), 3.60 (m, 1H), 3.58, (d, J = 16.5, , 6.8 Hz, 1 H), 2.70 (m, 1 H).
b) (짹) -2,3,4,5-Tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -4- [2- Methylene dioxyphenyl) ethyl] -3-oxo-1H-1, 4-benzodiazepin-
To a stirred solution of methyl (±) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -4 (0.11 g, 0.19 g) in H ₂ O (1 ml) was added dropwise to a solution of 2- (3,4-methylenedioxyphenyl) ethyl] -3-oxo-1H-1,4-benzodiazepine- A solution of lithium monohydrate (0.01 g, 0.23 mmol) was added. The resulting solution was stirred overnight and concentrated to dryness. The residue was dissolved in water, the solution was washed with ethyl acetate and the pH was adjusted to 4 with 3 N HCl. The resulting precipitate was collected by filtration to give the title compound (0.055 g, 51%) as a white solid. MS (ES) m / e 556.2 [M + H] &lt; ⁺ &gt;. C ₃₀ H ₂₉ N ₅ O ₆ .H ₂ O Theoretical: C, 62.82; H, 5.45; N, 12.21. Found: C, 62.69; H, 5.26; N, 12.15.
Example 13
(2-phenylethyl) -lH-indol-2-yl) acetyl] amino] -5-oxo-4- Preparation of 1,4-benzodiazepin-2-acetic acid
a) Preparation of methyl (±) -2,3,4,5-tetrahydro-7 - [[2- (benzimidazol- -1H-l, 4-benzodiazepin-2-acetate
At room temperature, EDC (0.27 g, 1.4 mmol) was added to a solution of (±) -2,3,4,5-tetrahydro-7-amino- (0.40 g, 1.1 mmol), benzimidazole-2-acetic acid (Archiv. Der Pharmazie 1960, 293, 758; 0.25 g, 1.4 mmol), HOBt.H ₂ O 0.20 g, 1.5 mmol) and DIEA (0.35 ml, 2 mmol). The resulting solution was stirred for 2 days and then concentrated to dryness. The residue was partitioned between ethyl acetate and water and the layers separated. The organic phase was washed with brine, dried (MgSO ₄₎ and concentrated. Purification by silica gel chromatography _{(1% - 10% -CH 3} OH -containing CH ₂ Cl ₂₎ to give the title compound (0.21 g, 36%) as an amber foam: MS (ES) m / e 512.2 (M + H) + .
b) Preparation of (±) -2,3,4,5-tetrahydro-7 - [[2- (benzimidazol- 1H-1, 4-benzodiazepin-2-acetic acid
Methyl (±) -2,3,4,5- tetrahydro -7 in a stirred at room temperature THF (10 ml) and _{H 2 O (2 ml) -} [[2- ( benzimidazol-2-yl) acetyl (0.21 g, 0.41 mmol) and lithium hydroxide monohydrate (0.022 g, 0.52 mmol) in anhydrous tetrahydrofuran (10 ml) at room temperature Lt; / RTI &gt; and concentrated. The residue was dissolved in water, the solution was washed with ethyl acetate and the pH was adjusted to 4 with 3 N HCl. The resulting precipitate was collected by filtration to give the title compound (0.12 g, 59%) as an off-white solid. MS (ES) m / e 498.2 [M + H] &lt; ⁺ &gt;. C ₂₈ H ₂₇ N ₅ O _{4 ·} 1.5H ₂ O Theoretical: C, 64.11; H, 5.76; N, 13.35. Found: C, 64.36; H, 5.57; N, 13.21.
Example 14
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] Preparation of 4-benzodiazepin-2-acetamide
a) (S) -2,3,4,5-Tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -4-methyl- 1,4-benzodiazepin-2-acetamide
To a solution of methyl (±) -2,3,4,5-tetrahydro-7- [[[(benzimidazol-2-yl) methyl] amino] carbonyl] (330 mg, 0.76 mmol) was bubbled into the solution for 0.5 hour while cooling in an ice bath. The reaction was plugged at room temperature for 18 hours. After concentration, the residue was purified by silica gel flash chromatography (90: 10 CH ₂ Cl ₂ / MeOH) to give the title compound (52%) as a white solid. MS (ES) m / e 421.2 [M + H] &lt; ⁺ &gt;. C ₂₂ H ₂₄ N ₆ O ₃ .1.5H ₂ O Theoretical: C, 59.05; H, 6.08; N, 18.78. Found: C, 58.90; H, 6.04; N, 18.45.
Example 15
(2-benzyloxycarbonyl) amino] carbonyl] -3-oxo-4- (2- Phenylethyl) -1H-1,4-benzodiazepin-2-yl] methyl] tetrazole
a) Methyl (±) -2,3,4,5-tetrahydro-7- (tert-butoxycarbonyl) -3-oxo- 2-acetate
To a solution of methyl (±) -2,3,4,5-tetrahydro-7-carboxy-3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine- (1.0 g, 2.6 mmol) was suspended and N, N-dimethylformamide-di-tert-butyl acetal (5 ml, 20.8 mmol) was added dropwise. The reaction mixture was heated at 80 ℃ for 1.5 hours, cooled to room temperature and poured into 5% Na ₂ CO ₃ solution. Each layer was separated and the aqueous layer was extracted with toluene (2X). The combined organic layers were washed with brine, dried over MgSO _4. This was filtered and evaporated to give the title compound (0.91 g, 82%): MS (ES) m / e 439.2 (M + H) <^+> .
b) (±) -2,3,4,5-Tetrahydro-7- (tert-butoxycarbonyl) -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepin- - acetic acid
To a solution of methyl (±) -2,3,4,5-tetrahydro-7- (tert-butoxycarbonyl) -3-oxo-4- (2- -1,4-benzodiazepine-2-acetate (1.5 g, 3.4 mmol) was treated with H ₂ O (20 ml) and 0.91 N NaOH (5 ml). The reaction was stirred at room temperature under argon for 24 h, then the pH was adjusted to 3 with glacial acetic acid, concentrated to a small volume (10 ml) and poured into ice water. The precipitated solid was collected and dried to give the title compound in quantitative yield: MS (ES) m / e 425.2 (M + H) &lt; ⁺ & gt ^; .
c) (±) -2,3,4,5-Tetrahydro-7- (tert-butoxycarbonyl) -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepin- - [N- (2-cyanoethyl) acetamide]
To a stirred solution of (±) -2,3,4,5-tetrahydro-7- (tert-butoxycarbonyl) -3-oxo-4- (2- (0.65 g, 5 mmol), EDC (0.764 g) and HOBt.H ₂ O (0.54 g, 4 mmol) was added dropwise to a solution of 1,4-benzodiazepin- Respectively. The resulting solution was stirred for 10 minutes and then treated with 3-aminopropionitrile fumarate in dry DMF (2 ml) containing diisopropylethylamine (0.85 g, 6.6 mmol). The reaction was stirred under argon for 18 hours and then concentrated to dryness. The residue was partitioned between water and EtOAc and the layers separated. The organic layer was washed with brine, dried over MgSO _4, filtered and concentrated. Purification of the oily residue by silica gel flash chromatography (98: 2 CH ₂ Cl ₂ / MeOH) gave the title compound (750 mg, 50%): MS (ES) 477.2 (M + H) ⁺ .
d) (±) -1- (2-Cyanoethyl) -5 - [[2,3,4,5 -tetrahydro-7- (tert-butoxycarbonyl) 2-phenylethyl) -1H-1,4-benzodiazepin-2-yl] methyl] tetrazole
To a solution of (±) -2,3,4,5-tetrahydro-7- (tert-butoxycarbonyl) -3-oxo-4- (2- phenylethyl) -1H- A solution of triphenylphosphine (1.14 g, 4.6 mmol), trimethylsilyl azide (0.52 g, 4.6 mmol) was added to a solution of 1,4-benzodiazepin-2- [N- (cyanoethyl) acetamide] ), And diethyl azodicarboxylate (0.8 ml, 4.6 mmol) under argon at room temperature. After 50 hours, the reaction was concentrated to dryness and the residue was purified by silica gel column chromatography (98.5: 1.5 CH ₂ Cl ₂ / MeOH) to give the title compound (0.56 g, 86% e 502.2 (M + H) &lt; ⁺ & gt ^; .
e) (±) -1- (2-Cyanoethyl) -5 - [[2,3,4,5-tetrahydro-7-carboxy- -1,4-benzodiazepin-2-yl] methyl] tetrazole
(±) in CH ₂ Cl ₂ (20 ml) under argon at room temperature for 1 - (2-cyanoethyl) -5 - [[2,3,4,5, - tetrahydro -7- (tert- butoxycarbonyl Methyl] tetrazole (0.5 g, 1 mmol) in dioxane (10 ml) was added dropwise to a solution of 4 (4-benzyloxy- M HCl. After 20 h, the reaction was concentrated to dryness, the residue was diluted with 5% Na ₂ CO ₃ , the solution was extracted with EtOAc and the EtOAc layer was discarded. The aqueous layer was acidified with dilute HCl and extracted with EtOAc (3X). The combined EtOAc extracts were washed with brine, dried over MgSO ₄ and evaporated to give the title compound (0.36 g, 81%): MS (ES) m / e 445.4 (M + H) +.
f) (짹) -1- (2-cyanoethyl) -5 - [[2,3,4,5-tetrahydro-7 - [[[(benzimidazol- Carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepin-2-yl] methyl]
To a solution of (±) -1- (2-cyanoethyl) -5 - [[2,3,4,5, -tetrahydro-7-carboxy- (129 mg, 1 mmol), EDC (172 mg, 0.9 mmol) and HOBt (2 ml) were added under argon to a solution of 2- H ₂ O (122 mg, 0.9 mmol). The reaction was stirred at room temperature for 10 minutes and then a solution of 2-aminomethylbenzimidazole dihydrochloride hydrate (352 mg, 1.6 mmol) in DMF (2 ml) containing DIEA (413 mg, 3.2 mmol) Respectively. After 20 hours, the reaction was concentrated to dryness and the residue was partitioned between water and EtOAc. Each layer was separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO _4, filtered and concentrated. The residue was purified by silica gel flash chromatography (95: 5 CH ₂ Cl ₂ / MeOH) to give the title compound (120 mg, 21%): MS (ES) m / e 575.2 (M + H) ⁺ .
g) Preparation of (±) -5 - [[2,3,4,5-tetrahydro-7 - [[[[(benzimidazol-2- yl) methyl] amino] carbonyl] -3- 2-phenylethyl) -1H-1,4-benzodiazepin-2-yl] methyl] tetrazole
To a solution of (±) -1- (2-cyanoethyl) -5 - [[2,3,4,5, -tetrahydro-7 - [[[(benzimidazol- Methyl] tetrazole (100 mg, 0.2 mmol) in tetrahydrofuran (1 ml) was treated with thiophenol (0.02 ml) and 1 N NaOH solution (2.2 ml). After 3 h, the reaction was concentrated to dryness and the residue was purified by silica gel preparative TLC (85: 15 CH ₂ Cl ₂ / MeOH). The separated product was dissolved in water and the solution was filtered to remove insoluble matter. The filtrate was treated with 2 drops of glacial acetic acid. The precipitated solid was collected and dried to give the title compound (45 mg, 41%). MS (ES) m / e 522.2 [M + H] &lt; ⁺ &gt;. C ₃₀ H ₃₁ N ₉ O ₄揃 2.25H ₂ O Theoretical: C, 56.15; H, 5.52; N, 19.65. Found: C, 56.51; H, 5.05; N, 19.72.
Example 16
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] Amino] but-1-yl] -1H-1,4-benzodiazepine-2-acetic acid
a) Preparation of N - [[2- (N-4-hydroxybut-1-yl) aminomethyl-4-tert-butoxycarbonyl] phenyl] -L-aspartic acid [
(WO 95/18619; 2.55 g, 7.26 mmol), 4 &lt; RTI ID = 0.0 &gt; A &lt; / RTI &gt; The mixture of molecular sieves and 4-hydroxybutylamine (0.64 g, 7.26 mmol) was stirred at room temperature under argon for 30 minutes and then sodium cyanoborohydride (0.49 g, 0.79 mmol) and acetic acid (0.3 ml) Was added. The reaction mixture was left at room temperature overnight and then the solvent was removed in vacuo. The residue was dissolved in water and the solution was adjusted to pH 4 with dilute HCl. Extraction with EtOAc, drying (MgSO ₄ ), filtration and concentration gave the title compound (1.75 g, 57%) as a pale yellow solid. _{TLC R f (4: 20:} 20: 56 MeOH / EtOAc / hexane / CH ₂ Cl ₂₎ 0.22; _{^{1 H NMR (CDCl 3) δ}} 1.55 (s, 9H), 1.56 (m, 2H), 1.80 (m, 2H), 3.01 (m, 4H), 3.55 (m, 2H), 3.70 (s, 3H), (M, 1H), 4.55 (m, 1H), 6.81 (d, J = 8.4 Hz, 1H), 7.70 ).
b) Synthesis of methyl (S) -7- (tert-butoxycarbonyl) -2,3,4,5-tetrahydro-3-oxo-4- (4-hydroxybut- , 4-benzodiazepine-2-acetate
To a stirred solution of N - [[2- (N-4-hydroxybut-1-yl) aminomethyl-4-tert-butoxycarbonyl] phenyl] -L-aspartic acid 1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (2.08 g, 14.7 mmol) was added to a solution of the title compound (1.75 g, 4.1 mmol) and triethylamine (1.15 ml, 8.2 mmol) Was added. After stirring overnight the reaction mixture at room temperature, washed successively with ice-cooled dilute HCl, water, 5% sodium bicarbonate, saturated brine, dried (MgSO _4). Filtration and concentration gave a residue which was purified by silica gel flash chromatography (5% methanol: ethyl acetate) to give the title compound (0.631 g, 38%). TLC R _f (4% MeOH / EtOAc) 0.26; _{^{1 H NMR (CDCl 3) δ}} 1.46-1.61 (m, 4H), 1.57 (s, 9H), 2.64 (d, J = 6.9 Hz 1H), 2.66 (dd, J = 15.9, 6.3 Hz 1H), 2.99 ( (d, J = 15.6, 6.9 Hz, 1H) 3.56-3.54 (m, 4H), 3.74 ), 5.41 (d, J = 16.2 Hz, 1H), 6.49 (d, J = 8.3 Hz, 1H) ; MS (ES) m / e 407.2 [M + H] &lt; ⁺ &gt;; _{[α] D = -185.4. (} c = 1, CH 3 OH).
c) Synthesis of methyl (S) -7- (tert-butoxycarbonyl) -2,3,4,5-tetrahydro-3-oxo-4- (4-phthalimobut- , 4-benzodiazepine-2-acetate
To a solution of methyl (S) -7- (tert-butoxycarbonyl) -2,3,4,5-tetrahydro-3-oxo-4- (4-hydroxybut- Phthalimide (173 mg, 1.17 mmol) and diethyl (2-chloro-pyridin-3-yl) Azodicarboxylate (205 mg, 1.17 mmol) were added in turn. The reaction mixture was stirred overnight at room temperature, the solvent was removed and the residue was purified by silica gel flash chromatography (4:20:20:56 methanol / ethyl acetate / hexane / methylene chloride) to give the title compound (0.430 g, 75 %). _{TLC R f (4: 20:} 20: 56 MeOH / EtOAc / hexane / CH ₂ Cl ₂₎ 0.32; _{^{1 H NMR (CDCl 3) δ}} 1.55 (s, 9H), 1.55-1.61 (m, 4H), 2.68 (dd, J = 14.0, 5.7 Hz, 2H), 2.98 (dd, J = 14.0, 6.6 Hz, 2H ), 3.46-3.64 (m, 4H), 3.71 (s, 3H), 3.85 (d, J = 16.5, J = 8.3, 1.8 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.72-7.76 (m, 2H), 7.81-7.86 (m, 2H). MS (ES) m / e 435 [M + H] &lt; ⁺ &gt;.
d) Methyl (S) -2,3,4,5-tetrahydro-7-carboxy-3-oxo-4- (4-phthalimidobutyl) -lH-1,4-benzodiazepine-
To a solution of methyl (S) -7- (tert-butoxycarbonyl) -2,3,4,5-tetrahydro-3-oxo-4- (4- phthalimidobutyl) 4 N HCl / dioxane (5 ml, 20 mmol) was added to a solution of 1,4-benzodiazepine-2-acetate (660 mg, 0.89 mmol) under argon at room temperature. The reaction mixture was stirred for 18 hours. The suspension was concentrated to give the title compound as an off-white solid (425 mg, 98%): ¹ H NMR (CDCl ₃ ) 1.55-1.61 (m, 4H), 2.71 (dd, J = 14.1, 6.0 Hz, , 3.01 (dd, J = 14.1, 6.3 Hz 1H), 3.50-3.65 (m, 4H), 3.75 (s, 3H), 3.89 (d, J = 16.5 Hz, (Dd, J = 6.0, 6.3 Hz, 1H), 5.40 (d, J = 16.6 Hz 1H), 6.41 (bs, 1H), 6.53 (d, J = 8.4 Hz 1H), 7.69-7.75 m, 4H), 7.82-7.85 (m, 2H); MS (ES) m / e 480.2 [M + H] &lt; ⁺ &gt;.
e) Preparation of methyl (S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -3- Imidobut-1-yl) -1H-l, 4-benzodiazepin-2-acetate
To a solution of methyl (S) -2,3,4,5-tetrahydro-7-carboxy-3-oxo-4- (4-phthalimidobutyl) benzodiazepine-2-acetate (0.85 g, 0.88 mmol), 2- ( aminomethyl) benzimidazole dihydrochloride (230 mg, 1.04 mmol), HOBt · H 2 O (169 mg, 1.25 mmol) and diisopropylethylamine Amine (0.78 ml, 4.5 mmol) in DMF (5 ml) was added EDC (240 mg, 1.25 mmol). After 19 h, the reaction was concentrated by rotary evaporation (high vacuum) and the residue was partitioned between water (5 ml) and EtOAc (5 ml). Each layer was separated and the organic layer was washed with H ₂ O (5 ml). It was dried (MgSO ₄ ) and concentrated to give the title compound (230 mg, 43%) as an off-white solid via silica gel chromatography (5% MeOH / CH ₂ Cl ₂ ). TLC R _f (5% MeOH / Cl ₂ CH ₂ ) 0.30; _{^{1 H NMR (CD 3 OD)}} δ 1.42-1.56 (m, 5H), 2.63 (dd, J = 6.4, 16.2 Hz, 1H), 2.95 (dd, J = 6.7, 16.2 Hz, 1H), 3.33-3.40 ( (m, 2H), 3.48-3.55 (m, 2H), 3.57 (d, J = Hz, 1H), 5.20 (d, J = 16.5 Hz 1H), 6.44 (d, J = 8.4 Hz 1H), 7.18-7.21 (m, 2H), 7.52-7.63 (m, 6H); 7.74-7.76 (m, 2H), 9.08 (br s, 1H).
f) (S) -2,3,4,5-Tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] 2-carboxybenzoyl) amino] but-1-yl] -1H-1,4-benzodiazepine-
Methyl (S) -2,3,4,5- tetrahydro -7 in MeOH (2 ml) and H ₂ O (3 ml) at room temperature - [[[methyl] amino] (benzimidazol-2-yl) (30 mg, 0.71 mmol) was added to a solution of 3-oxo-4- (4-phthalimido) Was added. The reaction mixture was stirred at room temperature for 19 hours. Acidified with dilute HCl to pH 4, and concentrated to give a solid. This was filtered to give the title compound (145 mg, 66%) as a white solid. _{[α] D = -100.4 (c} = 1, CH 3 OH).; _{^{1 H NMR (CD 3 CO)}} δ 1.32-1.65 (m, 5H), 2.58 (dd, J = 16.4, 6.7 Hz, 1H), 2.90 (dd, J = 16.4, 7.9 Hz, 1H), 3.06 (m, J = 7.9, 6.7 Hz, 1H), 5.36 (d, J = 16.7 Hz, 1H), 3.69 (m, Hz), 6.50 (d, J = 8.4 Hz 1H), 7.29 (m, 2H), 7.37 (m, 4H); 7.51 (m, 2 H), 7.664 (s, 1 H), 7.74 (d, J = 6.8 Hz, 1 H); MS (ES) m / e 613.2 [M + H] &lt; ⁺ &gt;. C ₃₂ H ₃₂ N ₆ O ₇ .1.5H ₂ O Theoretical: C, 60.08; H, 5.51; N, 113.14. Found: C, 59.77; H, 5.46; N, 12.98.
Example 17
Methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2- Acetic acid
a) Methyl (±) -1- (tert-butoxycarbonyl) -7- (4-hydroxy-1-butyn-1-yl) -4-methyl- -Tetrahydro-l, 4-benzodiazepin-2-acetate
(65 mg, 0.93 mmol), bis (triphenylphosphine) palladium (II) chloride (5 mg, 0.007 mmol), triphenylphosphine (10 mg, 0.038 mmol) and Copper (II) iodide (10 mg, 0.052 mmol) was added to a solution of methyl (±) -2,3,4,5-tetrahydro-1- (tert- butoxycarbonyl) -7- Methyl-3-oxo-lH-l, 4-benzodiazepine-2-acetate (obtained in example 7c, 440 mg, 0.94 mmol). The reaction mixture was heated at reflux for 4 hours, then filtered through Celite (R) and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography purification (4: 20:: 20 56 MeOH / EtOAc / hexane / CH ₂ Cl ₂₎ to give the title compound (390 mg, 94%) as a pale yellow liquid. TLC R _f (5% MeOH / Cl ₂ CH ₂ ) 0.37; ^{1 H NMR (400 MHz, CDCl} 3) δ 7.34 (dd, J = 1.8, 8.1 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 5.15 2H), 3.59 (s, 3H), 3.04 (m, 2H), 4.75 (d, J = 14.4 Hz, (s, 3H), 2.88 (dd, J = 5.5,15.2 Hz, 1H), 2.45 (t, J = 6.4 Hz, 2H), 2.26 (dd, J = 9.5,15.2 Hz, 1H) , &Lt; / RTI &gt; 1H), 1.34 (br s, 9H); MS (ES) m / e 417 [M + H] &lt; ⁺ &gt;.
b) Methyl (±) -1- (tert-butoxycarbonyl) -7- (4-hydroxybut- 1 -yl) -4-methyl-3-oxo-2,3,4,5-tetrahydro -1,4-benzodiazepine-2-acetate
To a solution of methyl (±) -1- (tert-butoxycarbonyl) -7- (4-hydroxy-1-butyn- 1 -yl) -4-methyl- Was added 10% Pd / C (40 mg), and the mixture was stirred at room temperature under H ₂ (50 psi), to which was added a solution of 4-bromo-4-methoxybenzaldehyde Lt; / RTI &gt; After 12 hours, the reaction was filtered through Celite (R) and the filtrate was concentrated to give the title compound (350 mg, 94%) as a pale yellow liquid. _{TLC R f (4: 20:} 20: 56 MeOH / EtOAc / hexane / CH ₂ Cl ₂₎ 0.55; _{^{1 H NMR (400 MHz CDCl 3}} ) δ 7.10-7.19 (m, 3H), 5.59-5.77 (m, 1H), 4.85 (d, J = 15.0, Hz, 1H), 3.68 -3.60 (m, 5H), (Dd, J = 5.4,15.3 Hz, 1H), 2.65 (t, J = 6.4 Hz, 2H), 2.34 (m, 13H); MS (ES) m / e 421 [M + H] &lt; ⁺ &gt;.
c) Methyl (±) -1- (tert-butoxycarbonyl) -7- (4-carboxybut- 1 -yl) -4-methyl-3-oxo-2,3,4,5-tetrahydro- 1,4-benzodiazepine-2-acetate
From 0 ℃ methyl in _{CH 2 Cl 2 (±) -1-} (tert- butoxycarbonyl) -7- (4-hydroxy-boot-yl) -4-methyl-3-oxo -2,3, To a solution of 4,5-tetrahydro-1,4-benzodiazepine-2-acetate (350 mg, 0.82 mmol) was added 2,2,6,6-tetramethyl-oxopiperidinium chloride (J. Org. 50, 3930-3931; 220 mg, 1.1 mmol). The mixture was stirred for 2 h at 0 &lt; 0 &gt; C in an argon atmosphere. After the addition of 2-methyl-2-butene _{(1 ml), NaClO 2 (} 0.76 g, 6.7 mmol), NaH 2 PO 4 · H 2 O (0.78 g, 5.68 mmol) and H ₂ O (25 newly prepared ml) was added. The cooling bath was removed and the mixture was dissolved in EtOAc and washed successively with 0.05 M HCl and brine. Dried (MgSO ₄ ), concentrated and the title compound (350 mg, 98%) was obtained by silica gel chromatography (4: 20: 20: 56 MeOH / EtOAc / hexane / Cl ₂ CH ₂ containing 5% AcOH). TLC R _f (5% AcOH in 4: 20: 20: 56 MeOH / EtOAc / hexane / Cl ₂ CH ₂ ) 0.32; ¹ H NMR (400 MHz CDCl ₃ ) 7.13-7.18 (m, 3H), 5.60-5.69 (m, IH), 4.83 (d, J = 14.2, J = 7.3 Hz, 2H), 2.36 (t, &lt; RTI ID = 0.0 &gt; J = 7.3 Hz, 2H), 2.30-2.34 (m, 1H), 1.95 (q, J = 7.3 Hz, 2H), 1.34 (s, 9H); MS (ES) m / e 435 [M + H] &lt; ⁺ &gt;.
d) Methyl (±) -1- (tert-butoxycarbonyl) -7- [3- (benzimidazol-2-yl) propyl] -4-methyl- -Tetrahydro-l, 4-benzodiazepin-2-acetate
To a solution of methyl (±) -1- (tert-butoxycarbonyl) -7- (4-carboxybut-1-yl) -4-methyl- 5-tetrahydro-1,4-benzodiazepine-2-acetate (350 mg, 0.8 mmol) and Et ₃ N isobutyl chloroformate to a stirred and cooled (-10 ℃) a mixture of (81 mg, 0.8 mmol) ( 97 mg, 0.8 mmol). After 10 minutes, a solution of 1,2-phenylenediamine (1.43 g, 0.9 mmol) in THF (2 ml) was added. After stirring overnight at room temperature, the solvent was evaporated. The residue was dissolved in EtOAc and the solution was washed sequentially with aqueous NaHCO ₃ and brine. Dried (MgSO ₄₎ and concentrated to give a pale yellow solid. This was dissolved in glacial acetic acid (5 ml) and the reaction was heated to 60 &lt; 0 &gt; C. After 3 hours, the mixture was cooled, concentrated, neutralized with 2.5 N NaOH, and extracted with CH ₂ Cl ₂ . The title compound (200 mg, 50%) was obtained by drying (MgSO ₄ ), concentration and silica gel chromatography (gradient 1-5% MeOH / CH ₂ Cl ₂ ). _{TLC R f (4: 20:} 20: 56 MeOH / EtOAc / hexane / CH ₂ Cl ₂₎ 0.18; _{^{1 H NMR (400 MHz CDCl 3}} ) δ 7.57-7.61 (m, 2H), 7.15-7.28 (m, 4H), 7.08 (s, 1H), 5.60-5.55 (m, 1H), 4.75-4.88 (m, 2H), 3.71 (d, J = 14.2 Hz, 1H), 3.70 (s, ), 2.73-2.79 (m, 2H), 2.32-2.36 (m, 1H), 2.15-2.23 (m, 1H), 1.34 and (br s, rotamer 9H); MS (ES) m / e 507 [M + H] &lt; ⁺ &gt;.
e) (±) -7- [3- (Benzimidazol-2-yl) propyl] -4-methyl-3-oxo-2,3,4,5-tetrahydro- 2-acetic acid
To a solution of methyl (±) -1- (tert-butoxycarbonyl) -7- [3- (benzimidazol-2-yl) propyl] -4-methyl -3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine-2-acetate (200 mg, 0.395 mmol) in DMF (5 mL) was added LiOH (17 mg, 0.71 mmol). The reaction mixture was stirred at room temperature for 4 hours. Acidified to pH 4 with dilute HCl and concentrated to give a white solid. This was dissolved in a mixture of methylene chloride (10 ml) and trifluoroacetic acid (5 ml) at 0 ° C and the reaction was allowed to stand at 0 ° C for 30 minutes. The solvent was evaporated The residue was triturated with ether and purified by ODS flash chromatography (0.1% TFA 10 to _{18% CH 3 CN / H 2} O gradient containing). Concentrated and lyophilized to give the title compound (75 mg, 48%) as a colorless powder. _{^{1 H NMR (400 MHz CDCl 3}} ) δ 7.58-7.61 (m, 2H), 7.37-7.39 (m, 2H), 6.79 (d, J = 8.2, Hz, 1H), 6.68 (s, 1H), 6.39 ( (d, J = 8.2 Hz, 1H), 5.18 (d, J = 16.8 Hz, 1H), 4.77 m, 3H), 2.97 (s, 3H), 2.83 (dd, J = 7.0, 16.4Hz, 1H), 2.52-2.56 (m, 2H), 2.08-2.12 (m, 2H); MS (ES) m / e 393.0 [M + H] &lt; ⁺ &gt;. C ₂₂ H ₂₄ N ₄ O ₃ C ₂ HF ₃ O ₂ .0.5 H ₂ O Theoretical: C, 55.92; H, 5.08; N, 10.89. Found: C, 56.16; H, 4.92; N, 10.88.
Example 18
(S) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol-2-yl) methyl] -N- (4-aminobutyl) amino] carbonyl] -4- Preparation of methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid
a) 4 - [(Benzimidazol-2-yl) methyl] aminobutyronitrile
Nitrile To a stirred mixture of 2-aminomethyl-benzimidazole dihydrochloride (0.5 g, 2.2717 mmol) and _{NaHCO 3 (0.67 g, 7.951 mmol} ) in dry DMF (10 ml) with 4-bromo-butyronitrile (0.37 g, 2.4989 mmol). After stirring for 24 hours at room temperature, the mixture was concentrated. The residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic extracts were dried over MgSO ₄ , concentrated, and purified by silica gel flash column chromatography (5% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.15 g, 35%) as a brown oil. ^{1 H NMR (250 MHz, DMSO} -d 6) δ 1.82 (m, 2H), 2.45 (t, J = 4Hz, 2H), 2.85 (t, J = 4Hz, 2H), 4.11 (s, 2H), 7.14 (m, 2 H), 7.50 (m, 2 H).
b) Preparation of methyl (S) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol-2- yl) methyl] -N- (4- cyanopropyl) amino] carbonyl ] -4-methyl-3-oxo-1H-1, 4-benzodiazepine-
Dry CH ₃ CN (7 ml) of 4 - [(benzimidazol-2-yl) methyl] acrylonitrile-amino butyric (0.159 g, 0.7422 mmol), methyl 2,3,4,5-tetrahydro-7-carboxy (0.217 g, 0.7422 mmol), HOBt.H ₂ O (0.120 g, 0.8906 mmol) and i-Pr ₂ NEt (0.192 g, 1.4844 mmol) in THF (10 mL) was added EDC (0.265 g, 0.8906 mmol). After stirring at room temperature for 48 hours, the mixture was concentrated. The residue was dissolved in water and extracted with CH ₂ Cl ₂ . Successively washed the organic layer with NaHCO ₃ saturated solution and brine, dried over MgSO _4, and concentrated to give a brown oil. Purification by silica gel flash column chromatography (3% MeOH / CH ₂ Cl ₂ ) gave the title compound (0.261 g, 74%) as an off-white foam. ^{1 H NMR (250 MHz, DMSO} -d 6) δ 1.95 (m, 2H), 2.66 (dd, J = 16.4, 3.5 Hz, 1H), 2.78 (dd, J = 16.4, 3.5 Hz, 1H), 2.85 ( J = 8.7 Hz, 2H), 3.45 (t, J = 8.7 Hz, 2H), 3.80 (d, 2H), 5.15 (m, 1H), 5.48 (d, J = 16 Hz, 1H), 6.40 (d, J = 3.5 Hz, 1H) 4H), 7.50 (m, 1H), 7.62 (m, 1H).
c) (S) -2,3,4,5-Tetrahydro-7 - [[N - [(benzimidazol-2- yl) methyl] -N- (4- cyanopropyl) amino] carbonyl] -4-methyl-3-oxo-lH-l, 4-benzodiazepin-
To a solution of methyl (S) -2,3,4,5-tetrahydro-7- [[N - [(benzimidazol-2- yl) methyl] -N- (4-cyanopropyl) Was added 2.5 N NaOH (0.7 ml, 1.6433 mmol) to a stirred solution of 4-amino-3-oxo-1H-1,4-benzodiazepine-2-acetate (0.261 g, 0.5478 mmol) After stirring overnight at room temperature, the mixture was concentrated. After dissolving the residue in water, the solution was acidified with 6 N HCl to pH = 4. The white solid was filtered and dried to give the title compound (0.21 g, 81%). ^{1 H NMR (250 MHz, DMSO} -d 6) δ 1.95 (m, 2H), 2.66 (dd, J = 16.4, 3.5 Hz, 1H), 2.78 (dd, J = 16.4, 3.5 Hz, 1H), 2.85 ( (t, J = 8.7 Hz, 2H), 3.45 (t, J = 8.7 Hz, 2H), 3.60 J = 8.9 Hz, 2H), 5.15 (m, 1H), 5.48 (d, J = 16 Hz, 1H), 6.40 1H), 7.25 (m, 4H); 7.50 (m, 1H), 7.62 (m, 1H).
d) (S) -2,3,4,5-Tetrahydro-7 - [[N - [(benzimidazol-2- yl) methyl] -N- (4- aminobutyl) amino] carbonyl] 4-methyl-3-oxo-lH-l, 4-benzodiazepin-
To a solution of (S) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol-2- yl) methyl] -N- (4- cyanopropyl) amino ] carbonyl] room temperature a mixture of 4-methyl-3-oxo -1H-1,4- benzodiazepine-2-acetate (0.200 g, 0.4325 mmol) and _{NH 4 OH (1 ml, 30} % solution) for 24 hours 0.0 &gt; Ra / Ni &lt; / RTI &gt; The catalyst was filtered off and the filtrate was concentrated and purified by reverse phase chromatography (10% CH ₃ CN / H ₂ O with 0.1% TFA) to give the title compound (0.100 g, 33%) as an off-white solid. ^{1 H NMR (400 MHz, DMSO} -d 6) δ 1.45 (m, 2H), 1.72 (m, 2H), 2.54 (dd, J = 16.4, 3.5 Hz, 1H), 2.70 (m, 2H), 2.75 ( (d, J = 16.4, 3.5 Hz, 1H), 2.95 (s, 3H), 3.65 (t, J = 8.7 Hz, 2H), 3.85 2H), 7.75 (m, 2H), 7.75 (s, 2H, &lt; RTI ID = 0.0 & ), 7.85 (m, 2H); IR (KBr) 3425, 3000, 3100, 1728, 1675, 1630, 1625, 1613 cm ^-1; MS (ES) m / e 479 (M + H). C ₂₅ H ₃₀ N ₆ O ₄ 2 CF ₃ CO ₂ H: Theoretical: C, 49.30; H, 4.56; N, 11.89. Found: C, 49.22; H, 4.89; N, 11.84.
Example 19
(S) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol-2-yl) methyl] -N- (2- cyanomethyl) amino] carbonyl] Preparation of methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetic acid
a) [(Benzimidazol-2-yl) methyl] aminoacetonitrile
According to the procedure of Example 18 (a) except that bromoacetonitrile was used instead of 4-bromobutylnitrile, the title compound was obtained as an off-white solid (0.15 g, 35%). ^{1 H NMR (250 MHz, DMSO} -d 6) δ 3.71 (S, 2H), 3.98 (s, 2H), 7.14 (m, 2H), 7.50 (m, 2H).
b) Preparation of methyl (S) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol-2- yl) methyl] -N- (2- cyanomethyl) ] -4-methyl-3-oxo-1H-1, 4-benzodiazepine-
The procedure of Example 18 (b) was repeated except that [(benzimidazol-2-yl) methyl] aminoacetonitrile was used instead of 4 - [(benzoimidazol- , The title compound was prepared as an off-white foam (0.487 g, 66%). ^{1 H NMR (250 MHz, DMSO} -d 6) δ 2.66 (dd, J = 16.4, 3.5 Hz, 1H), 2.78 (dd, J = 16.4, 3.5 Hz, 1H), 2.92 (s, 2H), 3.60 ( (d, J = 6.9 Hz, 2H), 5.15 (m, 1H), 5.48 (d, J = 16 Hz, 1H), 6.40 (d, J = 3.5 Hz, 1H), 6.54 (d, J = 8.3 Hz, 1H), 7.25 (m, 4H), 7.50 (m, 2H), 7.62 (m, 2H).
c) (S) -2,3,4,5-Tetrahydro-7 - [[N - [(benzimidazol-2- yl) methyl] -N- (2- cyanomethyl) -4-methyl-3-oxo-lH-l, 4-benzodiazepin-
(S) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol-2-yl) methyl] -N- (2 4-methyl-3-oxo-1H-1, 4-benzodiazepine-2-acetate and the product was recrystallized from EtOH to afford the title compound as a white solid (0.420 g, 89%). ^{1 H NMR (400 MHz, DMSO} -d 6) δ 2.66 (dd, J = 16.4, 3.5 Hz, 1H), 2.78 (dd, J = 16.4, 3.5 Hz, 1H), 2.92 (s, 2H), 3.80 ( (d, J = 16Hz, 1H), 4.52 (s, 2H), 4.84 (d, J = 2.9Hz, 2H), 5.15 d, J = 3.5 Hz, 1H), 6.54 (d, J = 8.3 Hz, 1H), 7.25 (m, 4H), 7.50 (m, 1H), 7.62 (m, 1H); MS (ES) m / e 465 (M + H) &lt; ⁺ & gt ^; . C ₂₃ H ₂₂ N ₆ O _{4 ·} 2 HCl Theoretical: C, 53.19; H, 4.66; N, 16.18; Found: C, 52.98; H, 4.43; N, 16.53.
Example 20
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -3-oxo-1H-1,4-benzodiazepin- Preparation of 2-acetic acid
a) Dimethyl (R) -2-Trifluoromethanesulfonylsuccinate
To a stirred, cooled (0 C) mixture of dimethyl D-malate (5.5 g, 33.9213 mmol) and dry pyridine (2.82 g, 35.7164 mmol) in dry CH ₂ Cl ₂ (55 ml) was added anhydrous trifluoromethanesulfonic acid g, 35.7164 mmol) was added dropwise. After stirring for 4 hours at 0 &lt; 0 &gt; C, the mixture was quenched with water and the layers separated. The organic layer was washed sequentially with dilute HCl and brine, dried over MgSO _4, and concentrated to give the title compound (8.50 g, 96%) as a white solid. ^{1 H NMR (250 MHz, (} CDCl 3) δ 3.10 (d, J = 5.8 Hz, 2H), 3.74 (s, 3H), 3.78 (s, 3H), 5.52 (t, J = 5.8 Hz, 1H).
b) Dimethyl D- (2-cyanophenyl) malate
2-aminobenzonitrile (0.5 g, 4.2323 mmol), 2,6-di-tert-butylpyridine (0.85 g, 4.4439 mmol) and dimethyl (R) -2-tri The fluoromethane sulfonyl succinate mixture was stirred at room temperature for 76 hours. The mixture was concentrated and the residue was dissolved in water and extracted with EtOAc. The organic extracts were washed successively with 10% HCl and brine, dried over MgSO _4, concentrated and purified to give the title compound (0.886 g, 80%) on a silica gel flash column chromatography (10% EtOAc / hexane). ^{1 H NMR (250 MHz, CDCl} 3) δ 2.95 (d, J = 5.8 Hz, 1H), 3.74 (s, 3H), 3.78 (s, 3H), 4.60 (m, 1H), 5.28 (d, J = 5.8 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.80 (t, J = 8.5 Hz, 1H), 7.47 (m, 2H).
c) Methyl (S) -2,3,4,5-tetrahydro-3-oxo-lH-l, 4- benzodiazepin-
MeOH (NH ₃ (g) being pre-saturated for 10 minutes, 100 ml) Dimethyl D- (2- cyanophenyl) malate (10.75 g, 41.0006 mmol) H 2 (55 psi) for 48 hours in solution under And hydrogenated on Ra / Ni. The catalyst was filtered off and the filtrate was concentrated and purified by silica gel flash column chromatography (40% EtOAc / hexane) to give the title compound (5.03 g, 53%) as an off-white solid. ^{1 H NMR (250 MHz, (} CDCl 3) δ 2.65 (dd, J = 16.3, 7.6 Hz, 1H), 2.99 (dd, 16.3, 5.9 Hz, 1H), 3.74 (s, 3H), 3.95 (dd, J J = 7.6 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H) J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz,
d) Methyl (S) -2,3,4,5-tetrahydro-7-bromo-3-oxo-lH-l, 4- benzodiazepin-
Methyl (S) -2,3,4,5- tetrahydro-3-oxo -1H-1,4- benzodiazepine-2-acetate (5.03 g, 21.4746 mmol) and n-Bu ₄ in CHCl ₃ (100 ml) The mixture of NBr ₃ (10.35 g, 21.4746 mmol) was stirred at room temperature for 3 hours and then the mixture was concentrated. The residue was dissolved in water, stirred and filtered to give the title compound (5.61 g, 83%) as an off-white solid. ^{1 H NMR (250 MHz, (} CDCl 3) δ 2.74 (dd, J = 16.3, 7.6 Hz, 1H), 3.05 (dd, 16.3, 5.9 Hz, 1H), 3.75 (s, 3H), 4.05 (dd, J J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H) J = 5.3 Hz, 1H), 7.14 (s, 1H), 7.25 (d, J = 7.6 Hz, 1H).
e) methyl (S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2- yl) methyl] -N-methylamino] carbonyl] 1,4-benzodiazepin-2-acetic acid
To a solution of methyl (S) -2,3,4,5-tetrahydro-7-bromo-3-oxo-1H-1,4-benzodiazepine-2-acetate (1.26 g, 4.7905 mmol), n-Bu ₃ N (6.21 g, 33.5333 mmol), 2- (methylaminomethyl) benzimidazole dihydrochloride (2.24 g, 9.5809 mmol) mmol) and (Ph ₃ P) ₄ Pd (1.10 g, 0.9581 mmol) was flushed with argon and carbon monoxide for 10 min. The mixture was then heated at 100-105 DEG C for 8 hours under a carbon monoxide balloon. The mixture was cooled and acidified to pH 2 with 6 N HCl. The solution was extracted with EtOAc and the EtOAc layer was discarded. The aqueous layer was neutralized with 30% NaOH and extracted with CH ₂ Cl ₂ . The organic extracts were dried over MgSO ₄ , concentrated and purified by silica gel flash column chromatography (5% MeOH / CH ₂ Cl ₂ ) to give the title compound (1.62 g, 80%) as an off-white solid. ^{1 H NMR (250 MHz, DMSO} -d 6) δ 2.65 (dd, J = 16.3, 7.6 Hz, 1H), 2.81 (dd, J = 16.3, 5.9 Hz, 1H), 3.05 (s, 2H), 3.60 ( (dd, J = 16.3, 6.9 Hz, 1H), 4.78 (s, 2H), 4.95 J = 5.9 Hz, 1H), 6.55 (d, J = 7.6 Hz 1H), 7.25 (m, 4H), 7.55 (m, 2H), 8.21 (t, J = 5.3 Hz, 1H).
f) (S) -2,3,4,5-Tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -3- Benzodiazepin-2-acetic acid
(S) -2,3,4,5-tetrahydro-7- [[[(benzimidazol-2-yl) methyl] -N-methylamino] carbaldehyde according to the procedure of Example 18 (c) -3-oxo-1H-1,4-benzodiazepine-2-acetate was converted to the title compound (0.060 g, 57%) as an off-white solid. ^{1 H NMR (400 MHz, DMSO} -d 6) δ 2.52 (dd, J = 16.3, 7.6 Hz, 1H), 2.84 (dd, J = 16.3, 5.9 Hz, 1H), 3.20 (s, 3H), 3.75 ( (d, J = 16.3, 6.9 Hz, 1H), 4.95 (t, J = 5.9 Hz, 1H), 5.05 J = 7.6 Hz, 1H), 7.48 (m, 2H), 7.69 (m, 2H), 7.90 (d, J = 5.3 Hz, 1H) ; IR (KBr) 3600-3100, 3100-2800, 1681, 1613, 1601, 1485, 1445, 1314, 830, 764, 742, cm ^-1 ; MS (ES) m / e 422 (M + H) &lt; ⁺ & gt ^; . C ₂₁ H ₂₁ N ₅ O ₄ Theoretical: C, 61.91; H, 5.20; N, 17.19. Found: C, 61.57; H, 5.32; N, 17.29.
Example 21
(S) -2,3,4,5-tetrahydro-7 - [[[1- (2-hydroxyethyl) benzimidazol-2-yl] methyl] amino] carbonyl] -Oxo-lH-l, 4-benzodiazepin-2-acetic acid
a) Ethyl 2 - [[(benzimidazol-2-yl) methyl] amino] acetate
Dry DMF (60 ml) 2-aminomethyl-benzimidazole dihydrochloride hydrate of (4.0 g, 18.1736 mmol), NaHCO 3 (7.63 g, 90.868 mmol) and ethyl 2-bromoacetate (4.55 g, 27.2603 mmol) Was stirred at room temperature for 24 hours and then concentrated. The residue was dissolved in H ₂ O and extracted with CH ₂ Cl ₂ . The organic extracts were dried over MgSO ₄ , concentrated and purified by silica gel flash column chromatography (5% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.50 g, 12%) as a brown oil. ^{1 H NMR (250 MHz, (} CDCl 3) δ 1.95 (s, 3H), 3.48 (s, 2H), 4.50 (m, 4H), 7.25 (m, 2H), 7.35 (m, 1H), 7.73 (m , 1H).
yl) methyl] amino] carbonyl] -4- (4-methylpiperazin-1- Methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetate
Except that ethyl 2 - [[(benzimidazol-2-yl) methyl] amino] acetate was used in place of 4 - [(benzimidazol-2-yl) methyl] aminobutyronitrile. Following the procedure of b), the title compound (0.251 g, 78.5%) was obtained as a white solid. ^{1 H NMR (250 MHz, (} CDCl 3) δ 1.95 (s, 3H), 2.66 (dd, J = 16.4, 3.5 Hz, 1H), 2.95 (s, 3H), 3.05 (dd, J = 16.4, 3.5 Hz J = 5.9 Hz, 2H), 4.62 (s, 2H), 4.92 (t, J = 5.9 Hz, (M, 2H), 5.10 (m, 1H), 5.40 (d, J = 16 Hz, 1H), 6.49 (d, J = 8.3 Hz, (m, 1 H), 8.15 (t, J = 5.3 Hz, 1 H).
c) Preparation of (S) -2,3,4,5-tetrahydro-7- [[1- (2-hydroxyethyl) benzimidazol-2- yl] methyl] amino] carbonyl] -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid
To a solution of methyl (S) -2,3,4,5-tetrahydro-7- [[[[1- (2-acetyloxyethyl) benzimidazol- Was added 1.0 N LiOH (1.4 ml, 1.425 mmol) to a stirred, partial suspension of 4-methyl-3-oxo-lH-l, 4- benzodiazepine-2-acetate (0.241 g, 0.475 mmol) After stirring overnight at room temperature, the mixture was concentrated. The residue was dissolved in water and acidified to pH 4 using AcOH. The off-white solid was filtered and triturated with acetone to give the title compound (0.16 g, 75%) as a white solid. ^{1 H NMR (400 MHz, DMSO} -d 6): δ 2.54 (dd, J = 16.4, 3.5 Hz, 1H), 2.95 (s, 3H), 3.05 (dd, J = 16.4, 3.5 Hz, 1H), 3.60 (d, J = 16 Hz, 1H), 4.45 (d, J = 5.9 Hz, 2H), 4.62 (s, 2H), 4.92 (d, J = 16 Hz, 1H), 6.49 (d, J = 8.3 Hz, 1H), 7.32 (m, 3H), 7.60 5.3 Hz, 1H); MS (ES) m / e 452 (M + H) &lt; ⁺ & gt ^; . C ₂₃ H ₂₅ N ₅ O ₅ 0.75 H ₂ O Theoretical: C, 59.71; H, 5.72; N, 15.14. Found C, 59.65, H, 5.70; N, 14.88.
Example 22
Amino] butyl] amino] -1H-pyrazolo [3,4-d] pyrimidin- Carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-2-acetic acid
a) 4 - [[(Benzimidazol-2-yl) methyl] amino] butylphthalimide
2-Aminomethylbenzimidazole dihydrochloride hydrate (22.10 g, 100.7269 mmol), NaHCO ₃ (42.40 g, 503.6347 mmol) and bromobutyl phthalimide (34.10 g, 120.8723 mmol) in dry DMF (250 ml) Was heated to 100-110 &lt; 0 &gt; C for 6 hours, then cooled and concentrated. The residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic extract was dried over MgSO ₄ , concentrated and purified by silica gel flash column chromatography (5% MeOH / CH ₂ Cl ₂ ) to give the title compound (10.8 g, 31%) as a brown foam. ^{1 H NMR (250 MHz, CDCl} 3) δ 1.65 (m, 2H), 1.85 (m, 2H), 2.75 (t, J = 8.9 Hz, 2H), 3.78 (t, J = 8.9 Hz, 2H), 4.17 (s, 2H), 7.20 (m, 2H), 7.60 (m, 2H), 7.72 (m, 2H), 7.88 (m, 2H).
b) Preparation of methyl (±) -2,3,4,5-tetrahydro-7- [[N- (benzimidazol- Carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-
4 in dry _{CH 3 CN (30 ml) -} [[( benzimidazol-2-yl) methyl] amino] butyl phthalimide (1.75 g, 5.0525 mmol), methyl (±) -2,3,4,5 (1.61 g, 4.2104 mmol), HOBt.H ₂ O (0.69 g, 5.0525 mmol) and _2- bromo-4- mmol), and i-Pr ₂ NEt (1.10 g, 8.4209 mmol) in DMF (5 mL) was added EDC (1.50 g, 5.0525 mmol). After stirring at room temperature for 24 hours, the mixture was concentrated. The residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic extracts were washed sequentially with a saturated solution of NaHCO ₃ and brine, dried over MgSO ₄ , concentrated and purified by silica gel flash column chromatography (5% MeOH / CH ₂ Cl ₂ ) to give the title compound (2.85 g, 95% ) As a yellow foam. ^{1 H NMR (250 MHz, DMSO} -d 6) δ 160 (m, 2H), 2.65 (m, 2H), 2.85 (dd, J = 16.4, 3.5 Hz, 1H), 3.55 (m, 4H), 3.65 ( J = 16.0 Hz, 2H), 4.75 (s, 3H), 4.00 (d, J = (D, J = 7.6 Hz, 1H), 7.20 (m, 7H), 7.55 (m, 4H), 7.90 (m, 4H).
c) Preparation of methyl (±) -tetrahydro-7 - [[N - [(benzimidazol-2-yl) methyl] -N- (4- aminobutyl) amino] carbonyl] 2-phenylethyl) -1H-1,4-benzodiazepine-2-acetate
To a solution of methyl (±) -2,3,4,5-tetrahydro-7 - [[N- (benzimidazol-2-yl) methyl] -N - [[4- (phthalimido) (0.50 g, 0.7015 mmol) and hydrazine (0.07 g, 2.1045 mmol) in anhydrous THF (5 mL) After refluxing for 6 hours, it was cooled and concentrated. The residue was dissolved in water, acidified to pH 2 with 6 N HCl, and filtered to remove the white solid. This solid was discarded. The aqueous filtrate was extracted with EtOAc and the EtOAc layer was discarded. The aqueous layer using Na ₂ CO ₃ was a base to pH 9 screen, and extracted with CHCl _3. Dry the organic layer over MgSO _4, and concentrated to give the title compound (0.41 g, 89%) as an off-white solid. ^{1 H NMR (250 MHz, DMSO} -d 6) δ 1.47 (m, 2H), 1.75 (m, 2H), 2.65 (m, 5H), 2.85 (dd, J = 16.3, 5.9 Hz, 1H), 3.65 ( (d, J = 7.6 Hz, 1H), 5.05 (s, 2H), 5.15 , 7.25 (m, 6H), 7.41 (s, IH), 7.60 (m, 2H), 7.85 (m, 2H).
d) Preparation of (±) -2,3,4,5-tetrahydro-7- [[N- (benzimidazol- Amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-
Amino] carbonyl] -3-oxo-4- (2 (trifluoromethyl) -Phenylethyl) -1H-l, 4-benzodiazepine-2-acetate (0.34 g, 0.47 mmol) in THF (10 mL) was added 1.0 N LiOH (1.2 mL). The mixture was stirred overnight at room temperature, the mixture was concentrated, and the pH was adjusted to 4 by acidifying the residue with AcOH. The solid was filtered and triturated with acetone / ether to give the title compound (0.130 g, 39%) as a white solid. ^{1 H NMR (400 MHz, DMSO} -d 6) δ 1.47 (m, 2H), 1.75 (m, 2H), 2.54 (dd, J = 16.3, 3.5 Hz, 1H), 2.65 (m, 2H), 2.85 ( 2H), 5.15 (m, 1H, d, J = 16.3, 5.9 Hz, 1H), 3.20 (m, 2H), 3.75 ), 5.45 (d, J = 16, IH), 6.65 (d, J = 7.6 Hz, IH), 7.25 (m, 6H), 7.41 (s, ); IR (KBr) 3400, 3326, 3100-3000, 1721, 1637, 1626, 1616, 1607, 1300, 750, 694 cm ^-1 ; MS (ES) m / e 717 (M + H) &lt; ⁺ & gt ^; . C ₄₀ H ₃₈ N ₆ O ₈ .3H ₂ O Theoretical: C, 63.56; H, 5.87; N, 11.12. Found: C, 63.56; H, 5.83; N, 11.04.
Example 23
(-) - 2,3,4,5-tetrahydro-7 - [[N- (benzimidazol-2- yl) methyl] -N - [[4- (4-azido- ) Amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepin-
a) Methyl (±) -2,3,4,5-tetrahydro-7 - [[N- (benzimidazol- Hydroxybenzoyl) amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4- benzodiazepine-
Dry _{2: 1 CH 3 CN / DMF} (10 ml) methyl (±) -2,3,4,5- tetrahydro of -7 - [[N- methyl -N- (benzimidazol-2-yl) [ (0.409 g, 0.702 mmol), 4- (2-phenylethyl) -1H-1,4-benzodiazepine- EDC (0.25 g, 0.8424 mmol) was added to a mixture of aziricillan-N-hydroxysuccinimide ester (0.194 g, 0.702 mmol) and i-Pr ₂ NEt (0.272 g, 2.106 mmol). After stirring at room temperature for 24 hours, the mixture was concentrated. The residue was dissolved in water, stirred and filtered to dryness to give the title compound (0.204 g, 39%) as an off-white solid. ^{1 H NMR (250 MHz, DMSO} -d 6) δ 1.40 (m, 2H), 1.75 (m, 2H), 2.65 (m, 3H), 2.75 (dd, J = 16.3, 5.9 Hz, 1H), 3.20 ( (m, 2H), 3.51 (m, 4H), 3.65 (m, 3H), 3.95 (d, J = 16 Hz, = 16 Hz, 1H), 6.20 (s, 1H), 6.55 (m, 3H), 7.20 (m, 8H), 7.55 (m, 3H), 7.85 (d, J = 7.6 Hz, 1H) , &Lt; / RTI &gt; 1H), 8.75 (s, 1H).
b) (짹) -2,3,4,5-Tetrahydro-7 - [[N- (benzimidazol- Carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-
According to the procedure of Example 22 part (d), methyl (±) -2,3,4,5-tetrahydro-7- [[N- (benzimidazol- - (4-azido-2-hydroxybenzoyl) amino] carbonyl] -3-oxo-4- (2- phenylethyl) -1H-1,4-benzodiazepine- 0.100 g, 50%) as a white solid. ^{1 H NMR (400 MHz, DMSO} -d 6) δ 1.40 (m, 2H), 1.75 (m, 2H), 2.65 (m, 3H), 2.75 (dd, J = 16.3, 5.9 Hz, 1H), 3.20 ( J = 16 Hz, 1H), 4.79 (s, 2H), 5.12 (m, 1H), 5.37 (d, (D, J = 7.6 Hz, 1 H), 7.98 (s, 1 H), 8.75 (m, 3H) , 1H); MS (ES) m / e 730 (M + H) &lt; ⁺ & gt ^; . C ₃₉ H ₃₉ N ₉ O ₆ 2.5 _H 20 Theoretical: C, 60.46; H, 5.72; N, 16.27. Found: C, 60.46; H, 5.43; N, 15.90.
Example 24
Amino] carbonyl] amino] carbonyl] amino] carbonyl] amino] ] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine- (2RS)
a) Preparation of methyl 2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol-2-yl) methyl] -N - [[ ] Carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine- (2RS)
1: 2 DMF / CH ₃ CN-methyl-of (12 ml) (±) - tetrahydro -7 - [[N- [benzimidazol-2-yl) methyl -N- (4- aminobutyl) amino] carbonyl (0.40 g, 0.6865 mmol), (+) - biotin (0.17 g, 0.6865 mmol), HOBt 占 H EDC (0.25 g, 0.8239 mmol) was added to a mixture of _2- O (0.11 g, 0.8239 mmol) and i-Pr ₂ NEt (0.18 g, 1.3730 mmol). After stirring at room temperature for 24 hours, the mixture was concentrated. The residue was dissolved in water and extracted with CHCl _3. The organic extracts were washed sequentially with saturated NaHCO ₃ solution and brine, dried over MgSO ₄ , concentrated and purified by silica gel flash column chromatography (10% MeOH / CH ₂ Cl ₂ ) to afford the title compound (0.24 g, 44 %) As a yellow foam. ^{1 H NMR (250 MHz, DMSO} -d 6) δ 1.30 (m, 2H), 1.60 (m, 4H), 2.05 (t, J = 8.9 Hz, 2H) ;, 2.60 (m, 3H), 2.68 (dd 2H), 3.60 (m, 2H), 3.65 (s, 3H), 4.01 (d, J = 16 Hz, 1H) , 4.12 (t, J = 8.9 Hz, IH), 4.30 (t, J = 8.9 Hz, IH), 4.78 (s, 2H), 5.10 , 6.20 (d, J = 5.3 Hz, 1H), 6.40 (d, J = 8.9 Hz, 2H), 6.55 (d, J = 7.6 Hz, 1H) , 7.55 (m, 1 H), 7.70 (t, J = 8.6 Hz, 1 H).
amino] butyl] amino] - &lt; RTI ID = 0.0 &gt; thiophen-2- Carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine- (2RS)
Methyl-N - [[[(+) - 1 -methyl- lH-indol- (2RS) -acetate (0.24 g, 0.2967 mmol) in dichloromethane (5 mL) was added to a stirred solution of 4-amino-2- Was added 1.0 LiOH (0.44 ml). After stirring overnight at room temperature, the mixture was concentrated. The residue was dissolved in water and acidified with AcOH to adjust the pH to 4. The off-white solid was filtered and triturated with hot acetone to give the title compound (0.160 g, 68%) as a white solid. ^{1 H NMR (400 MHz, DMSO} -d 6) d 1.30 (m, 2H), 1.60 (m, 4H), 2.05 (t, J = 8.9 Hz, 2H), 2.60 (m, 3H), 2.68 (dd, J = 16.3, 5.9 Hz, 1H), 3.10 (m, 4H), 3.45 (m, 2H), 3.60 (m, 2H), 4.01 J = 8.9 Hz, 1H), 4.78 (s, 2H), 5.10 (m, 1H), 5.45 1H), 7.45 (m, 1H), 7.55 (m, 1H), 6.40 (d, J = 8.9 Hz, 2H) 7.70 (t, J = 8.6 Hz, 1 H); MS (ES) m / e 795 (M + H) &lt; ⁺ & gt ^; . C ₄₂ H ₅₀ N ₈ O ₆ S · 1.75 _H 20 Theoretical Value: C, 61.04; H, 6.52; N, 13.56. Found: C, 60.89; H, 6.24; N, 13.31.
Example 25
(4-aminobutyl) amino] carbonyl] -3- (4-fluorobenzyl) Oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-2-acetic acid
a) Preparation of (±) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol- Oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-2-acetic acid
According to the procedure of Example 24 (b), methyl (±) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol- (0.250 g, 80%) was converted to an off-white solid as an off-white solid by subjecting the title compound (0.250 g, 80%) to an amorphous solid . ^{1 H NMR (400 MHz, DMSO} -d 6) δ 1.37 (m, 2H), 1.62 (m, 2H), 2.52 (dd, J = 3.5 Hz, 1H), 2.64 (m, 2H), 2.75 (dd, J = 16.3, 5.9 Hz, 1H), 3.51 (m, 4H), 3.91 (d, J = 16 Hz, 1H), 4.98 Hz, 1H), 6.53 (d, J = 7.9 Hz, 2H) 7.17 (m, 7H), 7.52 (m, 1H), 7.62 (s, 1H), 7.78 (m, 1H); IR (KBr): 3386, 3100-3000, 1647, 1613, 1403, 740, 699 cm &lt; ^{-1 &} gt ;; MS (ES) m / e 569 (M + H) &lt; ⁺ & gt ^; . C ₃₂ H ₃₆ N ₆ O ₄ · 2.75 H ₂ O Theoretical: C, 62.18; H, 6.77; N, 13.60. Found: C, 62.11; H, 6.68; N, 13.57.
Example 26
(-) - 2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol- Amino] butyl] amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-
a) 3-Iodo-4-azido salicylic acid-N-hydroxysuccinimide ester
To a stirred mixture of 4-azidicarboxylic acid N-hydroxysuccinimide ester (0.500 g, 1.8103 mmol) and trifluoroacetate in CHCl ₃ (10 ml) was added iodine (0.510 g, 1.9913 mmol) mmol). After stirring overnight at room temperature, the reaction was filtered and the solid precipitate was removed. The filtrate was washed sequentially with water, saturated NaHCO ₃ solution and brine, dried over MgSO ₄ and concentrated to give the title compound (0.703 g, 97%) as a light purple solid. ^{1 H NMR (250 MHz, CDCl} 3) δ 2.98 (s, 4H), 6.83 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H).
b) Methyl (+) - 2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol- Amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-2-acetate
Except that 3-iodo-4-azido salicylic acid-N-hydroxysuccinimide ester was used instead of 4 - [[(benzimidazol-2-yl) methyl] amino] butyl phthalimide According to the procedure of Example 22 (b) the title compound (0.312 g, 56%) was prepared as yellow foam. ^{1 H NMR (250 MHz, DMSO} -d 6) δ 1.42 (m, 2H), 1.60 (m, 2H), 2.52 (dd, J = 16.3, 3.5 Hz, 1H), 2.63 (m, 2H), 2.79 ( (d, J = 16.3, 5.9 Hz, 1H), 3.25 (s, 2H), 3.55 (m, 6H), 3.65 ), 5.02 (m, 1H), 5.35 (d, J = 16 Hz, 1H), 6.14 (d, J = 5.3 Hz, 1H) = 7.9 Hz, 1H), 7.25 (m, 10H), 7.51 (s, 2H), 7.90 (d, J = 7.9 Hz, 1H), 9.01 (s, 1H).
c) Preparation of (±) -tetrahydro-7 - [[N - [(benzimidazol-2-yl) methyl] -N - [[4- (4-azido- ) Amino] butyl] amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-
Yl) methyl] -N - [[4- (4-azido-pyridin-2-yl) 2-hydroxybenzoyl) amino] butyl] amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-2-acetate. Purification by silica gel flash column chromatography (0.5, 0.5, 9.5 AcOH / MeOH / CH ₂ Cl ₂ ) gave the title compound (0.170 g, 58%) as an off-white solid. ^{1 H NMR (400 MHz, DMSO} -d 6) δ 1.42 (m, 2H), 1.60 (m, 2H), 2.52 (dd, J = 16.3, 3.5 Hz, 1H), 2.63 (m, 2H), 2.79 ( (d, J = 16.3, 5.9 Hz, 1H), 3.25 (s, 2H), 3.55 (m, 6H), 3.95 (d, J = 7.9 Hz, 1 H), 7.25 (m, &lt; RTI ID = 0.0 & , 10H), 7.51 (s, 2H), 7.90 (d, J = 7.9 Hz, 1H), 9.01 (s, 1H); MS (ES) m / e 856 (M + H) &lt; ⁺ &gt;; IR (KBr): 3360, 3100-3000, 2116, 1704, 1643, 1610, 1586, 1477, 1305, 1274, 766, 700 cm ^-1 . C ₃₉ H ₃₈ IN ₉ O ₆ 4.5 _H 20 Theoretical: C, 50.01; H, 5.06; N, 13.46. Found: C, 50.19; H, 5.01; N, 13.12.
Example 27
Preparation of 5 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -1H-benzimidazole-
a) Methyl 5 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -1H-benzimidazole-
To a solution of methyl 5-carboxy-benzimidazole-2-aminoacetate (0.24 g, 0.96 mmol), 2- (methylaminomethyl) benzimidazole bis-trifluoroacetate (0.56 g, Diisopropylethylamine (1.1 ml, 6.48 mmol) was added to a stirred solution of HOBt.H ₂ O (0.19 g, 1.44 mmol) and EDC (0.28 g, 1.44 mmol). After 23 h, the reaction mixture was diluted with CH ₂ Cl ₂ (100 ml) and washed successively with 5% NaHCO ₃ (30 ml) and brine (30 ml). Dried (MgSO _4), concentrated and purified by silica gel chromatography _{(10% MeOH / CH 2 Cl} 2) to give the title compound (0.16 g, 42%) as an off-white solid: MS (ES) m / e 393.0 (M + H ) ⁺ .
b) 5 - [[[(Benzimidazol-2-yl) methyl] methylamino] carbonyl] -1H-benzimidazole-
To a solution of methyl 5 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -1H-benzimidazole- 2-aminoacetate (0.16 mmol) in THF (10 ml) g, 0.41 mmol) was added 1.0 N LiOH (1.0 ml, 1.0 mmol) dropwise. After 1 h, the reaction mixture was concentrated by rotary evaporation to a small volume, cooled in an ice bath and neutralized with 1.0 N AcOH (1.0 ml). The solid was collected, washed with cold water and air dried to give the title compound (0.15 g, 100%) as an off-white solid: MS (ES) m / e 379.2 (M + H) &lt; ⁺ & gt ^; .
Example 28
Methyl] amino] carbonyl] -4- (3,3-dimethylbutyl) -3, 4- diazabicyclo [ -Oxo-lH-l, 4-benzodiazepin-2-acetic acid
a) Methyl (±) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -4- (3,3- ) -3-oxo-lH-l, 4-benzodiazepin-2-acetate
To a solution of methyl (±) -7-carboxy-4- (3,3-dimethylbutyl) -3-oxo-2,3,4,5-tetrahydro-1H- (0.42 g, 1.08 mmol), HOBt.H ₂ O (0.22 g, 1.62 mmol), benzodiazepine-2-acetic acid (0.39 g, 1.08 mmol), 2- (methylaminomethyl) benzimidazole bis (trifluoroacetate) And EDC (0.31 g, 1.62 mmol) in DMF (5 mL) was added diisopropylethylamine (0.94 mL, 5.4 mmol). After 23 h, the reaction mixture was diluted with CH ₂ Cl ₂ (100 ml) and washed successively with 5% NaHCO ₃ (2 x 25 ml) and brine (25 ml). Dried (MgSO _4), concentrated and purified by silica gel chromatography _{(7% MeOH / CH 2 Cl} 2) to give the title compound (0.39 g, 71%) as a white solid: MS (ES) m / e 506.4 (M + H ) ⁺ .
b) Preparation of (±) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2- yl) methyl] methylamino] carbonyl] -4- (3,3- -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid
To a solution of methyl (±) -2,3,4,5-tetrahydro-7- [[[(benzimidazol-2-yl) methyl] methylamino] carbaldehyde in 10 ml of THF 1.0 N LiOH (1.0 ml, 1.0 mmol) was added to a mixture of 4- (3,3-dimethylbutyl) -3-oxo-1H-1,4-benzodiazepine- . After 50 min, the reaction mixture was concentrated by rotary evaporation to a small volume, cooled in an ice bath and neutralized with 1.0 N AcOH (2.5 ml). The solid was collected, washed with cold water and air dried to give the title compound (0.27 g, 73%) as a white solid: MS (ES) m / e 492.2 (M + H) <^+> .
Example 29
Methyl] amino] carbonyl] -4- (3,3-dimethylbutyl) -3- (2-methoxybenzyl) Oxo-lH-l, 4-benzodiazepin-2-acetic acid
a) methyl (±) -2,3,4,5-tetrahydro-7- [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -4- (3,3-dimethylbutyl) -3-oxo-lH-l, 4-benzodiazepin-2-acetate
To a solution of methyl (±) -7-carboxy-4- (3,3-dimethylbutyl) -3-oxo-2,3,4,5-tetrahydro-1H- (0.33 g, 0.91 mmol), 2- (methylaminomethyl) benzimidazole dihydrochloride hydrate (0.3 g, 1.36 mmol), HOBt.H ₂ O (0.18 g, 1.36 mmol) and EDC (0.26 g, 1.36 mmol) in THF (5 mL) was added diisopropylethylamine (0.79 mL, 4.56 mmol). After 20 h, the reaction mixture was diluted with CH ₂ Cl ₂ (70 ml) and washed successively with 5% NaHCO ₃ (2 x 20 ml) and brine (20 ml). Dried (MgSO _4), concentrated and purified by silica gel chromatography _{(7% MeOH / CH 2 Cl} 2) to give the title compound (0.25 g, 56%) as a white solid: MS (ES) m / e 492.4 (M + H ) ⁺ .
b) (±) -2,3,4,5-Tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -4- (3,3- Oxo-lH-l, 4-benzodiazepin-2-acetic acid
To a solution of methyl (±) -2,3,4,5-tetrahydro-7- [[[(benzimidazol-2-yl) methyl] amino] carbonyl 1.0 N LiOH (1.0 ml, 1.0 mmol) was added dropwise to a mixture of 4- (3,3-dimethylbutyl) -3-oxo-1H-1,4-benzodiazepine- Respectively. After 2.5 h, the reaction mixture was concentrated by rotary evaporation to a small volume, cooled in an ice bath and neutralized with 1.0 N AcOH (1.2 ml). The solid was collected, washed with cold water and air dried to give the title compound (0.25 g, 109%) as a white solid: MS (ES) m / e 478.2 (M + H) <^+> .
Example 30
Methyl] methylamino] carbonyl] -4- (3,3-dimethylbutyl) -2,3,4,5-tetrahydro-7 - [[[ ) -3-oxo-1H-1,4-benzodiazepin-2-acetic acid
a) Methyl (±) -2,3,4,5-tetrahydro-7 - [[[(4-azabenzimidazol-2-yl) methyl] methylamino] carbonyl] -4- -Dimethylbutyl) -3-oxo-lH-l, 4-benzodiazepin-2-acetate
Methyl (±) -7- carboxy-4- (3,3-dimethylbutyl) in anhydrous CH ₃ CN (12 ml) -3- oxo-2,3,4,5-tetrahydro -1H-1 at room temperature, (0.22 g, 0.61 mmol), 2- (methylamino) methyl-4-azabenzimidazole diacetate (0.29 g, 1.0 mmol), HOBt.H ₂ O (0.12 g, 0.91 mmol ) And EDC (0.17 g, 0.91 mmol) in DMF (5 mL) was added diisopropylethylamine (0.53 mL, 3.0 mmol). After 21 h, the reaction mixture was concentrated, diluted with CH ₂ Cl ₂ (100 ml) and washed successively with 5% NaHCO ₃ (2 x 20 ml) and brine (20 ml). Dried (MgSO _4), concentrated and purified by silica gel chromatography _{(7% MeOH / CH 2 Cl} 2) to give the title compound (0.147 g, 48%) as a white solid: MS (ES) m / e 507.4 (M + H ) ⁺ .
b) (짹) -2,3,4,5-tetrahydro-7 - [[[(4-azabenzimidazol-2- yl) methyl] methylamino] carbonyl] -4- Dimethylbutyl) -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid
To a solution of methyl (±) -2,3,4,5-tetrahydro-7- [[[(4-azabenzimidazol-2-yl) methyl] methyl] (0.14 g, 0.276 mmol) in anhydrous tetrahydrofuran (2 mL) was added 1.0 N LiOH (0.69 mL, 0.69 mmol) mmol) was added dropwise. After 2 hours, the reaction mixture was concentrated by rotary evaporation to a small volume, cooled in an ice bath and neutralized with 1.0 N AcOH (0.69 ml). The solid was collected, washed with cold water and air dried to give the title compound (0.074 g, 54%) as a white solid: MS (ES) m / e 493.2 (M + H) <^+> .
Example 31
(S) -2,3,4,5-tetrahydro-7 - [[[1 - [(benzimidazol-2-yl) methyl] benzimidazol- Methyl-3-oxo-1H-1, 4-benzodiazepin-2-acetic acid
methyl] amino] benzimidazol-2-yl] methyl] amino] -1H-pyrazolo [3,4- Carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine-
To a solution of methyl (S) -7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine- Methyl] amine bis (trifluoroacetate) (0.17 g, 0.34 mmol), 2 - [[1- (benzimidazol-2-yl) methyl] benzimidazole] Diisopropylethylamine (0.27 ml, 1.53 mmol) was added to a stirred solution of HOBt.H ₂ O (0.064 g, 0.48 mmol) and EDC (0.091 g, 0.48 mmol). After 22 h, the reaction mixture was concentrated, diluted with CH ₂ Cl ₂ (70 ml) and washed successively with 5% NaHCO ₃ (2 x 30 ml) and brine (20 ml). Dried (MgSO _4), concentrated and purified by silica gel chromatography _{(7% MeOH / CH 2 Cl} 2) to give the title compound (0.080 g, 43%) as a white solid: MS (ES) m / e 522.2 (M + H ) ⁺ .
b) (S) -2,3,4,5-Tetrahydro-7 - [[[[1- [(benzimidazol-2-yl) methyl] benzimidazol- Carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepin-
To a solution of methyl (S) -2,3,4,5-tetrahydro-7- [[[1 - [(benzimidazol-2-yl) methyl] Yl) methyl] amino] carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (0.08 g, 0.14 mmol) ml, 0.36 mmol) was added dropwise. After 2 hours, the reaction mixture was concentrated by rotary evaporation to a small volume, cooled in an ice bath and neutralized with 1.0 N AcOH (0.69 ml). The solution was lyophilized to give the crude product (0.086 g) as a white powder. Purification by C-18 Bond Elute (0% to 20% CH ₃ CN / H ₂ O with 0.1% TFA) gave the title compound as a white powder: MS (ES) m / e 538.2 (M + H) ⁺ .
Example 32
(S) -2,3,4,5-tetrahydro-7 - [[bis [(benzimidazol-2-yl) methyl] amino] carbonyl] -4- Preparation of 4-benzodiazepin-2-acetic acid
a) methyl (S) -2,3,4,5-tetrahydro-7 - [[bis [(benzimidazol-2-yl) methyl] amino] carbonyl] -1,4-benzodiazepine-2-acetate
Methyl in at room temperature in anhydrous _{CH 3 CN (10 ml) (} S) -7- carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro -1H-1,4- benzodiazepine-2-acetate (0.16 g, 0.26 mmol), HOBt.H ₂ O (0.05 g, 0.26 mmol), bis [(benzimidazol-2-yl) methyl] amine tris (trifluoroacetate) 0.36 mmol) and EDC (0.069 g, 0.36 mmol) in DMF (5 mL) was added diisopropylethylamine (0.22 mL, 1.29 mmol). After 17 h, the reaction mixture was concentrated, diluted with CH ₂ Cl ₂ (80 ml), and washed successively with 5% NaHCO ₃ (2 x 20 ml) and brine (20 ml). Dried (MgSO _4), concentrated and purified by silica gel chromatography _{(7% MeOH / CH 2 Cl} 2) to give the title compound (0.05 g, 36%) as a white solid: MS (ES) m / e 552.2 (M + H ) ⁺ .
b) (S) -2,3,4,5-Tetrahydro-7 - [[bis [(benzimidazol-2-yl) methyl] amino] carbonyl] -4- 1,4-benzodiazepin-2-acetic acid
To a solution of methyl (S) -2,3,4,5-tetrahydro-7 - [[bis [(benzimidazol-2-yl) methyl] amino] carbaldehyde in 6 ml of THF and 4 ml of water (0.23 ml, 0.23 mmol) was added dropwise to a mixture of 4-methyl-3-oxo-1H-1, 4-benzodiazepine-2-acetate (0.05 g, 0.09 mmol). After 1 h, the reaction mixture was concentrated by rotary evaporation to a small volume, cooled in an ice bath and neutralized with 1.0 N AcOH (0.3 ml). The solid was collected, washed with cold water and air dried to give the title compound (0.048 g, 98%) as a white solid: MS (ES) m / e 538.2 (M + H) <^+> .
Example 33
(2-phenethyl) -2,3,4,5-tetrahydro-7 - [[bis [(benzimidazol-2-yl) methyl] amino] carbonyl] -1H-l, 4-benzodiazepin-2-acetic acid
a) methyl (±) -2,3,4,5-tetrahydro-7 - [[bis (benzimidazol-2-yl) methyl] amino] carbonyl] Phenethyl) -lH-l, 4-benzodiazepin-2-acetate
Methyl in anhydrous CH ₃ CN (12 ml) at room temperature (±) -7- carboxy-3-oxo-2- (2-phenylethyl) 2,3,4,5-tetrahydro -1H-1,4- (0.11 g, 0.29 mmol), bis [(benzimidazol-2-yl) methyl] amine tris (trifluoroacetate) (0.18 g, 0.29 mmol), HOBt.H ₂ O , 0.43 mmol) and EDC (0.083 g, 0.43 mmol) in DMF (5 mL) was added diisopropylethylamine (0.3 mL, 1.74 mmol). After 21 h, the reaction mixture was concentrated, diluted with CH ₂ Cl ₂ (100 ml) and washed successively with 5% NaHCO ₃ (2 x 20 ml) and brine (20 ml). Dried (MgSO _4), concentrated and purified by silica gel chromatography _{(7% MeOH / CH 2 Cl} 2) to give the title compound (0.13 g, 70%) as a white solid: MS (ES) m / e 642.2 (M + H ) ⁺ .
b) Synthesis of (±) -2,3,4,5-tetrahydro-7 - [[bis [(benzimidazol-2-yl) methyl] amino] carbonyl] Ethyl) -1H-1,4-benzodiazepine-2-acetic acid
To a solution of methyl (±) -2,3,4,5-tetrahydro-7 - [[bis [(benzimidazol-2-yl) methyl] amino] carbaldehyde in 5 ml of THF 1.0 N LiOH (0.6 ml, 0.6 mmol) was added dropwise to a mixture of 3-oxo-4- (2-phenethyl) . After 18 h, the reaction mixture was concentrated by rotary evaporation to a small volume, cooled in an ice bath and neutralized with 1.0 N AcOH (0.6 ml). The solid was lyophilized to give the crude product (0.092 g, 77%) as a white powder. The title compound was obtained as a white powder by ODS chromatography (step gradient, 5-30% CH ₃ CN / H ₂ O with 0.1% TFA): MS (ES) m / e 628.2 (M + H) <^+> .
Example 34
Preparation of ethyl (±) -3 - [[[2- (benzimidazol-2-yl) ethyl] amino] succinoyl] amino-4-pentenoate
a) (±) -4-Ethynyl-2-azetidinone
4-Acetoxy-2-azetidinone (9.0 g, 69.7 mmol) was slowly added to a solution of ethynylmagnesium chloride (31 mL of 0.5 M THF, 0.55 mmol) at 0 ° C. After 1.5 hours 1.0 N HCl (100 mL) was added and the mixture was taken up in EtOAc (300 mL) and subsequently washed with 1.0 N HCl (100 mL), saturated NaHCO ₃ (100 mL) and brine (100 mL) . Dried (MgSO ₄₎ then concentrated to give the title compound as a pale brown brownish solid (4.57 g, 69%) was obtained. MS (ES) m / e 96.0 (M + H) &lt; ⁺ & gt ^; .
b) Ethyl (짹) -3-amino-4-pentynoate
(1.3 g, 13.68 mmol), EtOH (54 mL) and concentrated HCl (6 mL) was heated to reflux for 18 hours. The reaction was cooled to room temperature and then adjusted to pH 8.0 using saturated NaHCO ₃ . The reaction was extracted with EtOAc (3 x 70 mL) and the combined EtOAc layers were washed with brine (50 mL). Dried (MgSO ₄₎ and concentrated to give a brownish liquid with the title compound (1.06 g, 55%). MS (ES) m / e 141.9 (M + H) &lt; ⁺ & gt ^; .
c) Methyl- [[2- (benzimidazol-2-yl) ethyl] amino] succinate
3-carboxylic bome ethoxy propionyl chloride (0.6 g, 4.0 mmol) were added at 0 ℃ anhydrous _{CH 2 Cl 2 (45 ㎖)} 2- aminoethyl benzimidazole diacetate of (1.13 g, 4.0 mmol) and diisopropylethylamine Amine (2.59 g, 20 mmol). After stirring for 1.5 h at room temperature the reaction mixture was diluted with CH ₂ Cl ₂ (50 mL) and subsequently washed with H ₂ O (30 mL), 5% NaHCO ₃ (30 mL) and brine (30 mL) Respectively. Dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (8% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.2 g, 18%) as a yellow solid. MS (ES) m / e 276.4 (M + H) &lt; ⁺ & gt ^; .
d) [[2- (Benzimidazol-2-yl) ethyl] amino] succinic acid
A mixture of methyl- [[2- (benzimidazol-2-yl) ethyl] amino] succinate (0.2 g, 0.73 mmol), 1.0 N NaOH (1.82 mL, 1.82 mmol) and MeOH (10 mL) Stirred for 24 hours, and then concentrated to dryness. H ₂ O (5 mL) was added, the solution was neutralized with 1.0 N HCl (1.82 mL) and the resulting solution was lyophilized to give the crude title compound (0.23 g) as an off-white powder. MS (ES) m / e 261.9 (M + H) &lt; ⁺ & gt ^; .
e) ethyl (±) -3 - [[[2- (benzimidazol-2-yl) ethyl] amino] succinoyl] amino-4-pentenoate
Diisopropylethylamine (0.32 mL, 1.83 mmol) was added to a solution of ethyl (±) -3-amino-4-pentenoate (0.12 g, 0.88 mmol) in anhydrous CH ₃ CN (15 mL) and DMF (3 mL) (0.19 g, 0.73 mmol), HOBt.H ₂ O (0.15 g, 1.1 mmol) and EDC (0.21 g, 1.1 mmol) were added to a solution of Was added to the stirring solution. After 23 h, the reaction mixture was concentrated, diluted with CH ₂ Cl ₂ (100 mL) and subsequently washed with 5% NaHCO ₃ (2 x 25 mL) and brine (25 mL). Dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (7% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.07 g, 25%) as a white solid. MS (ES) m / e 385.4 (M + H) &lt; ⁺ & gt ^; .
Example 35
Ethyl] amino] succinoyl] amino-4-pentynoic acid was prepared in the same manner as in (1)
a) (±) -3 - [[[2- (Benzimidazol-2-yl) ethyl] amino] succinoyl]
1.0 N LiOH (0.78 ㎖, 0.78 mmol) of the ethyl (±) -3 in _{THF (5 ㎖), H 2} O (5 ㎖) and CH ₃ CN (1 ㎖) at room temperature - [[[2- (benzimidazole 2-yl) ethyl] amino] succinoyl] amino-4-pentenoate (0.12 g, 0.31 mmol). After 3 hours, the reaction mixture was concentrated by rotary evaporation to a small volume, cooled in an ice bath and neutralized with 1.0 N AcOH (0.78 mL). The solution was lyophilized to give the crude product (0.167 g) as a white powder. _{(10% CH 3 CN / H} 2 O containing 0.1% TFA) ODS chromatography to give the title compound as white powder. MS (ES) m / e 357.1 (M + H) &lt; ⁺ & gt ^; .
Example 36
(SB-237554) was synthesized in the same manner as in Production Example 1, except that the amount of (+) - 3 - [[[4- (4-azabenzimidazol-2-yl) butanoyl] glycyl] amino]
a) Preparation of methyl (4-azabenzimidazol-2-yl) butyrate
(2.59 g, 22.9 mmol) and methyl 4- (chloroformyl) butyrate (3.77 g, 22.9 mmol) in anhydrous THF (50 mL) at 0 &&Lt; / RTI &gt; mmol). After stirring at room temperature for 16 hours at 0, the reaction was concentrated to dryness under vacuum. The residue was dissolved in glacial AcOH (25 mL) and heated to 110 <0> C. After 93 hours, the reaction was cooled to room temperature and concentrated in vacuo. The dark brown residue was diluted with H ₂ O (40 mL) and CH ₂ Cl ₂ (40 mL) and the mixture was neutralized to pH 7 using 5 N NaOH. The layers were separated and the aqueous layer was further extracted with CH ₂ Cl ₂ (2 x 100 mL). The combined organic layers were washed with _{5% NaHCO 3 (2 x 30} ㎖) and brine (30 ㎖) and washed successively. Dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (7% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.47 g, 9%). MS (ES) m / e 220.0 (M + H) &lt; ⁺ & gt ^; .
b) (4-Azabenzimidazol-2-yl) butyric acid
A mixture of methyl (4-azabenzimidazol-2-yl) butyrate (0.47 g, 2.13 mmol), 1.0 N NaOH (6 mL, 6.0 mmol) and MeOH (10 mL) was stirred at room temperature for 5.5 hours, Concentrated and dried. The residue was diluted with H ₂ O (2 mL) and neutralized with 1.0 N HCl (0.73 mL). The resulting solid was collected and air-dried to give the title compound (0.32 g, 73%) as a yellow powder. MS (ES) m / e 206.0 (M + H) &lt; ⁺ & gt ^; .
c) Ethyl (짹) -3 - [[(N-t-butoxycarbonyl) glycyl] amino] -4-pentanoate
Diisopropylethylamine and ethyl (±) -3- amino-4-pen Martino benzoate (0.3 g, 2.13 mmol) in toluene (0.92 ㎖, 5.32 mmol) in dry CH ₃ CN (15 ㎖) at room temperature, Boc-Gly ( 0.56 g, 3.19 mmol), HOBt.H ₂ O (0.43 g, 3.19 mmol) and EDC (0.61 g, 3.19 mmol). After 34 h, the reaction mixture was concentrated, diluted with CH ₂ Cl ₂ (70 mL), and washed successively with 5% NaHCO ₃ (2 x 15 mL) and brine (15 mL). Dried (MgSO _4), concentrated, and purified by silica gel chromatography (1: 1 EtOAc / hexane) to give the title compound (0.5 g, 79%). MS (ES) m / e 299.2 (M + H) &lt; ⁺ & gt ^; .
d) Ethyl (±) -3 - [(glycyl) amino] -4-pentanoate Trifluoroacetate
Acetate A solution of TFA (5 ㎖) and CH ₂ Cl ₂ (15 ㎖) at room temperature (±) -3 - [[( Nt- butoxycarbonyl) glycyl] amino] 4-pentanoate (0.5 g , 1.68 mmol) was added all at once. After 30 min, the solution was concentrated by rotary evaporation and the residue was reconcentrated from toluene to remove residual TFA to give the title compound (0.55 g, 106%) as a light yellow syrup. MS (ES) m / e 199.2 (M + H) &lt; ⁺ & gt ^; .
e) ethyl (±) -3 - [[[4- (4-azabenzimidazol-2-yl) butanoyl] glycyl] amino-4-pentynoate
Acetate (0.55 to [(glycyl) amino] -4-pentanoate trifluoroacetate - diisopropylethylamine (0.94 ㎖, 5.43 mmol) of ethyl (±) -3 in anhydrous CH ₃ CN (15 ㎖) at room temperature, stirring g, 1.76 mmol), (4-aza-benzimidazol-2-yl) butyric acid (0.32 g, 1.55 _{mmol), HOBt · H 2 O (} 0.31 g, 2.33 mmol) and EDC (0.45 g, 2.33 mmol) Lt; / RTI &gt; After 64 h, the reaction mixture was concentrated, diluted with CH ₂ Cl ₂ (100 mL), and washed successively with 5% NaHCO ₃ (2 x 25 mL) and brine (25 mL). Dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (7% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.11 g, 18%) as a white solid. MS (ES) m / e 386.4 (M + H) &lt; ⁺ & gt ^; .
f) (±) -3 - [[[4- (4-azabenzimidazol-2-yl) butanoyl] glycyl] amino]
[[[4- (4- - 1.0 N LiOH of ethyl (±) -3 in (0.71 ㎖, 0.71 mmol) in the _{THF (5 ㎖), H 2} O (5 ㎖) and CH ₃ CN (1 ㎖) at room temperature Yl) butanoyl] glycyl] amino] -4-pentenoate (0.11 g, 0.285 mmol) in tetrahydrofuran. After 2 hours, the reaction mixture was concentrated by rotary evaporation to a small volume, cooled in an ice bath and neutralized with 1.0 N AcOH (0.70 mL). The solution was lyophilized to give the crude product (0.1 g, 100%) as a white powder. _{(5% CH 3 CN / H} 2 O containing 0.1% TFA) ODS chromatography to give the title compound as white powder. MS (ES) m / e 358.4 (M + H) &lt; ⁺ & gt ^; .
Example 37
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2-yl) methyl] methylamino] carbonyl] -1,4-benzodiazepin-2-acetic acid
a) dimethyl D-maleate-O-trifluoromethanesulfonate
Anhydrous CH ₂ Cl ₂ (50 ㎖) -D- dimethyl maleate (12.96 g, 80 mmol) and pyridine (6.8 ㎖, 84 mmol) was dried in a flame-dried flask under argon at 0 ℃ of CH ₂ Cl ₂ in the Was added dropwise to a solution of trifluoromethanesulfonic anhydride (14.2 mL, 84 mmol) in tetrahydrofuran (40 mL). The resulting yellowish orange mixture was stirred at 0 &lt; 0 &gt; C for 30 minutes and then at room temperature for 4 hours. The reaction was quenched with H ₂ O (5 mL) and the layers were separated. The organic layer was washed successively with H ₂ O (3 x) and brine. Dried (MgSO ₄₎ and concentrated to give the title compound (22.45 g, 95%) as an off-white solid. MS (ES) m / e 295 (M + H) &lt; ⁺ & gt ^; .
b) Dimethyl-N- (2-cyanophenyl) -D-aspartate
A solution of dimethyl D-maleate-O-trifluoromethanesulfonate (22.4 g, 76.2 mmol) in CHCl ₃ (40 mL) and hexane (40 mL) was added to a flame dried flask in CHCl ₃ 50 ml) and a solution of 2-aminobenzonitrile (9.0 g, 76.2 mmol) and 2,6-di-t-butylpyridine in hexane (50 ml) The resulting mixture was stirred at 0 &lt; 0 &gt; C for 30 minutes and then at room temperature for 3 days. The solvent was removed in vacuo and the residue taken up in EtOAc and washed successively with 5% HCl (10 x) and brine. Dried (MgSO ₄₎ and concentrated to give the title compound (12.3 g, 62%) by silica gel flash chromatography (12% EtOAc / hexane) as a clear oil by. MS (ES) m / e 263.3 (M + H) &lt; ⁺ & gt ^; .
c) Methyl (S) -2,3,4,5-tetrahydro-3-oxo-lH-l, 4- benzodiazepin-
CH ₃ OH (200 ㎖) dimethyl -N- (2- cyanophenyl) -D- aspartate (12 g, 45.7 _{mmol), Et 3 N (7.64 ㎖} , 54.84 mmol) and Raney Ni (46 g of, Wet, pre-washed with CH ₃ OH) in DMF ( ₂ mL) was stirred under H ₂ (Balun) at room temperature for 2 days. Remove the catalyst by filtration and washed with CH ₃ OH ₍₃ x). Concentrated, and silica gel flash chromatography _{(0-5% CH 3 OH / CH} 2 Cl 2) to give the title compound (7.93 g, 74%) as a white solid. MS (ES) m / e 235.3 (M + H) &lt; ⁺ & gt ^; .
d) Methyl (S) -2,3,4,5-tetrahydro-7-bromo-3-oxo-lH-l, 4- benzodiazepin-
Tetrabutylammonium tribromide (5.16 g, 10.7 mmol) to CHCl ₃ (50 ㎖) of methyl (S) -2,3,4,5- tetrahydro-3-oxo -1H-1,4- benzodiazepin-2- Acetate (2.5 g, 10.7 mmol) in dichloromethane, and the mixture was stirred at room temperature for 2 days. H ₂ O (30 mL) was then added and the organic layer was separated and washed successively with H ₂ O and brine. Dried (MgSO ₄ ), concentrated and purified by silica gel flash flash chromatography (0-5% CH ₃ OH / CH ₂ Cl ₂ ) to give the title compound (1.99 g, 60%) as a white solid. MS (ES) m / e 313.0 (M + H) &lt; ⁺ & gt ^; .
e) Methyl (S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol- Oxo-lH-l, 4-benzodiazepin-2-acetate
To a solution of methyl (S) -2,3,4,5-tetrahydro-7-bromo-3-oxo-1H-1, 4- benzodiazepine- 2- acetate (624 mg, 2 mmol) in NMP (22 mL) (695 mg, 2.8 mmol), DIEA (1.8 mL, 10 mmol) and (Ph ₃ P) ₂ PdCl ₂ (126 mg, 0.18 mmol) were added to a solution of 2- (aminomethyl) Mmol) were heated at 110 &lt; 0 &gt; C under a CO balun for 48 hours. The solvent removed by rotary evaporation (high vacuum), and the residue was purified by silica gel flash flash chromatography _{(0.5-5% CH 3 OH / CH} 2 Cl 2) to give the title compound as a pale yellow solid (170 mg, 19.5%) . MS (ES) m / e 437.5 (M + H) &lt; ⁺ & gt ^; .
f) (S) -2,3,4,5-Tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] methylamino] carbonyl] -3- -1H-l, 4-benzodiazepin-2-acetic acid
1.0 M LiOH (0.6 ㎖, 0.6 mmol) at room temperature CH ₃ OH (5 ㎖) and THF (5 ㎖) methyl (S) -2,3,4,5- tetrahydro of -7 - [[[(4 Yl) methyl] methylamino] carbonyl] -3-oxo-1H-1,4-benzodiazepine-2-acetate (170 mg, 0.39 mmol) in acetonitrile . The resulting mixture was stirred for 20 hours and then concentrated. The residue was dissolved in H ₂ O, acidified with 30% TFA and purified by ODS chromatography (5% CH ₃ CN / H ₂ O containing 0.1% TFA). &Lt; / RTI &gt; concentrated and lyophilized to give the title compound as an off-white powder. ^{_{[α] n 25 -74.5 ° (}} c = 1, CH 3 OH); MS (ES) m / e 423.2 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₁ H ₂₂ N ₆ O ₄ · 2TFA · 1.75H ₂ O; Calculated: C, 44.03; H, 4.06; N, 12.32. Measured: C, 44.33; H, 4.04; N, 12.28.
Example 38
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -3-oxo-1H-1,4-benzodiazepin- - Preparation of acetic acid
a) Methyl (S) -2,3,4,5-tetrahydro-7-iodo-3-oxo-lH-l, 4- benzodiazepin-
-ICI pyridine complex: iodine monochloride _{(100 ㎖, CH 2 Cl 2} 1M solution of) an under argon at 5 ℃ anhydrous CH ₂ Cl ₂ (20 ㎖) was added slowly to a solution of pyridine (8.5 ㎖, 105 mmol) in , And the temperature was maintained between 10 and 15 ° C. The mixture was stirred at 5-10 [deg.] C for 20 min, then hexane (50 mL) was added and the mixture was stirred in an ice bath for a further 30 min. The solid was collected by suction filtration, washed successively with hexane and petroleum ether and dried to give the reagent (22.5 g) as a yellow crystalline solid.
-ICI pyridine complex (1.27 g, 5.28 mmol) CH ₂ Cl ₂ (20 ㎖) and CH ₃ OH methyl (S) -2,3,4,5- tetrahydro-3-oxo -1H in (20 ㎖) -1,4-benzodiazepine-2-acetate (1.18 g, 4.8 mmol) in dichloromethane. After stirring for 40 minutes the resulting mixture at room temperature was added the _{following, 1 M NaHSO 3 (20 ㎖} ). The solid was collected by suction filtration and washed with Et ₂ O. And dried to give the title compound (1.72 g, quantitative yield) as an off-white solid. MS (ES) m / e 361.2 (M + H) &lt; ⁺ & gt ^; .
b) Preparation of methyl (S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -3- Benzodiazepin-2-acetate
A solution of methyl (S) -2,3,4,5-tetrahydro-7-iodo-3-oxo-1H-l, 4- benzodiazepine-2- acetate (1.08 g, 3 mmol) (211 mg, 0.3 mmol) and 2-aminomethylbenzimidazole dihydrochloride hydrate (924 mg, 4.2 mmol), DIEA (2.6 mL, 15 mmol) and (Ph ₃ P) ₂ PdCl ₂ And heated for 3 hours. The solvent removed by rotary evaporation (high vacuum) and the residue was purified by silica gel flash flash chromatography _{(0-7% CH 3 OH / CH} 2 Cl 2) the title compound as an off-white solid (530 mg, 44%) . MS (ES) m / e 408.1 (M + H) &lt; ⁺ & gt ^; .
c) Synthesis of (S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -3-oxo-1H-1,4-benzodiazepine -2-acetic acid
Methyl] methyl] carbonyl] -3-oxo-pyrrolidine-2-carboxylic acid methyl ester. (S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -3 The title compound (66%) was prepared as a white powder, following the procedure for example 37 (f), but substituting 2- oxo-1H-l, 4- benzodiazepine-2-acetate for the title compound. ^{_{[α] n 25 -145.3 ° (}} c = 1, CH 3 OH); MS (ES) m / e 394.2 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₀ H ₁₉ N ₅ O ₄ .2TFA. 0.125H ₂ O; Calculated: C, 46.22; H, 3.43; N, 11.23. Measured: C, 46.13; H, 3.78; N, 11.49.
Example 39
Methyl] methylamino] carbonyl] phenyl] aspartic acid was prepared in the same manner as in (1) except that the amount of (-) - N- [2- (aminomethyl)
a) Methyl (±) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol- Oxo-lH-l, 4-benzodiazepin-2-acetate
EDC (130 mg, 0.75 mmol) was added to a solution of methyl (±) -2,3,4,5-tetrahydro-7-carboxy-3-oxo-1H-1,4-benzodiazepine- 5-methylbenzimidazole dihydrochloride (169 mg, 0.68 mmol), HOBt.H ₂ O (101 mg, 0.75 mmol), and DIEA (190 mg, 0.68 mmol) 0.39 mL, 2.24 mmol). After 20 hours, The reaction is concentrated by rotary evaporation (high vacuum) and the residue was purified by silica gel _{(1-6.5% CH 3 OH / CH} 2 Cl 2) was chromatographed on a title compound as a white solid (260 mg, 88% ). MS (ES) m / e 437.5 (M + H) &lt; ⁺ & gt ^; .
b) Synthesis of (±) -N- [2- (aminomethyl) -4 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] methylamino] carbonyl] phenyl] aspartic acid
Methyl] methyl] carbonyl] -3-oxo-pyrrolidine-2-carboxylic acid methyl ester. Methyl-1H-1,4-benzodiazepin-2-acetate was reacted with methyl (±) -2,3,5,5-tetrahydro-7 - [[[(4- ] Methylamino] carbonyl] -3-oxo-1H-1,4-benzodiazepine-2-acetate, the title compound (66% . MS (ES) m / e 441.2 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₁ H ₂₄ N ₆ O ₅ .2TFA. 2.25H ₂ O; Calculated: C, 42.08; H, 4.38; N, 11.78. Measured: C, 42.01; H, 4.18; N, 11.55.
Example 40
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2-yl) methyl] amino] carbonyl] Preparation of 1,4-benzodiazepin-2-acetic acid
a) methyl (S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol- -1H-l, 4-benzodiazepin-2-acetate
Following the procedure of Example 38 (b) but replacing the 2-aminomethylbenzimidazole dihydrochloride hydrate with 2- (aminomethyl) -4-aza-5-methylbenzimidazole dihydrochloride, The title compound (63%) was prepared as an amber solid. MS (ES) m / e 423 (M + H) &lt; ⁺ & gt ^; .
b) (S) -2,3,4,5-Tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol- 2- yl) methyl] amino] carbonyl] -3- 1H-1, 4-benzodiazepin-2-acetic acid
Methyl] methyl] carbonyl] -3-oxo-pyrrolidine-2-carboxylic acid methyl ester. (S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol- (50%) was obtained as a white powder &lt; / RTI &gt; following the procedure of Example 37 (f), except substituting 2-amino-3- . MS (ES) m / e 409.2 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₀ H ₂₀ N ₆ O ₄ · 1.75 TFA · H ₂ O; Calculated: C, 45.09; H, 3.82; N, 3.45. Measured: C, 45.18; H, 4.10; N, 13.58.
Example 41
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -3-oxo- Yl) ethyl] -1H-1,4-benzodiazepine-2-acetate
a) t-Butyl-4-fluoro-3- [[2- (pyrid-3- yl) ethyl] amino] benzoate
A mixture of t-butyl-4-fluoro-3-methylbenzoate (3.83 g, 18.22 mmol), NBS (3.57 g, 20.24 mmol), benzoyl peroxide (0.22 g, 0.91 mmol) and CCl ₄ Was heated under reflux. After 16 h, the reaction was cooled in ice / H ₂ O, filtered and the filtrate was concentrated. The residue was passed through a short pad of silica gel (20% EtOAc / hexanes) to remove the reference material and the filtrate was concentrated. The residue was dissolved in THF (90 mL) and 3- (2-aminoethyl) pyridine (6.97 g, 57 mmol) was added rapidly. Endothermic relaxation occurred with addition. The reaction was then stirred overnight and concentrated. The residue was diluted with Et ₂ O (100 mL) and washed successively with 1.0 N NaOH (30 mL), H ₂ O (30 mL) and brine (30 mL). Dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (10% MeOH / CH ₂ Cl ₂ ) to give the title compound (2.58 g, 59%) as a yellow oil. MS (ES) m / e 331 (M + H) &lt; ⁺ & gt ^; .
b) Preparation of t-butyl (S) -4-fluoro-3- [2-aza-4- (benzyloxycarbonyl) amino-3,6-dioxo-6-methoxy- Yl) ethyl] hexyl] benzoate
DCC (1.86 g, 9 mmol) was added to a solution of t-butyl-4-fluoro-3 - [[2- (pyrid-3- yl) ethyl] amino] benzoate (2.7 g, , 8.18 mmol), N-Cbz-L-aspartic acid -Methyl ester (J. Am. Chem. Soc. 1957, 79, 5697; 2.53 g, 9 mmol) and HOBt.H ₂ O (1.2 g, 9 mmol Lt; / RTI &gt; After 24 h, the mixture was diluted with Et ₂ O (25 mL) and filtered. The filtrate was concentrated to dryness and the residue was diluted with Et ₂ O (50 mL) and washed successively with H ₂ O (2 × 10 mL) and brine (10 mL). Dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (CH ₂ Cl ₂ ) to give the title compound (2.4 g, 49%) as a colorless oil. MS (ES) m / e 594 (M + H) &lt; ⁺ & gt ^; .
c) Synthesis of t-butyl (S) -4-fluoro-3- [4-amino-2-aza-3,6-dioxo-6-methoxy- 2- [2- (pyrid- Ethyl] hexyl] benzoate
(S) -4-fluoro-3- [2-aza-4- (benzyloxycarbonyl) amino-3,6-dioxo-6-methoxy-2- [2- (2.4 g, 4 mmol), 10% Pd / C (184 mg, 0.17 mmol) and MeOH (17 mL) was shaken under H ₂ (50 psi) at room temperature . After 1.5 h, the reaction was filtered through Celite (Celite) and concentrated. Purification by silica gel chromatography (1: 1 10% MeOH in EtOAc / CHCl ₃₎ to give the title compound (1.1 g, 59%) as a colorless oil. MS (ES) 460 (M + H) &lt; ⁺ & gt ^; .
d) Methyl (S) -2,3,4,5-tetrahydro-7- (t-butoxycarbonyl) -4- [2- (pyrid- -1,4-benzodiazepine-2-acetate
To a solution of t-butyl (S) -4-fluoro-3- [4-amino-2-aza-3,6-dioxo-6-methoxy- 2- [2- Yl) ethyl] hexyl] benzoate (0.64 g, 1.39 mmol) was heated in an oil bath fixed at 120-125 [deg.] C under argon. After 17.5 h, the reaction was cooled in ice / H ₂ O and diluted with H ₂ O (12 mL). The mixture was extracted with EtOAc (3 x 20 mL) and the combined EtOAc layers were washed with H ₂ O (10 mL) and brine (10 mL). Dried (MgSO ₄ ), concentrated and purified by silica gel chromatography (9: 1 CH ₂ Cl ₂ / MeOH) to give the title compound (0.15 g, 33%) as a colorless oil. MS (ES) m / e 440 (M + H) &lt; ⁺ & gt ^; .
e) Methyl (S) -2,3,4,5-tetrahydro-7-carboxy-4- [2- (pyrid- 2-acetate
4 M HCl / dioxane (0.5 ㎖) in anhydrous CH ₂ Cl ₂ (5 ㎖) of methyl (S) -2,3,4,5- tetrahydro -7- (t- butoxycarbonyl) -4 Was added to a solution of [2- (pyrid-3-yl) ethyl] -3-oxo-1H-1,4-benzodiazepine-2- acetate (0.18 g, 4.1 mmol) and the reaction stirred overnight at room temperature. Concentration in vacuo followed by re-concentration from toluene (3 x 10 mL) gave the title compound (0.12 g, 65%). MS (ES) m / e 384 (M + H) &lt; ⁺ & gt ^; .
f) Preparation of methyl (S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] Yl) ethyl] -1H-1,4-benzodiazepine-2-acetate
(S) -2,3,4,5-tetrahydro-7-carboxy-4- [2- (pyrid- Acetate (0.12 g, 0.26 mmol) and thionyl chloride (15 mL) was refluxed for 1 h. The resulting orange solution was concentrated to dryness to give a yellow-orange foam. This was dissolved in CH ₂ Cl ₂ (10 mL) and a solution of 2-aminomethylbenzimidazole dihydrochloride hydrate (0.058 g, 0.26 mmol), pyridine (0.72 g, 0.26 mmol) in CH ₂ Cl ₂ (15 mL) , 9.1 mmol) and triethylamine (0.55 g, 5.46 mmol). The reaction mixture was then stirred under argon at room temperature. After 25.5 hours, CH ₂ Cl ₂ (200 mL) and 5% NaHCO ₃ (50 mL) were added to the reaction mixture to yield a pale yellow precipitate which was filtered and air dried to give the title compound (0.030 g, 22% yield). MS (ES) m / e 513 (M + H) &lt; ⁺ & gt ^; .
g) (S) -2,3,4,5-Tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] Yl) ethyl] -1H-1,4-benzodiazepine-2-acetate
1.0 N LiOH (0.57 ㎖, 0.57 mmol) at room temperature in THF (4 ㎖) and H ₂ O (5 ㎖) methyl (S) -2,3,4,5- tetrahydro of -7 - [[[(benz Yl) ethyl] -1H-1,4-benzodiazepine-2-acetate (0.030 g, 0.0 &gt; mmol) &lt; / RTI &gt; The resulting pale brownish yellow solution was stirred for 21.5 hours and then concentrated by rotary evaporation. The resulting residue was lyophilized to give a crude product as a yellowish powder. Preparative HPLC (registered trademark PRP-1 column, 10 to 20% containing a step _{gradient, 0.1% TFA CH 3 CN /} H 2 O) to give the title compound (0.010 g, 34% yield). MS (ES) m / e 499 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₇ H ₂₆ N ₆ O ₄ · 3C ₂ HF ₃ O ₂ · 3HCl · 3H ₂ O; Calculated: C, 37.41; H, 3.41; N, 7.52. Measured: C, 37.6; H, 3.52; N, 7.52.
Example 42
Methyl (3-methyl-3-oxo-1H-1 , Preparation of 4-benzodiazepine-2-acetate
a) Preparation of ethyl (S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -4-methyl- -1,4-benzodiazepine-2-acetate
HCl gas was bubbled through EtOH (200 mL) for 10 min and then a solution of (S) -2,3,4,5-tetrahydro-7- [[[(benzimidazol- ] Carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid (2.00 g, 4.5 mmol). The reaction was stirred at room temperature for 24 hours and then concentrated to dryness by rotary evaporation. The residue was reconcentrated from toluene (2 x) to remove residual EtOH and then chromatographed on silica gel (gradient: 7% MeOH / CH ₂ Cl ₂ (1 L) followed by 10% MeOH / CH ₂ Cl ₂ ) Respectively. The resulting residue was dissolved in EtOH and Et ₂ O was added to precipitate the solid. This is collected and washed with Et ₂ O to give the title compound as a white solid. MS (ES) m / e 450.2 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₄ H ₂₇ N ₅ O ₄ .1.5H ₂ O; Calculated: C, 60.49; H, 6.35; N, 14.70. Measured: C, 60.41; H, 6.27; N, 14.38.
Example 43
Propyl] amino] carbonyl] piperidine-1-acetic acid The title compound
a) Preparation of 2- [3- (N-t-butoxycarbonyl) aminopropyl] benzimidazole
A solution of isobutyl chloroformate (10.2 mL, 79 mmol) in THF (25 mL) was added to a solution of 4- (t-butoxycarbonyl) aminobutyric acid (Organic Synthesis 1984, 63 , 160; 13.5 g, 0.066 moles) and trimethylamine (11 mL, 80 mmol). After 0.5 h, a solution of 1,2-phenylenediamine (7 g, 64.8 mmol) in THF (50 mL) was added dropwise to the resulting white suspension. The reaction was stirred for 18 hours, then filtered and the filtrate was concentrated to give a semisolid. This was dissolved in AcOH (100 mL) and the solution was heated at 70 &lt; 0 &gt; C for 18 h. The reaction mixture was concentrated and the residue was reconcentrated several times from toluene. Silica gel flash chromatography gave the title compound (6.0 g, 33%). MS (ES) m / e 276 (M + H) &lt; ⁺ & gt ^; .
b) 2- (3-Aminopropyl) benzimidazole dihydrochloride
A solution of 2- [3- (Nt-butoxycarbonyl) aminopropyl] benzimidazole (1.2 g, 4.3 mmol) and 4 M HCl in dioxane (20 mL) and CH ₂ Cl ₂ (25 mL) Lt; / RTI &gt; for 18 hours. The resulting white suspension was filtered to give the title compound (1.07 g, 97%).
c) Preparation of ethyl 4 - [[[3- (1H-benzimidazol-2-yl) propyl] amino] carbonyl] piperidine-
A mixture of ethyl 4-carboxypiperidine-1-acetate hydrochloride (Yellin 's SB 223913 CIP) (0.76 g, 3 mmol) in thionyl chloride (10 mL) was heated to reflux for 15 min and then concentrated to dryness. After several evaporations from toluene, the residue was dissolved with 2- (3-aminopropyl) benzimidazole dihydrochloride (0.77 g, 3 mmol) and DIEA (3 mL) in DMF (25 mL) After 18 h, the reaction mixture was partitioned between EtOAc (50 mL) and 5% NaHCO ₃ (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed successively with H ₂ O and saturated NaCl solution and dried over MgSO ₄ . Concentrated and purified by silica gel flash chromatography (6% MeOH / CH ₂ Cl ₂ ) to give the title compound (40 mg, 3%).
b) Preparation of 4 - [[[3-benzimidazol-2-yl) propyl] amino] carbonyl] piperidine-
1 N NaOH solution (0.4 mL, 0.4 mmol) was added to a solution of ethyl 4 - [[[3- (1H-benzimidazol-2- yl) propyl] amino] carbonyl] piperidine- Was added to a stirred solution of 1-acetate (40 mg, 0.1 mmol). After 18 h, the mixture was neutralized with AcOH (1 mL) and concentrated to remove MeOH. The aqueous solution was loaded on a XAD-2 column and eluted with H ₂ O (500 mL) followed by 20% CH ₃ CN / H ₂ O. The fractions containing the product were poured into a vessel and lyophilized to give the title compound (9 mg, 25%). MS (ES) m / e 345.2 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₁₈ H ₂₄ N ₄ O ₃ .0.75 H ₂ O; Calculated: C, 60.40; H, 7.18; N, 15.65. Measured: C, 60.48; H, 7.16; N, 15.40
Example 44
4 - [[[3-benzimidazol-2-yl) propyl] amino] carbonyl] phenylacetic acid
a) Ethyl 4 - [[[3-benzimidazol-2-yl) propyl] amino] carbonyl] -1-phenylacetate
(0.5 g, 2.4 mmol), 2- (3-aminopropyl) benzimidazole dihydrochloride (0.7 g, 2.8 mmol) in DMF (15 mL) ), HOBt.H ₂ O (0.36 g, 2.6 mmol), EDC (0.5 g, 2.6 mmol) and DIEA (1.5 mL, 8.8 mmol) was slightly warmed and stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc (50 ㎖) and _{5% NaHCO 3 (100 ㎖)} , and extracted with EtOAc (2 x 50 ㎖). The combined organic extracts were washed successively with H ₂ O and saturated NaCl solution and dried over MgSO ₄ . The evaporated residue was triturated with Et ₂ O to give the title compound (0.56 g, 66%). MS (ES) m / e 366.0 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₁ H ₂₃ N ₃ O ₃ .0.25 H ₂ O; Calculated: C, 68.18; H, 6.40; N, 11.36. Measured: C, 68.16; H, 6.26; N, 11.36.
b) 4 - [[[3-benzimidazol-2-yl) propyl] amino] carbonyl] phenylacetic acid
1 N NaOH solution (6 mL, 6 mmol) was added at room temperature to a solution of ethyl 4 - [[[3- (1H-benzimidazol-2- yl) propyl] amino] carbonyl] Acetate (0.38 g, 1 mmol) in tetrahydrofuran. After 4 h, the mixture was neutralized with AcOH (6 mL) and the resulting solid was filtered to give the title compound (77 mg, 22%). Mp 108-110 [deg.] C; MS (ES) m / e 345.2 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₁₉ H ₁₉ N ₃ O ₃ .6H ₂ O; Calculated: C, 65.54; H, 5.85; N, 12.07. Measured: C, 65.63; H, 5.65; N, 11.95.
Example 45
(S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7 - [[[(5-trifluoromethylbenzimidazol- ] -1H-1,4-benzodiazepine-2-acetic acid
a) 3,4-diaminobenzotrifluoride
4-Amino-3-nitrobenzotrifluoride (3.7070 g, 17.98 mmol) was dissolved in MeOH and a catalytic amount of 10% Pd / C was added. Purge the reaction with H ₂ and stirred at room temperature under H ₂ (balloon). After 24 h, the reaction was filtered through a bed of celite and the filtrate was evaporated in vacuo to give the title compound (3.0878 g, 98%). The material was used without specification.
b) 2- [N- (Benzyloxycarbonyl) -N-methyl] aminomethyl-5-trifluoromethylbenzimidazole
Cbz-Sakosine (3.9950 g, 17.13 mmol) was dissolved in anhydrous THF and isobutyl chloroformate (2.5 mL, 19.27 mmol) followed by triethylamine (5.0 mL, 39.95 mmol) was added. A mixed anhydride was formed at room temperature for 30 minutes and then added to a solution of 3,4-diaminobenzotrifluoride (3.0818 g, 7.53 mmol) in anhydrous THF. After 20 hours at room temperature, the reaction was evaporated in vacuo. The residue was dissolved in EtOAc and 1.0 N NaHCO₃&Lt; / RTI &gt; and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried (MgSO4₄), Filtered and evaporated in vacuo. The residue was reconcentrated from toluene and then dissolved in glacial AcOH (125 mL). The solution was heated at 110 &lt; 0 &gt; C for 24 h, then the AcOH was evaporated in vacuo. The residue was reconcentrated from toluene and then adsorbed onto a silica gel and loaded onto a dry silica gel flash chromatography column. The column was washed with 1: 1 &lt; RTI ID =₃/ Meat₂O to give the title compound (2.9397 g, 47.2%). TLC R_f(1: 1 CH₂Cl₂/ Meat₂O); MS (ES) m / e 364.2 (M + H) &lt;⁺; ^One&Lt; 1 &gt; H NMR (250 MHz, CDCl3₃) [delta] 8.0-7.2 (m, 9H), 5.05 (s, 2H), 4.84 (s, 2H), 3.07 (s, 3H).
c) 2- (Methylaminomethyl) -5-trifluoromethylbenzimidazole
Methyl-5-trifluoromethylbenzimidazole (2.9397 g, 8.09 mmol) was dissolved in MeOH and a catalytic amount of 10% Pd / C was added Respectively. The reaction was purged with H ₂ and then stirred at room temperature under H ₂ . After 5 h, the reaction mixture was filtered through a bed of Celite (R) and the filtrate was evaporated in vacuo to give a tan oil. Since the Cbz protecting group was still shown to be present by 400 MHz NMR analysis, the reaction conditions were repeated. After 18 hours, the catalyst was removed by filtration through a bed of Celite (R) and the filtrate was evaporated in vacuo to give the title compound (1.7809 g, 96%). ¹ H NMR (250 MHz, CDCl ₃ ) 7.76-7.32 (m, 4H), 4.32 (s, 2H), 2.59 (s, 3H).
d) Methyl (S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7 - [[[(5-trifluoromethylbenzimidazol- ] Carbonyl] -1H-1,4-benzodiazepine-2-acetate
Methyl (S) -7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (179.2 mg, 0.61 mmol) The flask was weighed. It was added to a CH ₃ CN (10 ㎖), then _{HOBt · H 2 O (97.9 mg} . 0.72 mmol) and EDC (149.3 mg, 0.78 mmol). After dissolving all the solids, a solution of 2- (methylaminomethyl) -5-trifluoromethylbenzimidazole (186.1 mg, 0.81 mmol) in CH ₃ CN was treated with diisopropylethylamine (0.25 mL, 1.44 mmol) . After 24 hours at room temperature, the reaction was evaporated in vacuo, followed by chromatography of the residue on silica gel _(3% MeOH / CHCl 3) to give the title compound (308.1 mg, 100%). TLC R _f (5% MeOH / CHCl ₃ ) 0.21; ^{1 H NMR (250 MHz, CDCl} 3) δ 7.83-7.16 (m, 7H), 5.37 (d, 1H), 5.05-4.70 (m, 3H), 2.96 (m, 3H), 3.72 (s, 3H), 3.16 (s, 2 H), 2.11 (s, 3 H); MS (ES) m / e 504.0 (M + H) &lt; ⁺ & gt ^; .
e) (S) -2,3,4,5-Tetrahydro-4-methyl-3-oxo-7 - [[[(5-trifluoromethylbenzimidazol- Carbonyl] -1H-1,4-benzodiazepine-2-acetic acid
Methyl (S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7 - [[[(5-trifluoromethylbenzimidazol- Yl] -1H-1,4-benzodiazepine-2-acetate (308.1 mg, 0.61 mmol) was dissolved in MeOH (5 mL). H ₂ O (5 mL) was added followed by 1.0 N NaOH (2.0 mL, 2.0 mmol). After 24 hours at room temperature, the reaction was neutralized with 1.0 N HCl (2.0 mL). The milky mixture was stirred at room temperature for 15 minutes, then diluted with H ₂ O and the precipitate was collected on a sintered glass funnel. The white powder was dried overnight in a vacuum desiccator to give the title compound (268.0 mg, 90%). MS (ES) m / e 490.2 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₃ H ₂₂ N ₅ O ₄ F ₃揃 2.25H ₂ O 揃 0.25 HCl; Calculated: C, 51.24; H, 5.00; N, 12.99. Measured: C, 51.44; H, 4.96; N, 12.45.
Example 46
(S) -2,3,4,5-tetrahydro-7 - [[[(4,7-dimethoxybenzimidazol-2-yl) methyl] methylamino] carbonyl] Oxo-lH-l, 4-benzodiazepin-2-acetic acid
a) 2- [N- (Benzyloxycarbonyl) -N-methyl] aminomethyl-4,7-dimethoxybenzimidazole
The title compound was prepared following the procedure of Example 45 (b), except replacing 3,4-diaminobenzotrifluoride with 1,2-diamino-3,6-dimethoxybenzene. MS (ES) m / e 356.2 (M + H) &lt;⁺; ^One&Lt; 1 &gt; H NMR (250 MHz, CDCl3₃3H), 3.86 (s, 3H), 3.03 (s, 3H), 2.50 (s, 2H) .
b) 4,7-Dimethoxy-2- (methylaminomethyl) benzimidazole
(186.5 mg, 0.53 mmol) was dissolved in MeOH and a catalytic amount of 10% Pd / C was added to the solution. Respectively. Purge the reaction with H ₂ and stirred at room temperature under H ₂ (balloon). After 20 hours, the reaction was filtered through a bed of Celite (R) and the filtrate was evaporated in vacuo to give the title compound (96.9 mg, 83%). ^{1 H NMR (250 MHz, CDCl} 3) δ 6.52 (s, 2H), 3.94-3.86 (m, 6H), 2.36 (s, 3H).
c) Preparation of methyl (S) -2,3,4,5-tetrahydro-7 - [[[(4,7-dimethoxybenzimidazol-2- yl) methyl] methylamino] carbonyl] -3-oxo-lH-l, 4-benzodiazepin-2-acetate
Methyl (S) -7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (112.3 mg, 0.38 mmol) The flask was weighed. CH ₃ CN, followed by HOBt · H ₂ O (62.3 mg, 0.46 mmol) and EDC (120.0 mg, 0.63 mmol). When dissolving all solids, diisopropylethylamine (0.1 ㎖, 0.57 mmol) followed by diisopropylethylamine (0.1 ㎖, 0.57 mmol) of 4,7-dimethoxy-2 in CH ₃ CN containing ( Methylaminomethyl) benzimidazole (96.8 mg, 0.44 mmol) in dichloromethane (5 mL) was added. After 2.5 days at room temperature, the reaction was evaporated in vacuo. The residue was evaporated once with toluene and then chromatographed on silica gel (CHCl ₃ followed by 5% MeOH / CHCl ₃ ) to give the title compound (152.0 mg, 80.0%). TLC R _f (5% MeOH / CHCl ₃ ) 0.35; MS (ES) m / e 496.2 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (250 MHz, CDCl} 3) δ 7.25 (m, 2H), 6.56 (s, 2H), 5.36 (d, 1H), 3.91 (s, 6H), 3.70 (s, 3H), 3.08 (s, 3H).
d) (S) -2,3,4,5-Tetrahydro-7 - [[[(4,7- dimethoxybenzimidazol-2- yl) methyl] methylamino] carbonyl] Oxo-lH-l, 4-benzodiazepin-2-acetic acid
(S) -2,3,4,5-tetrahydro-7 - [[[(4,7-dimethoxybenzimidazol-2-yl) methyl] methyl] methyl Amino] carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate was saponified to obtain the title compound (110.0 mg, 74%). MS (ES) m / e 482.2 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₄ H ₂₇ N ₅ O ₆ .0.75 H ₂ O; Calculated: C, 58.23; H, 5.80; N, 14.15, found: C, 58.26; H, 5.59; N, 13.90.
Example 47
(S) -2,3,4,5-tetrahydro-7 - [[[(4-methylbenzimidazol-2-yl) methyl] methylamino] carbonyl] -4-methyl- -1,4-benzodiazepin-2-acetic acid
a) 1,2-Diamino-3-methylbenzene
Following the procedure of Example 45 (a), but replacing 4-amino-3-nitrobenzotrifluoride with 2-methyl-6-nitroaniline (3.0204 g, 19.98 mmol), the title compound (2.4815 g ). This was used without characterization.
b) 2- [N- (Benzyloxycarbonyl) -N-methyl] aminomethyl-4-methylbenzimidazole
Cbz-sarcosine (4.6466 g, 19.92 mmol) was dissolved in anhydrous THF in a 100 mL round bottom flask. Triethylamine (3.0 mL, 21.57 mmol) was added followed by isobutyl chloroformate (2.8 mL, 21.59 mmol). The white reaction was stirred at room temperature for 0.5 h and then added to a solution of 1,2-diamino-3-methylbenzene (2.4815 g) in dry THF at -20 캜 to -30 캜. After 20 minutes, the reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction is evaporated in vacuo and the residue is taken up in EtOAc and 1.0 N NaHCO₃Lt; / RTI &gt; The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4₄), Filtered and evaporated in vacuo. The residue was reconcentrated from toluene and the dried solid was dissolved in glacial AcOH (150 mL). The solution was heated at 110 &lt; 0 &gt; C for 18 h and then concentrated under high vacuum. The residue was reconcentrated from toluene and then adsorbed onto a silica gel and loaded onto a dry silica gel flash chromatography column. The column was washed with 1: 1 CH₂Cl₂/ Meat₂O to give the title compound (3.1586 g, 51%). MS (ES) m / e 310.2 (M + H) &lt;⁺; ^One&Lt; 1 &gt; H NMR (250 MHz, CDCl3₃) [delta] 7.35-7.01 (m, 10H), 5.00 (s, 2H), 4.72 (s, 2H), 2.99 (s, 3H), 2.55
c) 4-Methyl-2- (methylaminomethyl) benzimidazole
Methyl] aminomethyl-5-trifluoromethylbenzimidazole was prepared by reacting 2- [N- (benzyloxycarbonyl) -N-methyl] Methylbenzimidazole, the title compound (2.9916 g, quantitative yield) was prepared following the procedure of Example 45 (c). ^{1 H NMR (250 MHz, CDCl} 3) δ 7.36-7.01 (m, 4H), 4.01 (s, 2H), 2.52 (s, 3H), 2.41 (s, 3H).
d) Methyl (S) -2,3,4,5-tetrahydro-7 - [[[(4-methylbenzimidazol-2- yl) methyl] methylamino] carbonyl] Oxo-lH-l, 4-benzodiazepin-2-acetate
Methyl (S) -7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (188.5 mg, 0.64 mmol) The flask was weighed. CH ₃ CN, then was added successively _{HOBt · H 2 O (103.5 mg} . 0.77 mmol), EDC (149.3 mg, 0.78 mmol) and diisopropylethylamine (0.15 ㎖, 0.86 mmol). After 15 minutes, a solution of 4-methyl-2- (methylaminomethyl) benzimidazole (273.8 mg, 1.56 mmol) in CH ₃ CN was added. CH ₂ Cl ₂ (5 mL) was added to dissolve some of the material. After 18 hours at room temperature, The reaction is concentrated in vacuo, followed by chromatography of the residue on silica gel (5% MeOH / CHCl ₃₎ to give the title compound (307.3 mg, quantitative yield). MS (ES) m / e 450.2 (M + H) &lt; ⁺ &gt;; ^{1 H NMR (250 MHz, CDCl} 3) δ 7.23-7.03 (m, 7H), 6.41 (brs, 1H), 5.33 (d, J = 16.3 Hz, 1H), 3.69 (s, 3H), 3.46 (s, 3H), 3.10 (s, 3H).
e) (S) -2,3,4,5-Tetrahydro-7 - [[[(4-methylbenzimidazol-2- yl) methyl] methylamino] carbonyl] -4- -1H-l, 4-benzodiazepin-2-acetic acid
(S) -2,3,4,5-tetrahydro-7 - [[[(4-methylbenzimidazol-2-yl) methyl] methylamino] carbaldehyde according to the procedure of Example 45 (e) -3-oxo-1H-1,4-benzodiazepine-2-acetate (307.3 mg, 0.68 mmol) was saponified to obtain the title compound (243.9 mg, 82%). MS (ES) m / e 436.2 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₃ H ₂₅ N ₅ O ₄ · 2.75H ₂ O; Calculated: C, 56.96; H, 6.34; N, 14.44. Measured: C, 56.72; H, 6.27; N, 14.26.
Example 48
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5,7-dimethylbenzimidazol-2- yl) methyl] methylamino] carbonyl] -3-oxo-1H-1,4-benzodiazepin-2-acetic acid
a) 2-Amino-4,6-dimethyl-3-nitropyridine
2-Amino-4,6-dimethylpyridine (5.55 g, 45.43 mmol) was weighed into a 500 mL round bottomed flask. The flask was cooled to -78 &lt; 0 &gt; C. Concentrated H ₂ SO ₄ (25 mL, 450 mmol) was added followed by concentrated HNO ₃ (3.5 mL, 56.0 mmol). The mixture became a solid agglomerated mass. The cooling bath was removed and the reaction was allowed to warm to room temperature. After about 15 minutes, an exothermic reaction was evolved with a slight nitric oxide gas release, and the reactants became very dark red. The reaction was heated at 85-90 &lt; 0 &gt; C for 3 h, then cooled to room temperature, diluted with ice and neutralized with 6 N NaOH (160 mL). The aqueous solution was extracted with EtOAc (3 x) and the combined EtOAc layers were dried (MgSO ₄ ), filtered and evaporated in vacuo. The resulting yellowish orange solid was adsorbed onto the conducting carg gel and flash chromatographed on a dry silica gel column. Column 1: 1 by eluting with CHCl ₃ / Et ₂ O the title compound (1.0650 g, 14%) was obtained. MS (ES) m / e 168.0 (M + H) &lt; ⁺ & gt ^; .
b) 2,3-Diamino-4,6-dimethylpyridine
Following the procedure of Example 45 (a) but replacing 4-amino-3-nitrobenzotrifluoride with 2-amino-4,6-dimethyl-3-nitropyridine (1.0650 g, 6.37 mmol) , The title compound (836.1 mg, 95.7%) was prepared. This was used without characterization.
c) 4-aza-2- [N- (benzyloxycarbonyl) -N-methyl] aminomethyl-5,7-dimethylbenzimidazole
The procedure of Example 45 (b) was followed except that 3,4-diaminobenzotrifluoride was replaced with 2,3-diamino-4,6-dimethylpyridine (836.1 6.09 mmol) Photography _(3% MeOH / CHCl 3) to give the title compound (1.2273 g, 62%) was obtained. MS (ES) m / e 325.0 (M + H) &lt; ⁺ & gt ^; .
d) Preparation of 4-aza-2- (methylaminomethyl) -5,7-dimethylbenzimidazole
2- [N- (benzyloxycarbonyl) -N-methyl] aminomethyl-5-trifluoromethylbenzimidazole was prepared by reacting 2- [N- (benzyloxycarbonyl) Following the procedure of Example 45 (c), but substituting methyl 5,7-dimethylbenzimidazole (1.2273 g, 3.78 mmol), followed by Et ₂ O, the title compound was obtained as a white powder. This material was used without characterization.
e) methyl (S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5,7-dimethylbenzimidazol- 2- yl) methyl] methylamino] carbonyl] Methyl-3-oxo-lH-l, 4-benzodiazepine-2-acetate
Methyl (S) -7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (175.0 mg, 0.60 mmol) The flask was weighed. CH₃CN (10 mL), followed by HOBt · H₂O (115.9 mg, 0.86 mmol), EDC (124.9 mg, 0.65 mmol) and diisopropylethylamine (0.13 mL, 0.75 mmol). CH₃A suspension of 4-aza-2- (methylaminomethyl) -5,7-dimethylbenzimidazole (144.5 mg, 0.76 mmol) and diisopropylethylamine (0.13 mL, 0.75 mmol) in CN was added and the reaction was stirred at room temperature Lt; / RTI &gt; After 22 hours, the reaction was evaporated in vacuo and the residue was co-evaporated with toluene. Silica gel chromatography (3% MeOH / CHCl3₃ (1 L) followed by 5% MeOH / CHCl3₃) To obtain the title compound (76.9 mg, 28%). MS (ES) m / e 465.2 (M + H) &lt;⁺.
f) (S) -2,3,4,5-Tetrahydro-7 - [[[(4-aza-5,7-dimethylbenzimidazol-2- yl) methyl] methylamino] carbonyl] -4- -Methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetic acid
Methyl] methylamino] carbonyl] -4- (4-methylpiperazin-1-yl) methyl-3-oxo -1H-1,4- benzodiazepine-2-acetate (76.9 mg, 0.17 mmol) was dissolved in MeOH (5 ㎖) and H ₂ O (5 ㎖) and, 1.0 N NaOH (0.5 ㎖, 0.5 Mmol). After 24 hours at room temperature, the reaction was neutralized with 1.0 N HCl (0.5 mL) and the solvent was evaporated in vacuo. ODS chromatography (gradient: 5% CH ₃ CN / H ₂ O (500 mL) containing 0.1% TFA followed by 15% CH ₃ CN / H ₂ O (500 mL) with 0.1% TFA followed by 0.1% obtained a 30% CH residue with _{3 CN / H 2 O (500} ㎖)) containing TFA, evaporated once with toluene, it was dried in a high vacuum. The resulting residue was dissolved in MeOH (5 ㎖) was precipitated with Et ₂ O. The white solid was collected on a sintered glass funnel and dried in a vacuum desiccator overnight to give the title compound (52.0 mg, 68%). HPLC (ODS column, 15 mL / min, 5-50% CH ₃ CN / H ₂ O containing gradient 0.1% TFA) t _R 12.38 min, MS (ES) m / e 451.2 (M + H) <^+> . Analysis for C ₂₃ H ₂₆ N ₆ O ₄ .1H ₂ O .1CF ₃ CO ₂ H; Calculated: C, 51.55; H, 5.02; N, 14.43. Measured: C, 51.34; H, 5.00; N, 14.41.
Example 49
(S) -2,3,4,5-tetrahydro-7 - [[[(5,6-difluorobenzimidazol-2-yl) methyl] methylamino] carbonyl] -Oxo-lH-l, 4-benzodiazepin-2-acetic acid
a) 1,2-Diamino-4,5-difluorobenzene
Following the procedure of Example 45 (a), except substituting 4,5-difluoro-2-nitroaniline (2.0 g, 11.49 mmol) for 4-amino-3-nitrobenzotrifluoride, . This was used without characterization.
b) Preparation of 2- [N- (benzyloxycarbonyl) -N-methyl] aminomethyl-5,6-difluorobenzimidazole
Except that 1,2-diamino-3-methylbenzene was replaced with 1,2-diamino-4,5-difluorobenzene and the AcOH cyclization step was carried out at 80 ° C instead of 110 ° C. b), the title compound (1.3767 g, 36%) was prepared. TLC R _f (1: 1 CH ₂ Cl ₂ / Et ₂ O) 0.42; MS (ES) m / e 332.0 (M + H) &lt; ⁺ &gt;; ¹ H NMR (250 MHz, CDCl ₃ ) 7.50-7.14 (m, 8H), 5.13 (s, 2H), 4.61 (s, 2H), 3.06 (s, 3H).
c) 5,6-Difluoro-2- (methylaminomethyl) benzimidazole
(Benzyloxycarbonyl) -N-methyl] aminomethyl-4,7-dimethoxybenzimidazole was reacted with 2- [N- (benzyloxycarbonyl) The title compound (875.6 mg, quantitative yield) was prepared following the procedure of Example 46 (b), except substituting 6-difluorobenzimidazole (1.3767 g, 4.16 mmol). MS (ES) m / e 198.0 (M + H) ⁺ .
d) Methyl- (S) -2,3,4,5-tetrahydro-7 - [[[(5,6-difluorobenzimidazol-2- yl) methyl] methylamino] carbonyl] -4 -Methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetate
Methyl (S) -7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-lH-l, 4- benzodiazepine-2- acetate (415.7 mg, 1.42 mmol)₃CN, HOBt · H₂O (209.3 mg, 1.55 mmol) and EDC (314.9 mg, 1.64 mmol). After 5 minutes, diisopropylethylamine (0.25 mL, 1.64 mmol) was added to give a clear colorless solution. CH₃A solution of 5,6-difluoro-2- (methylaminomethyl) benzimidazole (284.5 mg, 1.44 mmol) in CN was added. After 30 minutes, the reaction became slightly cloudy and further diisopropylethylamine (0.25 mL) was added to make the reaction clear colorless again. After 24 h, the reaction was evaporated in vacuo. The residue was evaporated once with toluene and then purified by silica gel chromatography (CHCl3₃(0.25 L) followed by 2% MeOH / CHCl3₃ (1.5 L) followed by 5% MeOH / CHCl3₃) To obtain the title compound (456.8 mg, 68%). MS (ES) m / e 472.2 (M + H) &lt;⁺;^One&Lt; 1 &gt; H NMR (250 MHz, CDCl3₃3H), 3.14 (s, 3H), 2.96 (s, 3H), 3.70 (s, 3H) .
e) Synthesis of (S) -2,3,4,5-tetrahydro-7 - [[[(5,6- difluorobenzimidazol-2- yl) methyl] methylamino] carbonyl] -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid
Methyl] methylamino] carbonyl] -4-methyl-thiophene-2-carboxylic acid methyl ester was prepared by reacting methyl (S) -2,3,4,5-tetrahydro- a 3-oxo -1H-1,4- benzodiazepine-2-acetate (456.8 mg, 0.97 mmol) was dissolved in MeOH (10 ㎖) and H ₂ O (10 ㎖). 1.0 N NaOH (3.0 mL, 3.0 mmol) was added and the reaction was stirred at room temperature. After 18 h, the reaction was neutralized with 1.0 N HCl (3.0 mL). The precipitate formed was collected on a sintered glass filter and dried in a vacuum desiccator. ODS chromatography (gradient: 10% CH ₃ CN / H ₂ O (500 mL) containing 0.1% TFA followed by 18% CH ₃ CN / H ₂ O (500 mL) with 0.1% TFA followed by 0.1% 25% CH ₃ CN / H ₂ O (500 mL) containing TFA) gave a residue that was evaporated once with toluene. The resulting residue was dissolved in small amount of MeOH, and precipitated with Et ₂ O to give the title compound (330.9 mg) as white powder. HPLC (ODS column, 15 ㎖ / minute, 5-50% gradient containing _{0.1% TFA CH 3 CN / H} 2 O) t R = 14.12 min; MS (ES) m / e 458.2 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₂ H ₂₁ N ₅ O ₄ F ₂ .2.5H ₂ O; Calculated: C, 52.57; H, 5.22; N, 13.94. Measured: C, 52.76; H, 5.15; N, 13.67.
Example 50
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] amino] carbonyl] Oxo-lH-l, 4-benzodiazepin-2-acetic acid
a) methyl (S) -2,3,4,5-tetrahydro-7 - [[[4-aza-5-methylbenzimidazol-2- yl) methyl] amino] carbonyl] 3-oxo-lH-l, 4-benzodiazepin-2-acetate
Methyl (S) -7-carboxy-4-methyl-3-oxo-tetrahydro-1H-1,4-benzodiazepine-2- acetate (228.8 mg, 0.78 mmol)₃CN, and HOBt · H₂O (154.2 mg, 1.14 mmol), EDC (179.4 mg, 0.94 mmol) and diisopropylethylamine (0.50 mL, 0.94 mmol) were successively added. CH₃A solution of 2- (aminomethyl) -4-aza-5-methylbenzimidazole dihydrochloride (125.4 mg, 0.77 mmol) in CN / DMF was added and the reaction stirred at room temperature. After 24 h, the reaction was evaporated in vacuo and the residue was evaporated once with toluene. Silica gel chromatography (CHCl3₃(0.25 L) followed by 3% MeOH / CHCl3₃ (0.5 L) followed by 5% MeOH / CHCl3₃) To obtain the title compound (159.9 mg, 48%). MS (ES) m / e 437.2 (M + H) &lt;⁺.
b) Methyl (S) -2,3,4,5-tetrahydro-7 - [[[4-aza-5-methylbenzimidazol- Oxo-lH-l, 4-benzodiazepin-2-acetic acid
(S) -2,3,4,5-tetrahydro-7 - [[[[4-aza-5-methylbenzimidazol-2- yl) methyl] amino ] Carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (159.9 mg, 0.37 mmol) was saponified and purified to give the title compound. MS (ES) m / e 423.39 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₁ H ₂₂ N ₆ O ₄ .0.5H ₂ O .1.25 TFA; Calculated: C, 52.64; H, 5.02 N, 16.74. Measured: C, 52.65; H, 5.02; N, 16.74.
Example 51
(S) -2,3,4,5-tetrahydro-4-methyl-7- [[[(4-nitrobenzimidazol-2-yl) methyl] methylamino] carbonyl] -1,4-benzodiazepin-2-acetic acid
a) 2- [N- (t-Butoxycarbonyl) -N-methyl] aminomethyl-4-nitrobenzimidazole
Boc-sarcosine (2.0320 g, 10.74 mmol) was dissolved in anhydrous THF and cooled to-15 C in a dry ice / acetone bath. Triethylamine (5.0 mL, 3.6375 mmol) was added followed by isobutyl chloroformate (1.5 mL, 11.56 mmol). After 0.5 h, the mixture was added to a solution of 1,2-diamino-3-nitrobenzene (1.3047 g, 10.77 mmol) in anhydrous THF at -20 <0> C and the reaction was allowed to warm to room temperature. 24 hours, and vacuum evaporating the reaction, and the residue partitioned between EtOAc and 1.0 N NaHCO _3. The layers were separated and the aqueous layer was extracted with EtOAc. Dry the combined organic layers were (MgSO _4), filtered and evaporated under vacuum. The residue was dissolved in ice-cold AcOH (100 mL) and the solution was heated at 75 &lt; 0 &gt; C. After 24 h, the reaction was evaporated in vacuo and the residue was evaporated with toluene (2 x). By adsorbing the material on silica gel was dried by silica gel flash chromatography (gradient: CHCl ₃ (0.5 ℓ), followed by _{2% MeOH / CHCl 3 (1} ℓ), followed by 5% MeOH / CHCl _3), the title compound (2.2089 g , 75%). ¹ H NMR (250 MHz, CDCl ₃ ) 8.10 (dd, 2H), 7.40-7.32 (m, IH), 4.69 (s, 2H), 3.02 (s, 3H), 1.54 (s, 9H).
b) 2- (Methylaminomethyl) -4-nitrobenzimidazole
N- (t-butoxycarbonyl) -N-methyl] aminomethyl-4-nitrobenzimidazole (2.2089 g, 8.05 mmol) was treated with 4 N HCl in dioxane at room temperature. Upon addition, a white solid precipitated immediately. After 4 h, the reaction was evaporated in vacuo and the residue was triturated with diethyl ether to give the title compound (1.639 g) as a white solid. This was used without characterization.
c) Methyl (S) -2,3,4,5-tetrahydro-7 - [[[(4-nitrobenzimidazol-2- yl) methyl] methylamino] carbonyl] Oxo-lH-l, 4-benzodiazepin-2-acetate
Following the procedure of Example 49 (d), but replacing 5,6-difluoro-2- (methylaminomethyl) benzimidazole with 2- (methylaminomethyl) -4-nitrobenzimidazole The title compound (292.9 mg, quantitative yield) was prepared. MS (ES) m / e 481.2 (M + H) &lt; ⁺ & gt ^; .
methyl) methylamino] carbonyl] -4-methyl-3- (4-nitrobenzimidazol- Oxo-lH-l, 4-benzodiazepin-2-acetic acid
(S) -2,3,4,5-tetrahydro-7- [[[4-nitrobenzimidazol-2-yl) methyl] methylamino] carbonyl ] -4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (292.9 mg, 0.61 mmol) was saponified to obtain the title compound (211.0 mg, 68%). MS (ES) m / e 467.4 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₂ H ₂₂ N ₆ O ₆ .2.5H ₂ O; Calculated: C, 52.12; H, 5.27; N, 16.58. Measured: C, 52.07; H, 4.97; N, 16.40.
Example 52
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aminobenzimidazol-2-yl) methyl] methylamino] carbonyl] -4-methyl- -1,4-benzodiazepin-2-acetic acid
a) (S) -2,3,4,5-tetrahydro-7 - [[[(4-aminobenzimidazol-2- yl) methyl] methylamino] carbonyl] -1H-l, 4-benzodiazepin-2-acetic acid
(S) -2,3,4,5-tetrahydro-7 - [[[(4-nitrobenzimidazol-2-yl) methyl] methylamino] carbonyl] -1,4-benzedazepine-2-acetic acid (108.7 mg, 0.21 mmol) was dissolved in MeOH and a catalytic amount of 10% Pd / C was added. Purge the reaction with H ₂ and stirred at room temperature under H ₂ (balloon). After 20 hours, the catalyst was removed by filtration through Celite (R) and the filtrate was evaporated in vacuo. The resulting solid was dissolved in MeOH, re-precipitated with Et ₂ O, dried in a vacuum desiccator and purified by ODS chromatography (gradient 500 mL of H ₂ O containing 0.1% TFA, then 0.1% TFA 5% CH ₃ CN / H ₂ O (500 mL) followed by 10% CH ₃ CN / H ₂ O (500 mL) containing 0.1% TFA followed by 15% CH ₃ CN / H ₂ O (500 ㎖), then 20% containing _{0.1% TFA CH 3 CN / H} 2 O (500 ㎖), then 25% containing _{0.1% TFA CH 3 CN / H} 2 O (500 ㎖), and then subsequently containing 0.1% TFA was purified by _{30% CH 3 CN / H 2} O (500 ㎖)). The resulting material was evaporated once with toluene and then triturated with diethyl ether to give the title compound (34.7 mg). MS (ES) m / e 437.5 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₂ H ₂₄ N ₆ O ₄ · 1.5H ₂ O · 1.5TFA; Calculated: C, 47.32; H, 4.53; N, 13.24. Measured: C, 47.35; H, 4.86; N, 13.61.
Example 53
Ethyl] methylamino] carbonyl] -4-methyl-3-oxo-1 H-1, 2-benzothiazol- Preparation of 4-benzodiazepine- (2S) -acetic acid
a) Preparation of 2- [1 (R) - [N- (benzyloxycarbonyl) -N-methyl] aminoethyl] benzimidazole
Substituting 1,2-diamino-3-methylbenzene with 1,2-phenylenediamine and replacing the AcOH cyclization step with Cbz-N-methyl-D-alanine at 80 ° C , The title compound was prepared following the procedure of Example 47 (b). MS (ES) m / e 310.2 (M + H) &lt; ⁺ & gt ^; .
b) 2- [1 (R) - (Methylaminoethyl)] benzimidazole
(R) - [N- (benzyloxycarbonyl) -N-methyl] aminomethyl-4,7-dimethoxybenzimidazole was reacted with 2- [ ] Aminoethyl] benzimidazole, the title compound (276.0 mg, 48%) was prepared following the procedure of Example 46 (b). MS (ES) m / e 176.2 (M + H) &lt; ⁺ & gt ^; .
c) methyl 2,3,4,5-tetrahydro-7 - [[[(1R) - (benzimidazol-2- yl) ethyl] methylamino] carbonyl] -4-methyl- -1,4-benzodiazepine-2-acetate
(D), except substituting 2- [1 (R) - (methylaminoethyl) benzimidazole for 5,6-difluoro-2- , The title compound (203.5 mg, 90%) was prepared. MS (ES) m / e 450.5 (M + H) &lt; ⁺ & gt ^; .
ethyl] methylamino] carbonyl] -4-methyl-3-oxo-1H-1-indolecarboxamide [ 1,4-benzodiazepin-2-acetic acid
Ethyl] methylamino] carbonyl] piperidine was prepared according to the procedure of Example 49 (e), using methyl 2,3,4,5-tetrahydro-7 - [[[((1R) - (benzimidazol- (ES) m / e 436.5 &lt; RTI ID = 0.0 &gt; (ES) &lt; / RTI & _{^{. M + H) + C 23}} H 25 N 5 O 4 · 0.75H 2 O · analysis for 0.75TFA; calcd: C, 55.01; H, 5.14 ; N, 13.10 measured values:. C, 54.98; H, 5.42; N, 12.75.
Example 54
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] amino] carbonyl] -Oxo-lH-l, 4-benzodiazepine-2-acetate
a) Preparation of ethyl (S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol- -3-oxo-lH-l, 4-benzodiazepin-2-acetate
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] amino] carbonyl] Oxo-lH-l, 4-benzodiazepin-2-acetic acid (0.5 g) was dissolved in EtOH and the solution was cooled to 0 [deg.] C in an ice bath. Gas HCl was bubbled through the solution until the solution was saturated, then the flask was sealed with a rubber septum and the cooling bath was removed. The reaction was stirred at room temperature for 20 hours and then the solvent was evaporated in vacuo. The residue was evaporated with toluene (3 x) and three times, then dissolved in EtOH and was precipitated with Et ₂ O. The solid was collected on a sintered glass funnel and dried in a vacuum desiccator overnight to give the title compound (483.9 mg). MS (ES) m / e 451.4 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₃ H ₂₆ N ₆ O ₄ .HCl. 1.375H ₂ O; Calculated: C, 53.98; H, 5.86; N, 16.42. Measured: C, 54.00; H, 5.82; N, 16.42.
Example 55
Ethyl] methylamino] carbonyl] -4-methyl-3-oxo-1 H-1, 2-benzothiazol- Preparation of 4-benzodiazepine- (2S) -acetic acid
a) 2- [1 (S) -N- (t-Butoxycarbonyl) -N-methyl] aminoethyl] benzimidazole
The procedure of Example 51 (a) was repeated except that Boc-N-methyl-L-alanine was substituted for Boc-N-methyl-L-alanine and 1,2- , Followed by recrystallization from CHCl ₃ / hexane to give the title compound (1.7792 g, 65%). MS (ES) m / e 276.4 (M + H) &lt; ⁺ & gt ^; .
b) 2- [1 (S) - (Methylaminoethyl)] benzimidazole
N- (t-butoxycarbonyl) -N-methyl] aminomethyl-4-nitrobenzimidazole was reacted with 2- [1 (S) - [N- (t- Methyl] aminoethyl] benzimidazole following the procedure in Example 51 (b), the title compound was prepared. This was used without characterization.
c) Preparation of methyl (S) -2,3,4,5-tetrahydro-7 - [[[(1S) - (benzimidazol-2- yl) ethyl] methylamino] carbonyl] -Oxo-lH-l, 4-benzodiazepin-2-acetate
(D), except substituting 2- [1 (S) - (methylaminoethyl) benzimidazole for 5,6-difluoro-2- , The title compound (414.7 mg, 88%) was prepared. MS (ES) m / e 450.2 (M + H) &lt; ⁺ & gt ^; .
ethyl] methylamino] carbonyl] -4-methyl-3-oxo-1H-1-indolecarboxamide [ 1,4-benzodiazepin-2-acetic acid
(S) -2,3,4,5-tetrahydro-7 - [[[((1S) - (benzimidazol-2- yl) ethyl] methylamino (4-fluorophenyl) carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate was saponified to obtain 117.2 mg of the title compound. MS (ES) m / e 436.2 (M ⁺ Analysis for C ₂₃ H ₂₅ N ₅ O ₄ 0.75 H ₂ O 0.75 TFA; Calculated: C, 55.05; H, 5.14; N, 13.10. Measured: C, 55.14; H, 5.38; N, 13.04.
Example 56
Ethyl] amino] carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine -Benzodiazepine- (2S) -acetic acid &lt; / RTI &gt;
a) 2- [1 (S) - (t-Butoxycarbonyl) aminoethyl] benzimidazole
Following the procedure of Example 51 (a) but substituting Boc-L-alanine for Boc-L-alanine and replacing 1,2-diamino-3-nitrobenzene with 1,2- Compound (714.7 mg, 25%) was prepared. MS (ES) m / e 262.4 (M + H) &lt; ⁺ & gt ^; .
b) 2- [1 (S) - (aminoethyl)] benzimidazole
(2-amino-2-methyl-2-oxo-2-methyl-N- Following the procedure for example 51 (b), but substituting the sol for the title compound. This was used without characterization.
c) Preparation of methyl 2,3,4,5-tetrahydro-7- [[[(1S) - (benzimidazol-2- yl) ethyl] amino] carbonyl] 1,4-benzodiazepine-2-acetate
The procedure of Example 49 (d), except substituting 2- [1 (S) - (aminoethyl)] benzimidazole for 5,6-difluoro-2- (methylaminomethyl) , The title compound (270.7 mg, 80%) was prepared. MS (ES) m / e 436.0 (M + H) &lt; ⁺ & gt ^; .
d) Preparation of 2,3,4,5-tetrahydro-7 - [[[(1S) - (benzimidazol-2-yl) ethyl] amino] carbonyl] -4-methyl- , 4-benzodiazepin-2-acetic acid
(Methyl) 2,3,4,5-tetrahydro-7 - [[[((1S) - (benzimidazol-2- yl) ethyl] amino] carbonyl] - 4-methyl-3-oxo -1H-1,4- benzodiazepine-2-acetate was saponified to give the title compound (158.1 mg, 61%). MS (ES) m / e 422.0 (m + H) +. C Analysis for ₂₂ H ₂₃ N ₅ O ₄ .1.75 H ₂ O; Calculated: C, 58.37; H, 5.90; N, 15.46. Measured: C, 58.17; H, 5.77;
Example 57
Ethyl] amino] carbonyl] -4-methyl-3-oxo-1H-1,4-benzoimidazo [ -Benzodiazepine- (2S) -acetic acid &lt; / RTI &gt;
a) 2- [1 (R) - (Benzyloxycarbonyl) aminoethyl] benzimidazole
Except that Cbz-D-alanine was substituted for Cbz-D-alanine, 1,2-diamino-3-methylbenzene was replaced by 1,2-phenylenediamine and AcOH cyclization was performed at 80 ° C instead of 110 ° C , The title compound (1.1455 g, 43%) was prepared following the procedure of Example 47 (b). MS (ES) m / e 296.4 (M + H) &lt; ⁺ & gt ^; .
b) 2- [1 (R) - (aminoethyl)] benzimidazole
(Benzyloxycarbonyl) -N-methyl] aminomethyl-4,7-dimethoxybenzimidazole was reacted with 2- [1 (R) - (benzyloxycarbonyl) aminoethyl] benzimidazole The title compound (258.1 mg, 93%) was prepared following the procedure of Example 46 (b), except substituting. MS (ES) m / e 161.9 (M + H) &lt; ⁺ & gt ^; .
c) Preparation of methyl 2,3,4,5-tetrahydro-7 - [[[(1R) - (benzimidazol-2- yl) ethyl] amino] carbonyl] -4- Benzodiazepine- (2S) -acetate &lt; / RTI &gt;
Following the procedure of Example 49 (d), but replacing 5,6-difluoro-2- (methylaminomethyl) benzimidazole with 2- (1 (R) -aminoethyl) benzimidazole The title compound (263.6 mg, 84%) was prepared. MS (ES) m / e 436.3 (M + H) &lt; ⁺ & gt ^; .
d) Preparation of 2,3,4,5-tetrahydro-7 - [[[(1 R) - (benzimidazol-2-yl) ethyl] amino] carbonyl] -4-methyl- , 4-benzodiazepin-2-acetic acid
Ethyl] amino] carbonyl] - (1 H) -quinolinone Following the procedure of Example 49 (e), methyl 2,3,4,5-tetrahydro-7- (ES) m / e 422.0 (M + H) &lt; ⁺ & gt ^{;. [} _{. C 22 H 23 N 5 O} 4 · 0.5H 2 O · 1.25HCl analysis on; calcd: C, 55.51; H, 5.35 ; N, 14.71 measured values:. C, 55.70; H, 5.47; N, 14.53.
Example 58
(S) -2,3,4,5-tetrahydro-7- Oxo-lH-l, 4-benzodiazepin-2-acetic acid
a) 2-Carboethoxyimidazo [1,2a] pyridine
2-Aminopyridine (4 g, 42.50 mmol) was dissolved in MeOH (50 mL). Ethyl bromopyruvate (8.3 g, 42.50 mmol) was added and the reaction was stirred at 70 &lt; 0 &gt; C for 2 hours. The solvent was then removed and the solution was neutralized with 1 M NaOH. The reaction was extracted with EtOAc and the combined EtOAc layers were washed with brine. Dried (MgSO ₄ ), filtered and concentrated to give the title compound (4.5 g, 56%) as a pale yellow solid, which was purified by silica gel chromatography (2% MeOH / CH ₂ Cl ₂ ). ^{1 H NMR (400 MHz, CDCl} 3) δ 1.43 (t, J = 7 Hz, 3H), 4.45 (q, J = 7 Hz, 2H), 6.86 (t, J = 6.6 Hz, 1H), 7.24 (t , &Lt; / RTI &gt; J = 6.6 Hz, 1H).
b) Preparation of 2-hydroxymethylimidazo [1,2a] pyridine
2-Carbethoxyimidazo [1,2a] pyridine (0.5 g, 2.81 mmol) was dissolved in anhydrous THF at O &lt; 0 &gt; C and then a solution of lithium aluminum hydride (0.5 mL, 1.0 M in THF) was added. The reaction was allowed to warm to room temperature and stirred for 1 hour. H ₂ O (0.2 mL) followed by 15% NaOH (0.2 mL) and finally H ₂ O (0.6 mL). The solid was removed by filtration and washed with hot THF (2 x 100 ㎖) and CHCl ₃ (4 x 100 ㎖) of the high temperature. The filtrate and the washed solution were combined and dried (MgSO ₄ ). The filtrate was then filtered to remove the solvent under reduced pressure and the residue was purified by silica gel flash column chromatography (5% MeOH / CH ₂ Cl ₂ ) to give the title compound (0.1 g, 25%) as a pale yellow liquid. ^{1 H NMR (400 MHz, CDCl} 3) δ 4.85 (s, 2H), 6.76 (t, J = 6.8 Hz, 1H), 7.15 (t, J = 6.8 Hz, 1H), 7.53 (s, 1H), 7.54 (d, J = 6.7 Hz, 1H), 8.1 (d, J = 6.7 Hz, 1H). MS (ES) m / e 149 (M + H) &lt; ⁺ & gt ^; .
c) 2-Chloromethylimidazo [1,2a] pyridine
Thionyl chloride (0.4 mL, 3.2 mmol) was added to a solution of 2-hydroxymethylimidazo [1,2a] pyridine (0.4 g, 2.7 mmol) in CHCl ₃ (30 mL) at 0 ° C. After stirring for 1 hour at room temperature, the suspension was poured into a mixture of ice, 10% NaHCO ₃ and CHCl _3. Separate the layers and extract the award with CHCl _3. The organic extracts were combined, dried (MgSO _4). It was then filtered and the solvent removed under reduced pressure to give the title compound (0.4 g, 89%). ^{1 H NMR (400 MHz, CDCl} 3) δ 4.7 (s, 2H), 6.7 (t, 1H), 7.2 (t, 1H), 7.5 (d, 1H), 7.6 (s, 1H), 8.0 (d, 1H). MS (ES) m / e 167 (M + H) &lt; ⁺ & gt ^; .
d) 2- (Methylaminomethyl) imidazo [1,2a] pyridine
Freshly condensed methylamine (15 mL) was added to a solution of 2-chloromethylimidazo [1,2a] pyridine (317 mg, 2 mmol) in EtOH (5 mL) at 0 C and the reaction mixture was stirred at 0 [ Lt; / RTI &gt; for 2 h. The solvent was then removed and the residue was purified by reverse phase column chromatography (C-18 silica gel, H ₂ O with 1% TFA). And lyophilized to give the title compound (461 mg, 87%) as a white solid. ^{1 H NMR (250 MHz, CDCl} 3) δ 2.5 (s, 3H), 4.0 (s, 2H), 6.7 (t, 1H), 7.2 (t, 1H), 7.5 (d, 1H), 7.6 (s, 1H), &lt; / RTI &gt; 8.1 (d, 1H). MS (ES) m / e 162 (M + H) &lt; ⁺ & gt ^; .
e) methyl (S) -2,3,4,5-tetrahydro-7 - [[[(imidazo (1,2a) pyrid-2- yl) methyl] methylamino] carbonyl] -3-oxo-lH-l, 4-benzodiazepin-2-acetate
Methyl (S) -7- carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro -1H-1,4- benzodiazepine-2-acetate (828.2 mg, 2.83 mmol) CH ₃ CN while taking, it was added _{HOBt · H 2 O (398.1 mg} , 2.92 mmol), EDC (562.9 mg, 2.94 mmol) and diisopropylethylamine (1 ㎖, 5.74 mmol) in succession. When the solids dissolved, 2- (methylaminomethyl) imidazo [1,2a] pyridine (460.7 mg, 2.86 mmol) and diisopropylethylamine (1.5 mL, 8.61 mmol) in CH ₃ CN was added and the reaction Stir at room temperature. After 24 h, the reaction was concentrated and the residue was evaporated with toluene (2 x). The resulting residue is chromatographed on silica gel (5% MeOH / CHCl ₃₎ to give the title compound (694.6 mg, 56%). MS (ES) m / e 436.4 (M + H) &lt; ⁺ & gt ^; .
f) (S) -2,3,4,5-Tetrahydro-7 - [[[(imidazo (1,2a) pyrid-2- yl) methyl] methylamino] carbonyl] Oxo-lH-l, 4-benzodiazepin-2-acetic acid
Methyl] methylamino] carbonyl] -4-methyl-3 (1 H) -quinolinone (663.4 mg, 1.52 mmol) was dissolved in MeOH (10 mL). H ₂ O (10 mL) was added followed by 1.0 N NaOH (5 mL, 5.0 mmol) and the reaction was stirred at room temperature. After 20 h, the reaction was neutralized with 1.0 N HCl (5 mL) and the solution was evaporated in vacuo. The residue was purified by ODS chromatography (gradient: H ₂ O (500 mL) containing 0.1% TFA, then 10% CH ₃ CN / H ₂ O (500 mL) containing 0.1% TFA followed by 0.1% TFA _{15% CH 3 CN / H 2} O (500 ㎖), followed by re-chromatography on a _{20% CH 3 CN / H 2} O, followed by ODS (500 ㎖)) containing 0.1% TFA (gradient: 0.1% TFA Was added H ₂ O (250 mL) containing 10% CH ₃ CN / H ₂ O (1.5 L) containing 0.1% TFA followed by 20% CH ₃ CN / H ₂ O (1 L) l))). Fractions containing the pure material were combined and concentrated. Evaporating the residue with toluene and then dissolved in MeOH and was re-precipitated with Et ₂ O to give the title compound (96.4 mg). MS (ES) m / e 421.9 (M + H) &lt; ⁺ & gt ^; . Analysis for C ₂₂ H ₂₃ N ₅ O ₄ · 0.25H ₂ O · TFA; Calculated: C, 53.38; H, 4.57; N, 12.97. Measured: C, 53.68; H, 4.97; N, 12.94.
Example 59
Methyl] methylamino] carbonyl] -2,3,4,5-tetrahydro-4-methyl-3 (1H) -imidazo [ -Oxo-lH-l, 4-benzodiazepin-2-acetic acid
a) N- (Carbobenzyloxy) -N- (methyl) acetonitrile
Cbz chloride (7.40 mL, 49.3 mmol) was slowly added to a solution of N-methylamino acetonitrile hydrochloride (5.0 g, 46.92 mmol) and triethylamine (13.4 mL, 96.2 mmol) in dichloromethane (200 mL) Respectively. The reaction was stirred at room temperature for 18 hours, and the mixture was washed with 1N HCl, water and brine. The organic layer was dried (MgSO _4), and concentrated to give the title compound (6.97 g, 73%) as a clear oil.
b) Preparation of N- (carbobenzyloxy) -N- (methyl) aminothioacetamide
Hydrogen sulfide was bubbled through a solution of N- (carbobenzyloxy) -N- (methyl) acetonitrile (15 g, 73.5 mmol) and triethylamine (30.75 mL, 220.6 mmol) in DMF (250 mL). After 20 minutes, the flask was sealed and the reaction was stirred at room temperature for 18 hours. Then, the reaction was poured on _{2 N NaHCO 3 (1 ℓ)} , and extracted with dichloromethane. The combined organic phases were washed with 1: 1 water / brine (5 x), dried (MgSO ₄ ), concentrated and purified by silica gel flash chromatography (step gradient: 40-50% ethyl acetate / To give the title compound (12.26 g, 70%). MS (ES) m / e 239.0 (M + H) &lt; ⁺ & gt ^; .
c) N- (carbobenzyloxy) -N-methyl-S- (methyl) acetothioimidate
Iodomethane (17.66 mL, 283.6 mmol) was added to a solution of N- (carbobenzyloxy) -N- (methyl) aminothioacetamide (6.75 g, 28.36 mmol) in acetone (100 mL) at room temperature. The solution was stirred in the dark at room temperature for 3 hours and the resulting precipitate was filtered to give the title compound (9.63 g, 89%) as a white solid. MS (ES) m / e 253.4 (M + H) &lt; ⁺ & gt ^; .
d) (±) -2-amino-3,3-dimethoxybutane
Sodium borohydride was added to a solution of 3,3-dimethoxy-2-butanone (1.32 g, 10 mmol) and ammonium acetate (1.1 g, 100 mmol) in methanol (30 mL). The pH was adjusted to pH 6 with methanolic HCl and the reaction was stirred overnight at room temperature and concentrated. The residue was dissolved in water and adjusted to pH 5 with aqueous HCl. Basic to pH 10 for flower extract, and won the resulting solution with ether (3 x) with Na ₂ CO ₃ and extracted with ether. The organic layer was dried (MgSO _4), and concentrated to give the title compound (1.1 g, 83%) as a clear oil. MS (ES) m / e 134.2 (M + H) &lt; ⁺ & gt ^; .
e) N- (Carbobenzyloxy) -N-methyl- (4,5-dimethyl-1H-imidazol-
To a solution of (±) -2-amino-3,3-dimethoxybutane (1.05 g, 7.89 mmol) and N- (carbobenzyloxy) -N-methyl-S- (methyl) acetothioimine A solution of the tartrate (2.0 mg, 5.26 mmol) was heated at 60 &lt; 0 &gt; C for 2 h and concentrated to give a yellow oil. The crude oil was dissolved in 6 N HCl (30 mL) and stirred at room temperature for 1 hour. The solution was basified to pH 12 with aqueous NaOH and then extracted with dichloromethane. The combined organic phases were dried (MgSO ₄ ) and concentrated to a brown oil which was purified by silica gel flash chromatography (4% methanol / dichloromethane) to give the title compound (0.590 g, 41%) as a clear oil. MS (ES) m / e 274.0 (M + H) &lt; ⁺ & gt ^; .
f) N-Methyl- (4,5-dimethyl-1H-imidazol-2-yl)
To a solution of N- (carbobenzyloxy) -N-methyl- (4,5-dimethyl-1H-imidazole (prepared as described in example 1) in methanol (15 mL) and glacial acetic acid (5 mL) containing 10% Pd / 2-yl) methanamine (0.35 g, 1.28 mmol) in THF (10 mL) was shaken in a H ₂ atmosphere (45 Psi) for 6 h. The reaction was filtered and the filtrate was concentrated to give the title compound (0.22 g, 86%) as a brown oil which was used in the next step without further purification. MS (ES) m / e 140 (M + H) &lt; ⁺ & gt ^; .
methyl) amino] carbonyl] -2,3, 4, 5-tetrahydro-4- (2-methylpiperazin-1- Methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetate
(0.20 g, 1.1 mmol) and methyl (±) -7-carboxy-2,3,4,5-tetrahydro-naphthalen- A solution of 4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate (0.320 g, 1.1 mmol) was stirred at room temperature in the presence of DIEA (0.287 mL, 1.65 mmol). EDC (0.316 g, 1.65 mmol) was then added and DMAP (0.013 g, 0.11 mmol) was added. The mixture was stirred at room temperature for 18 hours and concentrated to an oil which was purified by silica gel flash chromatography (step gradient: 0.5-2% methanol / dichloromethane) to give the title compound (0.060 g, 9% &Lt; / RTI &gt; MS (ES) m / e 414.2 (M + H) &lt; ⁺ & gt ^; .
yl) methyl] methylamino] carbonyl] -2,3, 4, 5-tetrahydro-4-methyl (2- -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid
1 N sodium hydroxide (3 eq) was added to a solution of methyl (±) -7 - [[[(4,5-dimethyl-1H-imidazol-2- yl) methyl] methylamino] carbonyl] Was added to a solution of 5-tetrahydro-4-methyl-3-oxo-lH-l, 4-benzodiazepine-2-acetate (0.060 g, 0.145 mmol) and the mixture was stirred at room temperature for 5 hours and concentrated. The residue was dissolved in water and adjusted to pH 5 with 50% acetic acid. The solution was concentrated and purified by MPLC (ODS-AQ, 10% acetonitrile / water containing 0.1% TFA, UV detection at 220 nm) to give the title compound (0.050 g, 86%) as a white solid. MS (ES) m / e 400.2 (M + H) &lt; ⁺ & gt ^; .
Example 60
Preparation of 3 - [[3- [2- (benzimidazol-2-yl) ethyl] isoxazoline-5 (R,
a) 4- (Benzimidazol-2-yl) -1-butene
The title compound was prepared according to the general procedure of Preparation 4, P50256-1, but replacing the Boc-sarcosine with 4-pentenoic acid.
b) 4- (1-Toluenesulfonylbenzimidazol-2-yl) -1-butene
Sodium hydride was added to a solution of 4- (benzimidazol-2-yl) -1-butene (50 mmol) and 4-toluenesulfonyl chloride (55 mmol) in anhydrous THF (200 mL). The reaction was stirred until complete at room temperature, then quenched with saturated NH ₄ Cl (200 mL) and the mixture was extracted with EtOAc. The combined organic extracts were dried (MgSO ₄ ), concentrated and the residue was purified by silica gel chromatography to give the title compound.
c) 4- (1-Toluenesulfonylbenzimidazol-2-yl) -1-butanal
To a solution of 4- (1-toluenesulfonylbenzimidazol-2-yl) -1-butene (40 mmol) in CH ₂ Cl ₂ (160 mL) and MeOH (40 mL) at -78 ° C was added ozone Bubbling was continued until it was held, and excess of the ozone was removed by bubbling argon through the solution. Anhydrous dimethylsulfide (excess) was added and the reaction was allowed to warm to room temperature. The reaction was stirred at room temperature until complete, then concentrated and the residue was chromatographed on silica gel to give the title compound.
d) 4- (1-Toluenesulfonylbenzimidazol-2-yl) -1-butanal oxime
Hydroxylamine hydrochloride (33 mmol) was added to a solution of 4- (1-toluenesulfonylbenzimidazol-2-yl) -1-butanal (30 mmol) and anhydrous sodium acetate (66 mmol) in MeOH Gt; mmol) &lt; / RTI &gt; Is stirred until complete and then the reaction at 0 ℃, concentrated, and the residue was partitioned between H ₂ O and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed successively with 5% NaHCO ₃ and saturated brine, dried (MgSO ₄ ) and concentrated to give the title compound.
e) 4- (1-Toluenesulfonylbenzimidazol-2-yl) -1-butanoximinoyl chloride
Example 1 (b) of WO 95/14682 was repeated except that 4-cyanobenzoxime was replaced with 4- (1-toluenesulfonylbenzimidazol-2-yl) , The title compound was prepared.
f) t-butyl [3- [2- (1-toluenesulfonylbenzimidazol-2-yl) ethyl] isoxazoline- 5 (R,
4-cyanobenzoximinoyl chloride was substituted with (1-toluenesulfonylbenzimidazol-2-yl) -1-butanoximinoyl chloride, methyl 3-butenoate was replaced with t- The title compound was prepared according to the procedure of Example 1 (d) of International Patent Publication No. 95/14682, except that the compound was substituted with &lt; RTI ID = 0.0 &gt;
g) [3- (2- (1-Toluenesulfonylbenzimidazol-2-yl) ethyl] isoxazoline-5 (R,
Dioxane t- butyl [3- [2-4 (1-toluenesulfonyl-benzimidazole-2-yl) ethyl] movement speed of 4 M HCl in the _{0 ℃ CH 2 Cl 2 (40} ㎖) of (10 ㎖) (R, S) -yl acetate (5 mmol) in dichloromethane (5 mL). The reaction was stirred at room temperature until complete and then concentrated to give the title compound.
(R, S) -yl] acetyl] amino-3 (R, S) -tetrahydrobenzoimidazol-2- ) -Methylpropanoate
EDC (1.2 mmol) in anhydrous CH ₃ CN at room temperature to (5 ㎖) of [3- [2-ethyl] isoxazolyl sleepy-5 (1-toluenesulfonyl-benzimidazol -2-) (R, S) - Was added to a solution of acetic acid (1 mmol), ethyl 3 (R, S) -aminobutyrate (1.2 mmol), HOBt.H ₂ O (1.2 mmol) and diisopropylethylamine (4 mmol). The reaction was stirred at room temperature until complete, then concentrated and the residue was purified by silica gel chromatography to give the title compound.
Yl) acetyl] amino-3 (R, S) -methylpropanoic acid &lt; EMI ID =
1.0 N LiOH (2.5 mmol) was added to a solution of ethyl 3 - [[3- (2- (1-toluenesulfonylbenzimidazol-2-yl) ethyl] isoxazoline- (0.5 mmol) in dichloromethane (5 mL) at 0 C. The reaction was stirred at room temperature until complete and then neutralized with 1.0 N HCl. The solution was concentrated The residue was purified by reverse phase chromatography to give the title compound.
Example 61
2-yl) methyl] methylamino] carbonyl] -1-methyl-2,5-dioxo-1H-1,4-benzodiazepine A mixture of 3- {3,4-dihydro- } -4-propanoic acid
a) 2-Amino-4-iodobenzoic acid
4-iodo-2-nitrotoluene is oxidized according to the method of Sasson et al., J. Org. Chem. 1986, 51, 2880-2883 to give 4-iodo-2-nitrobenzoic acid, The nitro group was reduced using acetic acid to give the title compound.
b) 4-iodoisatoic anhydride
To a mechanically stirred ice cold solution of 2-amino-4-iodobenzoic acid (26.3 g, 0.1 mol), sodium carbonate (10.6 g, 0.1 mol) and water (250 mL) was added a solution of phosgene in toluene (80 mL, 1.93 M in solution) was added slowly. After 2 h, the precipitated product was separated by filtration and the solid washed successively with water (200 mL), ethanol / ether 1: 1 mixture (300 mL) and ether (200 mL). Drying in vacuo afforded the title compound.
c) N- (2-Amino-4-iodobenzoyl) - - alanine benzyl ester
(5.0 g, 0.0173 mol), beta -alanine benzyl ester tosylate (5.85 g, 0.0173 mol) and dimethylaminopyridine (0.5 g, 0.0041 mol) in pyridine (35 mL) Was heated at 80 &lt; 0 &gt; C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 mL) and washed successively with 10% copper sulfate (2 x 50 mL), saturated sodium bicarbonate (1 x 50 mL) and brine (1 x 50 mL). Dried (Na ₂ SO _4), filtered, concentrated, and purified by silica gel chromatography (1: 1 EtOAc / hexane) to give the title compound.
d) N- (4-Iodo-2-methylaminobenzoyl) - - alanine benzyl ester
(2.0 mmol), 2,6-lutidine (0.35 mL, 3.0 mmol) and methyl iodide (0.19 mmol) in DMF (15 mL) 0.0 &gt; mL, &lt; / RTI &gt; 3.0 mmol) was heated at 50 &lt; 0 &gt; C for 15 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (75 mL) and washed successively with 10% citric acid (1 x 50 mL), saturated sodium bicarbonate (1 x 50 mL) and brine (1 x 50 mL). Dried (Na ₂ SO _4), filtered, concentrated, and purified by silica gel chromatography (gradient: 35-65% EtOAc / hexane) to give the title compound.
e) benzyl 3- [3,4-dihydro-8-iodo-1-methyl-2,5-dioxo-lH-l, 4- benzodiazepine] -4-propanoate
(-30 (0.30 g, 0.69 mmol)) of N- (4-iodo-2-methylaminobenzoyl) - - alanine benzyl ester (0.305 g, 0.69 mmol) and triethylamine (0.144 g, 1.04 mmol) in methylene chloride To a mechanically stirred solution was added slowly to a solution of a-bromoacetyl bromide (0.09 mL, 1.04 mmol) in methylene chloride (2 mL) under argon. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with methylene chloride (40 mL), washed successively with 10% citric acid (1 x 50 mL) and saturated sodium bicarbonate (1 x 50 mL), dried (Na ₂ SO ₄ ) &Lt; / RTI &gt; The resulting residue was dissolved in DMF (3 mL) and added to a slurry of sodium hydride (25 mg, 1.04 mmol) in DMF (2 mL) cooled to 0 <0> C via addition funnel. After stirring for 2 h, the mixture was poured onto ice-cold solution of 10% citric acid (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined extracts were washed with saturated sodium bicarbonate (1 x 50 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. Silica gel chromatography (gradient 40-70% EtOAc / hexanes) gave the title compound.
f) Benzyl 3- [3,4-dihydro-8- [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -1-methyl-2,5-dioxo-1H- , 4-benzodiazepine] -4-propanoate
To a solution of benzyl 3- [3,4-dihydro-8-iodo-1-methyl-2,5-dioxo-lH-1,4-benzodiazepine] - (2 mmol), 2- (methylaminomethyl) benzimidazole dihydrochloride (3 mmol), DIEA (1.8 mL, 10 mmol) and (Ph ₃ P) ₂ PdCl ₂ (140 mg, 0.2 0.0 &gt; 110 C &lt; / RTI &gt; for 3 hours. The mixture was then concentrated and the residue was purified by silica gel flash chromatography to give the title compound.
g) Preparation of 3- [3,4-dihydro-8 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] Benzodiazepine] -4-propanoic acid
To a solution of benzyl 3- [3,4-dihydro-8- [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -1-methyl-2,5-dioxo -1H-1,4-benzodiazepine] -4-propanoate (2 mmol) and 10% Pd / C (0.02 g) was hydrogenated under H ₂ atmosphere (50 psi) for 6 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound.
Example 62
3- {4H-imidazo [1,2-a] [1,4] benzodiazepine-5- (6H) ] Methylamino] carbonyl]} - 4-propanoic acid
a) Ethyl N- (2-amino-4-iodobenzoyl) - - alanine
A mechanically stirred solution of 4-iodoisatoanhydride (0.0173 mol), beta -alanine ethyl ester hydrochloride (0.0173 mol) and dimethylaminopyridine (0.5 g, 0.0041 mol) in pyridine (35 ml) And heated for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 mL) and washed successively with 10% copper sulfate (2 x 50 mL), saturated sodium bicarbonate (1 x 50 mL) and brine (1 x 50 mL). Dried (Na ₂ SO _4), filtered, concentrated, and purified by silica gel chromatography (1: 1 EtOAc / hexane) to give the title compound.
b) Ethyl-3- [3,4-dihydro-8-iodo-2,5-dioxo-lH-1,4-benzodiazepine] -4-propanoate
(0.30 mmol) of ethyl N- (2-amino-4-iodobenzoyl) - - alanine (0.69 mmol) and triethylamine (0.144 g, 1.04 mmol) in methylene chloride Was added slowly to a solution of a-bromoacetyl bromide (0.09 mL, 1.04 mmol) in methylene chloride (2 mL) under argon. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was diluted with methylene chloride (40 mL), washed successively with 10% citric acid (1 x 50 mL) and saturated sodium bicarbonate (1 x 50 mL), dried (Na ₂ SO ₄ ) Lt; / RTI &gt; The resulting residue was dissolved in DMF (3 mL) and added to a slurry of sodium hydride (25 mg, 1.04 mmol) in DMF (2 mL) cooled to 0 <0> C via addition funnel. After stirring for 2 h, the mixture was poured onto ice-cold solution of 10% citric acid (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined extracts were washed with saturated sodium bicarbonate (1 x 50 mL), dried (Na ₂ SO ₄ ), filtered, concentrated and chromatographed on silica gel to give the title compound.
c) Ethyl-3- [3,4-dihydro-8-iodo-2-thione-5-oxo-lH-1,4-benzodiazepine] -4-propanoate
To a solution of ethyl-3- [3,4-dihydro-8-iodo-2,5-dioxo-1H-1,4-benzodiazepine] -4-propanoate (1.0 g, 2.49 mmol) was added a Lawesson reagent (1.0 g) and the reaction was heated at 50 &lt; 0 &gt; C for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Silica gel chromatography (gradient 40-60% EtOAc / hexanes) gave the title compound.
d) Ethyl 3- [4H-imidazo [1,2- a] [1,4] benzodiazepine-5 (6H) -l-methyl-6-oxo-9-iodo] -4-
CH ₂ Cl ₂ (10 ㎖) and water (10 ㎖) ethyl-3- [3,4-dihydro-8-iodo-2-thione-5-oxo -1H-1,4- benzodiazepine] -4 in 2N NaOH (1.2 mL) was added at room temperature to a vigorously stirred two-phase solution of tetrabutylammonium hydrogen sulphate (0.95 g, 2.27 mmol), methyl iodide (0.2 g) and a catalytic amount of tetrabutylammonium hydrogen sulfate . After 2 h, the layers were separated and the aqueous was washed with CH ₂ Cl ₂ (2 x 25 mL). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting residue was dissolved in toluene (10 mL) and treated with propargylamine (0.64 mL, 4-fold excess) and pyridine hydrochloride salt (0.23 g, 1 molar equivalent). The reaction was heated to reflux for 6 hours and then cooled to room temperature. Concentration and silica gel chromatography (EtOAc) gave the title compound.
e) Ethyl 3- [4H-imidazo [1,2-a] [1,4] benzodiazepine-5- (6H) ) Methyl] methylamino] carbonyl] -4-propanoate
To a solution of ethyl 3- [4H-imidazo [1,2-a] [1,4] benzodiazepine-5 (6H) -l-methyl-6-oxo-9 (2 mmol), 2- (methylaminomethyl) benzimidazole (3 mmol), DIEA (1.8 mL, 10 mmol) and (Ph ₃ P) ₂ PdCl ₂ (140 mg , 0.2 mmol) was heated to 110 &lt; 0 &gt; C under a CO balloon for 3 hours. The mixture was then concentrated and the residue was purified by silica gel flash chromatography to give the title compound.
f) 3- [4H-imidazo [1,2-a] [1,4] benzodiazepine-5 (6H) Methyl] methylamino] carbonyl] -4-propanoic acid
Methyl-6-oxo-9 - [[[(benzimidazol-2-yl) Methyl] methylamino] carbonyl] -4-propanoate (54 mmol), LiOH.H ₂ O (0.79 mmol), THF (5 ml) and water (2 ml) was stirred overnight at room temperature. The mixture was concentrated, the residue was dissolved in water and the resulting solution was neutralized with 3 N HCl. The precipitate was collected and dried in vacuo to give the title compound.
Example 63
Preparation of 4- [4- [2- (1H-benzimidazol-2-yl) ethyl] -1-piperazinyl] -1-piperidine acetic acid
a) Ethyl 4- [4 - [(t-butoxycarbonyl)] - 1-piperazinyl] -1-piperidine acetate
Piperazine carboxylate (Aldrich) and ethyl 4-oxo-1-piperidine acetate (Porter et al., European Patent Publication No. 0 542 363 A2 0.0 &gt; Na + &lt; / RTI &gt; 542 363 A2) by NaCNBH ₃ reduction amination.
b) Ethyl 4- (1-piperazinyl) -1-piperidine acetate
A solution of ethyl 4- [4 - [(t-butoxycarbonyl)] - 1-piperazinyl] -1-piperidine acetate and 4 M HCl / dioxane in CH ₂ Cl ₂ was stirred at room temperature for 18 h Lt; / RTI &gt; The reaction mixture was concentrated to give the title compound as the hydrochloride salt.
c) 2- [2-Chloroethyl)] benzimidazole
A solution of 2-benzimidazole ethanol and thionyl chloride in CH ₂ Cl ₂ was heated under reflux for 2 hours. The mixture was evaporated to give the title compound.
d) 4- [4- [2- (lH-Benzimidazol-2-yl) ethyl] -1- piperazinyl] -1-piperidine acetate
A solution of ethyl 4- (1-piperazinyl) -1-piperidine acetate, 2- [2-chloroethyl)] benzimidazole and DIEA in DMF was stirred at room temperature for 18 hours. The mixture was concentrated and purified by chromatography to give the title compound.
e) 4- [4- [2- (lH-benzimidazol-2-yl) ethyl] -1- piperazinyl] - 1- piperidine acetic acid
A solution of 4- [4- [2- (1H-benzimidazol-2-yl) ethyl] -1-piperazinyl] -1-piperidine acetate and 1.0 N NaOH in MeOH was stirred at room temperature. After 18 h, the mixture was neutralized with AcOH, desalted through an XAD-2 column and lyophilized to give the title compound.
Example 64
Preparation of 1-hydroxy-4- [4- [3- (1H-benzimidazol-2-yl) propyl] -1-piperazinyl] -cyclohexanoic Acid
a) Preparation of t-butyl 1-hydroxy-4- [4- [2- (1H-benzimidazol-2- yl) propyl] -1- piperazinyl] -cyclohexane acetate
(1-piperazinyl) -cyclohexane acetate (EP 0 537 980 A1), 2- (3-bromopropyl) benzimidazole (J. 1962, 27, 2165) and a solution of DIEA were stirred at room temperature for 18 hours. The mixture was concentrated and purified by chromatography to give the title compound.
b) Preparation of 1-hydroxy-4- [4- [2- (1H-benzimidazol-2- yl) propyl] -1-piperazinyl] -cyclohexane acetic acid
CH ₂ Cl ₂ in t- butyl-1-hydroxy -4- [4- [2- (1H- benzimidazol-2-yl) propyl] -1-piperazinyl] - cyclohexane-acetate, and 4 M HCl / The solution of hexane was stirred at room temperature. After 18 hours, the mixture was evaporated to give the title compound.
Example 65
Preparation of N- [3- [1 - [[2- (2-benzimidazolyl) ethyl] carbonyl] piperidinyl] carbonyl- beta -alanine
Following the procedure of Example 1 of WO 95/25091 (Beavers et al.) Except that N -Boc-D-lys (Cbz) -OH was replaced with (2-benzimidazolyl) , The title compound was obtained.
Example 66
Preparation of 2 - [(benzimidazol-2-yl) methyl] -5- [2- (carboxy-ethyl) amino] carbonyl] -2,3-dihydro-3-oxo-1H-isoindole
Except that Boc-4-piperidin-2-ethylamine was replaced with 2- (aminomethyl) benzimidazole (Aldrich), lH-isoindole-5-carboxamide, 2,3- The process of Example 1-12 of European Patent No. 0 540 334 Al (Hartman et al.) For the preparation of N- (2-carboxy-ethyl) -2- [2- (piperidinyl) ethyl] , The title compound was prepared.
Example 67
Preparation of [3 (R) - [2- (Benzimidazol-2-yl) ethyl] -2-oxopiperidinyl] acetyl-3
a) Methyl-4- (benzimidazol-2-yl) butanoate
Following the procedure for Example 36 (a), except substituting 2,3-diaminopyridine for 1,2-diaminobenzene, the title compound was prepared.
b) 4- (Benzimidazol-2-yl) butanoic acid
Following the procedure of Example 36 (b), methyl-4- (benzimidazol-2-yl) butanoate was saponified to give the title compound.
c) Preparation of [3 (R) - [2- (benzimidazol-2-yl) ethyl] -2-oxopiperidinyl] acetyl-
(Duggan et al., J. Med. Chem. 1995, 38, &lt; RTI ID = 0.0 &gt; 3332), the title compound was prepared.
Example 68
4 - [[[[[2- (benzimidazolyl) methyl] carbonyl] methylamino] -acetyl] phenoxyacetic acid
a) Preparation of 4- [2-Boc-methylamino) acetyl] phenol
A solution of di- t-butyl dicarbonate (5.96 g, 27.3 mmol) in 1,4-dioxane (25 mL) was added at 0 0 C to 4- [2- (methylamino) acetyl] phenol hydrochloride 24.8 mmol), 1,4-dioxane (30 mL), H ₂ O (25 mL) and 1.0 N NaOH (25 mL, 25 mmol). After 24 hours, the reaction was warmed to room temperature and stirred for 1.5 hours. Additional 1.0 N NaOH (25 mL, 25 mmol) was added and the reaction was stirred at room temperature for another 0.5 h and concentrated. The residue was diluted with EtOAc (80 ㎖), and the mixture using a 1.0 M NaHSO ₄ was acidified to pH 2. Extract the resulting mixture with EtOAc, wash the combined organic layers with H ₂ O, dried (Na ₂ SO _4). Filtration and concentration afforded the title compound (6.49 g, 99%). ¹ H NMR (250 MHz, CDCl ₃ ) 6.70-8.05 (m, 4H), 4.53 (s, 2H), 2.98 (s, 3H), 1.50 (s, 9H).
b) Benzyl 4- [2- (Boc-methylamino) acetyl] phenoxyacetate
A mixture of the compound of Example 68 (a) (5.04 g, 19.0 mmol) and K ₂ CO ₃ (2.63 g, 19.0 mmol) in acetone (100 mL) was stirred at reflux under argon for 1 hour. The mixture was cooled to room temperature and benzyl bromoacetate (5.23 g, 22.8 mmol) was added. The reaction was heated at reflux for 18 hours, then cooled and filtered. The filter cake was washed with acetone and the filtrate was concentrated. The residue was dissolved in CH ₂ Cl ₂ (300 mL) and washed successively with H ₂ O (50 mL) and brine (50 mL). Dried (Na ₂ SO _4), concentrated, and purified by flash chromatography (silica gel, 1: 3 EtOAc / hexane) afforded the title compound (7.28 g, 93%) was obtained. ^{1 H NMR (250 MHz, CDCl} 3) δ 6.85-7.95 (m, 9H), 5.23 (s, 2H), 4.71 (s, 2H), 4.55 (d, 2H), 2.95 (d, 3H), 1.45 ( d, 9H).
c) Benzyl 4- [2- (methylamino) acetyl] phenoxyacetate hydrochloride
A mixture of the compound of Example 68 (b) (7.26 g, 17.57 mmol) and 4 M HCl in 1,4-dioxane (150 mL) was stirred at room temperature for 1 hour. Concentrated Trituration with Et ₂ O to give the title compound (5.93 g, 97%) as white powder. ^{1 H NMR (250 MHz, CD} 3 OD) δ 7.05-8.00 (m, 9H), 5.23 (s, 2H), 4.88 (s, 2H), 4.65 (s, 2H), 2.80 (s, 3H).
d) Benzyl 4 - [[[[2- (benzimidazolyl) methyl] carbonyl] methylamino] acetyl] phenoxyacetate
A mixture of the compound of Example 68 (c) (1 mmol), 2- (benzimidazolyl) acetic acid (1 mmol), EDC (1.5 mmol) and DIEA (3 mmol) in DMF (25 mL) Respectively. The mixture is poured into 5% NaHCO _3, and extracted with EtOAc. The organic phase was washed with H ₂ O, dried (MgSO ₄ ) and concentrated. The residue was chromatographed (silica gel) to give the title compound.
e) 4 - [[[[2- (Benzimidazolyl) methyl] carbonyl] methylamino] acetyl] phenoxyacetate
CH ₃ OH (20 ㎖) stirring the compound (1 mmol) and 1 N NaOH (1.5 ㎖) of Example 68 (d) of, and concentrated. The residue was dissolved in H ₂ O, extracted with CH ₂ Cl ₂ , and the aqueous phase was adjusted to pH 5 with dilute HCl to give the title compound.
Example 69
Methyl] carbonyl] methylamino] acetyl] -1,2-phenylenedioxydiacetic acid was prepared in the same manner as in Production Example 1,
a) 4- [2- (Boc-methylamino) acetyl] -1,2-dihydroxybenzene
The procedure of Example 68 (a) was followed except that 4- [2- (methylamino) acetyl] phenol hydrochloride was replaced with adrenaline hydrochloride (5.0 g, 23.0 mmol) followed by flash chromatography Silica gel, 1: 1 EtOAc / hexanes) afforded the title compound (1.2 g, 19%). MS (ES) m / e 282.2 (M + H) &lt; ⁺ & gt ^; .
b) Preparation of dimethyl 4- [2- (Boc-methylamino) acetyl] -1,2-phenylenedioxy diacetate
Except that the compound of Example 68 (a) was replaced by the compound of Example 69 (a) (0.9 g, 3.2 mmol) and benzyl bromoacetate was replaced with methyl bromoacetate (1.23 g, 8.0 mmol) , The title compound (1.11 g, 81%) was prepared following the procedure of example 68 (b). MS (ES) m / e 426.2 (M + H) &lt; ⁺ & gt ^; .
c) Dimethyl 4- [2- (methylamino) acetyl] -1,2-phenylene dioxy diacetate hydrochloride
The title compound (1.1 g, quantitative yield) was prepared following the procedure of Example 68 (c), but substituting the compound of Example 68 (b) for the compound of Example 69 (b) (1.11 g, 2.6 mmol) . MS (ES) m / e 326.0 (M + H) &lt; ⁺ & gt ^; .
d) Dimethyl 4 - [[[[2- (benzimidazolyl) methyl] carbonyl] methylamino] acetyl] -1,2-phenylenedioxydiacetate
Following the procedure of Example 68 (d), except substituting the compound of Example 68 (c) for the compound of Example 69 (c), the title compound was obtained.
e) Synthesis of 4 - [[[[2- (benzimidazolyl) methyl] carbonyl] methylamino] acetyl] -1,2-phenylenedioxydiacetic acid
The title compound was obtained following the procedure of Example 68 (e), except substituting the compound of Example 68 (d) for the compound of Example 69 (d).
Example 70
Preparation of N- [3 - [[[(2-benzimidazolyl) methyl] carbonyl] amino] benzoyl] - - alanine
a) Preparation of benzyl N- [3 - [[[(2-benzimidazolyl) methyl] carbonyl] amino] benzoyl] - -
(1 mmol), (2-benzimidazolyl) acetic acid (1 mmol) in DMF (25 mL) and a solution of benzyl N- (3-aminobenzoyl) - - alaninate (Alig et al., European Patent Publication No. 372486) , EDC (1.5 mmol) and DIEA (3 mmol) was stirred at room temperature. The mixture was poured into 5% NaHCO ₃ and extracted with EtOAc. The combined organic phases were washed with H ₂ O, dried (MgSO ₄ ) and concentrated. The residue was chromatographed (silica gel) to give the title compound.
b) N- [3 - [[[(2-benzimidazolyl) methyl] carbonyl] amino] benzoyl] - - alanine
A mixture of the compound of Example 70 (a) (1 mmol) and 1 N NaOH (1.5 mL) in CH ₃ OH (20 mL) was stirred and concentrated. The residue was dissolved in H ₂ O, extracted with CH ₂ Cl ₂ , and the aqueous phase was adjusted to pH 5 with dilute HCl to give the title compound.
Example 71
[[1- [N - [[(2-benzimidazolyl) methyl] carbonyl] tyrosyl] -4-piperidinyl] oxy] acetic acid
a) t-butyl [[1- [N - [[(2-benzimidazolyl) methyl] carbonyl] tyrosyl] -4-piperidinyl] oxy]
A solution of t-butyl [(1-tyrosyl-4-piperidinyl) oxy] acetate (Alig et al., EP 372,866) (1 mmol), (2-benzimidazolyl) acetic acid (1 mmol), EDC (1.5 mmol) and DIEA (3 mmol) was stirred at room temperature. The mixture was poured into 5% NaHCO ₃ and extracted with EtOAc. The combined organic phases were washed with H ₂ O, dried (MgSO ₄ ) and concentrated. The residue was chromatographed (silica gel) to give the title compound.
b) Synthesis of [[1- [N - [[(2-benzimidazolyl) methyl] carbonyl] tyrosyl] -4-piperidinyl] oxy]
A mixture of the compound of Example 71 (a) (1 mmol) and CF ₃ CO ₂ H in CH ₂ Cl ₂ was stirred and concentrated to give the title compound.
Example 72
(S) -4 - [[[(2-benzimidazolyl) methyl] carbonyl] glycyl] -3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid
The title compound was obtained following the procedure of European Patent No. 0529858 (Sugihara et al.), Example 59 except that 4-aminobenzoic acid hydrochloride was substituted with (2-benzimidazolyl) acetic acid.
Example 73
(3S, 5S) -5 - [[4- [(2-benzimidazolyl) methyl] phenyl] oxymethyl] -3- carboxymethyl-2-pyrrolidone
a) 4 - [(2-Benzimidazolyl) methyl] phenol
Following the general procedure of literature (Wahlgren and Addison, J. Heterocycl. Chem. 1989, 26, 541-543), except substituting 4- (hydroxy) phenylacetic acid for 2- (hydroxy) phenylacetic acid, The title compound was obtained.
b) Synthesis of (3S, 5S) -5 - [[4 - [(2-benzimidazolyl) methyl] phenyl] oxymethyl] -3 - [(t-butoxycarbonyl) methyl] -2-
(Himmelsbach et al.), Except that 4'-cyano-3'-fluoro-4-hydroxybiphenyl was replaced with the compound of Example 73 (a) 51, the title compound was obtained.
c) Synthesis of (3S, 5S) -5 - [[4- [(2-benzimidazolyl) methyl] phenyl] oxymethyl] -3-carboxymethyl-2-pyrrolidinone
The compound of Example 73 (b) was treated with CF ₃ CO ₂ H in CH ₂ Cl ₂ to give the title compound.
Example 74
Preparation of 1 - [(2-benzimidazolyl) methyl] -3- [4- (2-carboxyethyl) phenyl] -4- methoxy-3-pyrrolin-
Following the procedure of European Patent No. 0567968 (Linz et al.) Except that 4-cyanoaniline was replaced with (2-benzimidazolyl) methanamine, the title compound was obtained.
Example 75
Preparation of 2- [6- (benzimidazol-2-yl) methylaminocarbonyl) -1,2,3,4-tetrahydroisoquinolinyl] acetic acid
a) 6-Methoxy-l, 2,3,4-tetrahydroisoquinoline
6-methoxy-1,2,3,4-tetrahydroisoquinoline was prepared according to the method of D. J. Sall and G. L. Grunewald, J. Med. Chem. 1987, 30, 2208-2216.
b) Ethyl 2- [6-methoxy-1,2,3,4-tetrahydroisoquinolinyl] acetate
A solution of the compound of Example 75 (a) (1.1 mmol), ethyl chloroacetate (1.17 mmol) and potassium carbonate (1.17 mmol) in acetonitrile (10 mL) was stirred for 18 hours. The mixture was partitioned in a mixture of EtOAc and H ₂ O. The organic phase was rotary evaporated to an oil and purified by silica gel chromatography to give the title compound.
c) Ethyl 2- [6-hydroxy-1,2,3,4-tetrahydroisoquinolinyl] acetate
A solution of the compound of Example 75 (b) (0.249 g, 1.0 mmol) and boron tribromide (1 M in CH ₂ Cl ₂ ) (1.0 mL, 1.0 mmol) was stirred at -70 ° C for 2 hours, Lt; / RTI &gt; The solution was rotary evaporated to an oil. The residue was taken up in EtOAc. The EtOAc was washed with water (1 x), 5% NaHCO ₃ (2 x) and water (1 x). Dry the EtOAc onto Mg ₂ SO ₄ and, filtered and rotovapped to give the title compound.
d) Ethyl 2- [6-trifluoromethylsulfonyl-l, 2,3,4-tetrahydroisoquinolinyl] acetate
A solution of the compound of Example 75 (c) (0.235 g, 1.0 mmol), trifluorosulfonic anhydride (0.23 mL, 1.1 mmol) and Et ₃ N (0.32 mL, 1.5 mmol) in CH ₂ Cl ₂ (5 mL) Was stirred for 8 hours. The solution was rotary evaporated to an oil. The residue was taken up in EtOAc. The EtOAc was washed with 5% NaHCO ₃ (2 x) and water (1 x). Dry the EtOAc onto Mg ₂ SO ₄ and, filtered and rotovapped to give the title compound.
e) Ethyl 2- [6-carboxy-1,2,3,4-tetrahydroisoquinolinyl] acetate
A solution of the compound of Example 75 (d) (0.367 g, 1.0 mmol), palladium (II) bis-acetate (0.022 g, 0.1 mmol), triphenylphosphine (0.262 g, 1.0 mmol) in aqueous ammonium carbonate (10% , Diisopropylamine (0.34 mL, 2.5 mmol), NMP (5 mL) was stirred under a carbon monoxide atmosphere for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
f) Ethyl- [6- (benzimidazol-2-yl) methylaminocarbonyl) -1,2,3,4-tetrahydroisoquinolinyl] acetic acid
A solution of the compound of Example 75 (e) (0.263 g, 1.0 mmol), (2-benzimidazolyl) acetic acid (0.34 g, 1.0 mmol), EDC (0.191 g, 1.0 mmol) in DMF (7 mL) A solution of HOBt (0.151 g, 1.0 mmol) and triethylamine (0.235 mL, 2.0 mmol) was stirred for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel column to give the title compound.
g) 2- [6- (Benzimidazol-2-yl) methylaminocarbonyl) -1,2,3,4-tetrahydroisoquinolinyl] acetic acid
A solution of the compound of Example 75 (f) (0.42 g, 1.0 mmol) in aqueous 1 N sodium hydroxide (1.5 mL, 1.5 mmol) and ethanol (5 mL) was stirred for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel column to give the title compound.
Example 76
Preparation of 2- [6- (benzimidazol-2-yl) methylaminocarbonyl) -1-oxo-1,2,3,4-tetrahydroisoquinolinyl] acetic acid
a) 6-Methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline
According to the method of DJ Sall and GL Grunewald, J. Med. Chem. 1987, 30, 2208-2216, 6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline was prepared Respectively.
b) Ethyl 2- [6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinolinyl] acetate
A mixture of the compound of Example 76 (a) (0.39 mmol) and NaH (0.17 g, 0.43 mmol, 60% oil dispersion) in THF (5 mL) was heated at reflux for 1 hour and then cooled to room temperature. Ethyl acetate (0.43 mmol) was added to the mixture, and the mixture was stirred for 1 hour. The mixture was quenched with water (10 mL) and washed with EtOAc (2 x 15 mL). The organic layers were combined, washed with water (10 mL) and rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
c) Ethyl 2- [6-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinolinyl] acetate
A solution of the compound of Example 76 (b) (0.263 g, 1.0 mmol) and boron tribromide (1 M in CH ₂ Cl ₂ , 1.1 mL) was stirred at -70 ° C for 2 hours and then at room temperature for 4 hours . The solution was rotary evaporated to an oil. The residue was taken up in EtOAc. The EtOAc was washed with water (1 x), 5% NaHCO ₃ (2 x) and water (1 x). Dry the EtOAc onto Mg ₂ SO ₄ and, filtered and rotovapped to give the title compound.
d) Ethyl 2- [6-trifluoromethylsulfonyloxy-1-oxo-1,2,3,4-tetrahydroisoquinolinyl] acetate
A solution of the compound of Example 76 (c) (3.4 mmol) and trifluorosulfonic anhydride (3.4 mmol) in pyridine (5 ml) was cooled at 0 &lt; 0 &gt; C and warmed to room temperature for 1 hour. The mixture was quenched with water (5 mL) and washed with EtOAc (2 x 7 mL). The organic layers were combined, washed with water (7 mL) and rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
e) Ethyl 2- [6-carboxy-1-oxo-1,2,3,4-tetrahydroisoquinolinyl] acetate
Acetate (0.026 g, 0.1 mmol), triphenylphosphine (0.262 g, 1.0 mmol) in anhydrous ammonium carbonate (10%) and a solution of the compound of Example 76 (d) (0.23 g, 1.0 mmol), palladium (II) , Diisopropylamine (0.23 mL, 2.0 mmol) and NMP (7 mL) was stirred under a carbon monoxide atmosphere for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
f) Ethyl- [6- (benzimidazol-2-yl) methylaminocarbonyl) -1,2,3,4-tetrahydroisoquinolinyl] acetic acid
A solution of the compound of Example 76 (e) (0.34 g, 1.0 mmol), (2-benzimidazolyl) acetic acid (0.43 g, 1.0 mmol), EDC (0.191 g, 1.0 mmol) in DMF (8 mL) A solution of HOBt (0.15 g, 1.0 mmol) and triethylamine (0.234 mL, 2.3 mmol) was stirred for 8 hours. The solution was concentrated. The residue was purified by silica gel chromatography to give the title compound.
Alternatively, a solution of the compound of Example 76 (d) (0.23 g, 1.0 mmol), palladium (II) bis-acetate (0.026 g, 0.1 mmol), triphenylphosphine (0.262 g, 1.0 mmol), diisopropylamine (0.25 mL, 2.1 mmol), NMP (7 mL) and a solution of the compound of Intermediate A (0.31 g, 1.0 mmol) in carbon monoxide atmosphere for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
g) 2- [6 - ((Benzimidazol-2-yl) methylaminocarbonyl) -1,2,3,4-tetrahydroisoquinolinyl] acetic acid
A solution of the compound of Example 76 (f) (0.25 g, 1.0 mmol) in aqueous 1 N sodium hydroxide (1.5 mL, 1.5 mmol) and ethanol (8 mL) was stirred for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
Example 77
Preparation of 2- [6 - ((benzimidazol-2-yl) methylcarbonylamino) tetralin] acetic acid
a) t-Butyl-5-amino-tetralin-2-acetate
t-butyl-5-amino-tetralin-2-acetate was prepared according to the method described in the literature (M.J. Fisher et al., Scheme 12 and Example 28, Part A-D, EO 0635492, 1995.1.25).
b) 2- [6 - ((Benzimidazol-2-yl) methylcarbonylamino) tetralin] acetate
A solution of the compound of Example 77 (a) (0.261 g, 1.0 mmol), 2- (aminomethyl) benzimidazole (0.256 g, 1.0 mmol), EDC (0.191 g, 1.0 mmol) A solution of hydroxybenzotriazole hydrate (0.152 g, 1.0 mmol) and triethylamine (0.234 mL, 2.1 mmol) was stirred for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
A solution of the crude ester amide (0.32 g, 1.0 mmol) and trifluoroacetic acid (5 mL) in methylene chloride (5 mL) was stirred for 1 hour. The solution was rotary evaporated to an oil. The residue was treated with Et ₂ O. Filtered and dried in vacuo to give the title compound.
Example 78
Preparation of 2- [6 - ((benzimidazol-2-yl) methylaminocarbonyl) tetralin] acetic acid
a) Ethyl-5-hydroxy-tetralin-2-acetate
Ethyl-5-hydroxy-tetralin-2-acetic acid was prepared according to the method of M.J. Fisher et al., EP 0635492, Scheme 6 and Example 20, Part A-D, p71.
b) Ethyl-5-trifluoromethylsulfonyloxy-tetralin-2-acetate
A solution of the compound of Example 78 (b) (0.321 g, 1.0 mmol) in CH ₂ Cl ₂ (10 mL) was cooled to 0 ° C. Trifluoromethylsulfonic anhydride (0.125 mL, 1.1 mmol) was added. The solution was stirred for 2 hours. The solution was rotary evaporated to an oil. The residue was taken up in EtOAc. The EtOAc was washed with water (1 x), 5% NaHCO ₃ and water (1 x). Dry the EtOAc on MgSO ₄ and filtered. The filtrate was rotary evaporated to give the title compound.
c) Ethyl 6-carboxy-tetralin-2-acetate
A solution of the compound of Example 78 (c) (0.26 g, 1.0 mmol), palladium (II) bis-acetate (0.023 g, 0.1 mmol), triphenylphosphine (0.262 g, 1.0 mmol) in aqueous ammonium carbonate (10% , Diisopropylamine (0.245 mL, 2.1 mmol) and NMP (10 mL) was stirred under a carbon monoxide atmosphere for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
d) Ethyl- [6 - ((benzimidazol-2-yl) methylaminocarbonyl) -tetralin-1-acetate
A solution of the compound of Example 78 (c) (0.34 g, 1.0 mmol), (2-benzimidazolyl) acetic acid (0.32 g, 1.0 mmol), EDC (0.191 g, 1.0 mmol) in DMF (6 mL) A solution of HOBt (0.152 g, 1.0 mmol) and triethylamine (0.23 mL, 2.1 mmol) was stirred for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
Alternatively, a solution of the compound of Example 78 (b) (0.34 g, 1.0 mmol), palladium (II) bis-acetate (0.023 g, 0.1 mmol), triphenylphosphine (0.262 g, 1.0 A solution of the compound of intermediate A (0.32 g, 1.0 mmol), diisopropylamine (0.23 mL, 2.1 mmol), NMP (10 mL) and a solution of intermediate A (0.32 g, 1.0 mmol) was stirred for 8 hours under a carbon monoxide atmosphere. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
e) 2- [6 - ((Benzimidazol-2-yl) methylaminocarbonyl) -tetralin-
A solution of the compound of Example 78 (d) (0.31 g, 1.0 mmol) in aqueous 1 N sodium hydroxide (1.5 mL, 1.5 mmol) and ethanol (5 mL) was stirred for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
Example 79
Preparation of 2- [5 - ((benzimidazol-2-yl) methylcarbonylamino) -benzofuran] -propionic acid
a) Preparation of ethyl 1-carboxymethyloxy-4-nitrosalicylaldehyde
A solution of 1-hydroxy-4-nitrosalicylaldehyde (Aldrich) (0.167 g, 1.0 mmol), ethyl bromoacetate (0.166 g, 1.0 mmol), potassium carbonate (0.276 g, 2.0 mmol) and A solution of sodium iodide (0.015 g, 0.1 mmol) was heated to 80 &lt; 0 &gt; C for 24 h. The solution was rotary evaporated to an oil and the residue was purified by silica gel chromatography to give the title compound.
b) Ethyl 2-carboxy-5-nitrobenzofuran
A solution of the compound of Example 79 (a) (0.229 g, 1.0 mmol), DBU (0.152 g, 1.0 mmol) in ethyl alcohol (10 mL) was stirred at room temperature for 18 hours. The solution was rotary evaporated with oil and the residue was treated with EtOH (10 mL). The solution was bubbled with HCl gas for 2 minutes and refluxed for 5 hours. The solution was rotary evaporated to an oil. EtOAc was added and washed with water (2 x), 5% citric acid (2 x), water (1 x), 5% NaHCO ₃ (2 x) and water (1 x). The EtOAc was rotary evaporated to give the title compound.
c) Ethyl 2- (2-carboxy) ethylene-5-nitrobenzofuran
A cold solution (-78 ° C) of the compound of Example 79 (b) (0.235 g, 1.0 mmol) in THF (5 mL) was treated with DiBAL (1.0 M in THF, 0.1 mL, 1.0 mmol). The solution was stirred at -78 &lt; 0 &gt; C for 30 minutes and at room temperature for 3 hours. The solution was treated with CH ₃ COOH ₍₃ ㎖), followed by water (2 ㎖). The solution was rotary evaporated to an oil and treated with toluene to acetic acid azeotropically. And dried under vacuum to obtain crude aldehyde.
A solution of the phosphonate ester (0.224 g, 1.0 mmol) in THF (5 mL) was treated with sodium hydride (60% suspension in mineral oil, 0.04 g, 1.0 mmol) at 0 C for 1 h. To the solution was added aldehyde (0.235 g, 1.0 mmol). The solution was stirred at room temperature for 18 hours. The solution was rotary evaporated to an oil and the residue was purified by silica gel chromatography to give the title compound.
d) t-Butyl-2- [5-amino-benzofuranyl] propionate
A solution of the compound of Example 79 (c) (0.261 g, 1.0 mmol) in ethanol (5 mL) containing 10% palladium on carbon (0.026 g, 10 wt%) was hydrogenated at 45 psi for 1 hour. The solution was filtered through celite and the filtrate was rotary evaporated to an oil. Silica gel chromatography gave the title compound.
e) 2- [5 - ((Benzimidazol-2-yl) methylcarbonylamino) -benzofuran] -propionic acid
A solution of the compound of Example 79 (d) (0.263 g, 1.0 mmol), EDC (0.191 g, 1.0 mmol), 1-hydroxybenzotriazole (0.150 g, 1.0 mmol), 2- (amino Methyl) benzimidazole (0.234 g, 1.0 mmol) and triethylamine (0.288 mL, 2.0 mmol) was stirred for 8 hours. The solution was rotary evaporated to an oil and the residue was purified by silica gel chromatography to give the title compound.
A solution of the crude ester (0.263 g, 1.0 mmol) in MeOH (3.0 mL) was treated with 1 N NaOH (1.5 mL, 1.5 mmol) and water (2 mL). The solution was stirred at room temperature for 18 hours. The solution was rotary evaporated with oil and purified by reverse phase chromatography to give the title compound.
Example 80
Preparation of 2- [5 - ((benzimidazol-2-yl) methylcarbonylamino) -2,3-dihydrobenzofuran] -propionic acid
a) Ethyl-2- [5-amino-2,3-dihydro-benzofuranyl] propionate
The compound of Example 79 (d) was purified by chromatography to give the title compound as well.
b) 2- [5- (6-aminopyridinyl-2-methylcarbonylamino) -benzofuran] -propionic acid
A solution of the compound of Example 80 (a) (0.263 g, 1.0 mmol), EDC (0.191 g, 1.0 mmol), 1-hydroxybenzotriazole (0.15 g, 1.0 mmol), 2- (amino Methyl) benzimidazole (0.32 g, 1.0 mmol) and triethylamine (0.288 mL, 2.0 mmol) was stirred for 18 hours. The solution was rotary evaporated to an oil and the residue was purified by silica gel chromatography to give the title compound.
A solution of the crude ester (0.290 g, 1.0 mmol) in MeOH (5.0 mL) was treated with 1 N NaOH (1.2 mL, 1.2 mmol) for 18 h. The solution was rotary evaporated with oil and purified by reverse phase chromatography to give the title compound.
Example 81
Preparation of 2- [5- (6-aminopyridinyl-2-methylaminocarbonyl) -benzofuran] -propionic acid
a) 2-Ethyloxycarbonyl-5- (t-butyl-dimethylsilyloxy) -benzofuran
Ethyloxycarbonyl-5- (hydroxy) -benzofuran (0.206 g, 1.0 mmol) in THF, prepared via the procedure described in the literature (ML Denny et al., EP 0655439, ), t-butyl-dimethylsilyl chloride (0.23 mL, 1.0 mmol) and imidazole (0.34 g, 1.0 mmol) in DMF (5 mL) was stirred for 4 hours. The solution was rotary evaporated to an oil. Add EtOAc and wash with water. The EtOAc was rotary evaporated to give the title compound.
b) 2-Hydroxycarbonyl-5- (t-butyl-dimethylsilyloxy) -benzofuran
A cold solution of compound of Example 81 (a) (0.35 g, 1.0 mmol) in THF (5 mL) (-78 <0> C) was treated with DiBAL (1.0 M in THF, 1.0 mL, 1.0 mmol). The solution was stirred at -78 &lt; 0 &gt; C for 30 minutes and at room temperature for 3 hours. The solution was treated with CH ₃ COOH ₍₃ ㎖), followed by water (2 ㎖). The solution was rotary evaporated to an oil and treated with toluene to acetic acid azeotropically. And dried under vacuum to obtain aldehyde.
c) Ethyl 2- [5- (t-butyl-dimethylsilyloxy) -benzofuran] -acrylate
A solution of the phosphonate ester (0.224 g, 1.0 mmol) in THF (5 mL) was treated with sodium hydride (60% suspension in mineral oil, 0.04 g, 1.0 mmol) at 0 C for 1 h. To the solution was added the above aldehyde (0.235 g, 1.0 mmol). The solution was stirred at room temperature for 18 hours. The solution was rotary evaporated to an oil and the residue was purified by silica gel chromatography to give the title compound.
d) 2-Ethyl-2- [5- (hydroxy) -benzofuran] -propionate
The compound of Example 81 (c) (0.234 g, 1.2 mmol) and 10% palladium on carbon (0.023 g, 10% by weight) in EtOH (5 mL) was hydrogenated at 50 psi for 1 hour. Filtration through Celite and concentration afforded the ester (0.169 g, 56%).
A solution of the crude ester (0.34 g, 1.0 mmol) and tetraethylammonium fluoride (0.149 g, 1.0 mmol) in THF (10 mL) was stirred at room temperature for 18 hours. The solution was rotary evaporated with oil and purified by silica gel chromatography.
e) 2-Ethyl 2- [5- (trifluoromethylsulfonyloxy) -benzofuran] -propionate
A solution of the compound of Example 81 (d) (0.366 g, 1.0 mmol) and Et ₃ N (0.23 mL, 1.5 mmol) in CH ₂ Cl ₂ (10 mL) at 0 ° C was treated with trifluoromethylsulfonic anhydride , 1.1 mmol). After 2 h, the solution was rotary evaporated to an oil. The residue was taken up in EtOAc. The EtOAc was washed successively with water (1 x), 5% NaHCO 3 (2 x) and water (1 x). Dry the EtOAc on MgSO ₄ and filtered. The filtrate was rotary evaporated to give the title compound.
f) 2-Ethyl-2- [5- (carboxy) -benzofuran] -propionate
A solution of the compound of Example 81 (e) (0.366 g, 1.0 mmol), palladium (II) bis-acetate (0.023 g, 0.1 mmol), triphenylphosphine (0.262 g, 1.0 mmol), diisopropylethylamine (0.23 mL, 2.1 mmol), and NMP (7 mL) was stirred. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
g) 2-Ethyl 2- [5- (6- (6-aminopyridinyl-2-methylaminocarbonyl) -benzofuran] -propionate
A solution of the compound of Example 81 (f) (0.366 g, 1.0 mmol), 2- (benzimidazolyl) acetic acid (0.23 g, 1.0 mmol), EDC (0.191 g, 1.0 mmol), HOBt 0.152 g, 1.0 mmol) and triethylamine (0.235 mL, 2.1 mmol) in DMF (5 mL) was stirred for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
Alternatively, a solution of the compound of Example 81 (e) (0.366 g, 1.0 mmol), palladium (II) bis-acetate (0.023 g, 0.1 mmol), triphenylphosphine (10 mmol) in aqueous ammonium carbonate (0.232 g, 1.0 mmol), diisopropylamine (0.23 mL, 2.1 mmol), NMP (10 mL) and the compound of Intermediate A (0.32 g, 1.0 mmol) was stirred under an atmosphere of carbon monoxide for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
h) 2- [5- (6- (6-aminopyridinyl-2-methylaminocarbonyl) -benzofuran] -propionic acid
A solution of the compound of Example 81 (g) (0.366 g, 1.0 mmol) in aqueous 1 N sodium hydroxide (1.5 mL, 1.5 mmol) and ethanol (8 mL) was stirred for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
Example 82
Preparation of 2- [5 - ((benzimidazol-2-yl) methylaminocarbonyl) -2,3-dihydrobenzofuran] -propionic acid
a) 2-t-Butyl-2- [5- (hydroxy) -2,3-dihydrobenzofuran] -propionate
Further purification by chromatography in Example 81 (d) gave the title compound.
b) 2-t-butyl 2- [5- (trifluoromethylsulfonyloxy) -2,3-dihydrobenzofuran] -propionate
CH ₂ Cl ₂ (5 ㎖) of Example 82 (a) of the compound (0.28 g, 1.0 mmol) and Et ₃ N-methyl sulfonic anhydride (0.15 ㎖ a solution of (0.23 ㎖, 2.1 mmol) in trifluoroacetic acid, 1.1 mmol of ) For 2 hours. The solution was rotary evaporated to an oil. The residue was taken up in EtOAc. The EtOAc was washed with water (1 x), 5% NaHCO ₃ (2 x) and water (1 x). Dry the EtOAc on MgSO ₄ and filtered, and the filtrate was rotary evaporated to give the title compound.
c) 2-t-butyl 2- [5- (carboxy) -2,3-dihydrobenzofuran] -propionate
A solution of the compound of Example 82 (b) (0.24 g, 1.0 mmol), palladium (II) bis-acetate (0.023 g, 0.1 mmol), triphenylphosphine (0.262 g, 1.0 mmol), diisopropylethylamine (0.23 mL, 2.1 mmol), NMP (8 mL) was stirred at room temperature for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
d) 2-t-butyl 2- [5- (6- (6-aminopyridinyl-2-methylaminocarbonyl) -2,3-dihydrobenzofuran] -propionate
A solution of the compound of Example 82 (c) (0.366 g, 1.0 mmol), 2- (benzimidazolyl) acetic acid (0.23 g, 1.0 mmol), EDC (0.191 g, 1.0 mmol) in DMF (8 mL) A solution of HOBt (0.152 g, 1.0 mmol) and triethylamine (0.23 mL, 2.1 mmol) was stirred for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
Alternatively, a solution of the compound of Example 82 (b) (0.366 g, 1.0 mmol), palladium (II) bis-acetate (0.023 g, 0.1 mmol), triphenylphosphine (10 mmol) in aqueous ammonium carbonate (0.23 g, 1.0 mmol), diisopropylamine (0.23 mL, 2.1 mmol), NMP (10 mL) and the compound of Intermediate A (0.23 g, 1.0 mmol) was stirred for 8 hours under a carbon monoxide atmosphere. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
e) 2- [5- (6 - ((Benzimidazol-2-yl) methylaminocarbonyl) -2,3-dihydrobenzofuran] -propionic acid
A solution of the compound of Example 82 (d) (0.37 g, 1.0 mmol) in aqueous 1 N sodium hydroxide (1.5 mL, 1.5 mmol) and ethanol (8 mL) was stirred for 8 hours. The solution was rotary evaporated to an oil. The residue was purified by silica gel chromatography to give the title compound.
Example 83
Preparation of 1 - [(1H-benzimidazol-2-yl) methyl] -3- {4 - [(2- ethoxycarbonyl) ethyl]] phenyl} -3-oxo-imidazolidine
a) 2-Aminomethyl-l-p-toluenesulfonyl-benzimidazole
A solution of water (2 ㎖) and THF (1 ㎖) 2- methyl-benzimidazole (1 mmol), p- toluenesulfonyl chloride (1.05 mmol) and Et ₃ N (1.05 mmol) was stirred for 4 hours. The mixture was concentrated by rotary evaporation and diluted with water (10 mL). The solution was washed with EtOAc (2 x 15 mL). The organic layers were combined, washed with water (5 mL) and rotary evaporated to an oil.
A solution of the above oil (2-methyl-1-p-toluenesulfonylbenzimidazole) (1 mmol) and N-bromosuccinimide (1.05 mmol) in CCl ₄ (10 mL) was refluxed for 18 h . Upon cooling, a white solid precipitated out of solution. The solid was filtered, and polished with CCl _4, and dried to a solid under vacuum.
A solution of Boc ₂ NH (1 mmol) and potassium hydroxide (1 mmol) in ethanol (5 mL) was stirred for 1 hour. Anhydrous ethyl ether (15 mL) was added and the mixture was filtered to give a salt as a white solid. A solution of the above solid 2-bromomethyl-1-p-toluenesulfonylbenzimidazole (1 mmol) and (Boc) ₂ N ^- K ⁺ (mmol) in THF (10 mL) Lt; / RTI &gt; The mixture was rotary evaporated to an oil.
A solution of 2- [bis- (t-butyloxycarbonyl) aminomethyl] -1-p-toluenesulfonylbenzimidazole (1 mmol) in TFA (1.1 mmol) and CH ₂ Cl ₂ was stirred for 1 hour . The solution was rotary evaporated with oil and purified by chromatography to give the title compound.
b) Ethyl 2- [4- (2-hydroxyethylamino) phenyl] propionate
This compound was prepared according to the procedure of F. Himmelsbach et al., Example V, p44, EP 0587134, September 8, 1993. The glycolaldehyde dimer (Aldrich) (millimole) was dissolved in aqueous acetonitrile was added to a solution of methyl 2- (4-aminophenyl) propionate 1 (1 mmol) in methanol (pH 6-7) (ml), followed by sodium cyanoborohydride (1.1 mmol) and the mixture was stirred Respectively. The mixture was rotary evaporated with oil, and the residue was dissolved in a mixture of ice water and ethyl acetate. The aqueous layer was neutralized with 4 N sodium hydroxide and washed with ethyl acetate. The organic phase was rotary evaporated to an oil. The oil solution in ethyl acetate was purified on a silica gel column to give the title compound.
c) N - [(1-p-toluenesulfonyl-1H-benzimidazol-2-yl) methyl] -N'- ] Phenyl} -urea
This compound was prepared according to the procedure of F. Himmelsbach et al., European Patent No. 0587134, September 8, 1993 and No. 0612741, February 21, 1994, in Example 83 ( A mixture of a) (1 mmol) and phosgene (1.1 mmol) was stirred at -20 &lt; 0 &gt; C for 20 min. The compound of Example 83 (b) (1.0 mmol) was added to the solution and the resulting mixture was stirred for 18 hours. The resulting solution was rotary evaporated. The residue solution in ethyl acetate was washed with 5% citric acid followed by water. The organic phase was rotary evaporated to an oil. The oil solution in ethyl acetate was purified on a silica gel column to give the title compound.
d) Preparation of N ¹ - [(1-p-toluenesulfonyl-1H-benzimidazol-2-yl) methyl] -N ³ - {4 - [(2-ethoxycarbonyl) ethyl] Oxo-imidazolidine
This compound was prepared by following the procedure in literature (F. Himmelsbach et al., Example III, EP 0587134, 1993. 9. 8 and 0612741, February 21, 1994), methylene chloride (5 ml A solution of the compound of Example 83 (c) (1 mmol), methanesulfonyl chloride (1.2 mmol) and triethylamine (1.2 mmol) in methanol was stirred at 0 <0> C for 1 h. The mixture was partitioned into a mixture of water and methyl chloride. The organic phases were combined, dried over anhydrous sodium sulfate and rotary evaporated.
A solution of the residue in acetone (5 mL) and sodium iodide (1.1 mmol) was heated at reflux for 3 hours and then rotary evaporated to an oil. Potassium bis (trimethylsilyl) azide (1.2 mmol) was added to the residue solution in DMF (5 mL) and cooled to 0 &lt; 0 &gt; C. The solution was allowed to warm to room temperature over 30 minutes and rotary evaporated with oil. The residue was partitioned into a mixture of water and methyl chloride. The organic phases were combined, dried over anhydrous sodium sulfate and rotary evaporated. The oil solution in ethyl acetate was purified on a silica gel column to give the title compound.
e) Synthesis of N ¹ - [( ¹ H-benzimidazol-2-yl) methyl] -N ³ - {4 - (2- carboxy) ethyl)] phenyl} -2-oxo- imidazolidine
A solution of the compound of Example 83 (d) (1 mmol) and 1 N sodium hydroxide (1.2 mL, 1.2 mmol) in THF (5 mL) was stirred for 18 hours. The mixture was neutralized with concentrated hydrochloric acid and purified on a silica gel column to give the title compound.
Example 84
Parenteral dosage unit composition
A preparation containing 20 mg of the compound of Example 1 as a sterile anhydrous powder was prepared as follows. 20 mg of the compound was dissolved in 15 ml of distilled water. The solution was filtered under aseptic conditions in 25 ml multi-dose ampoules and lyophilized. Powder was reconstituted by adding 20 ml of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosing amount was thereby determined by the injection volume. Subsequently, an additional volume of D5W may be added to the dosing unit of the weighed volume for injection to dilute it, or to another mechanism for dispensing the drug, such as in a bottle or bag for IV drop infusion or other injection infusion systems, The dosage can be added.
Example 85
Oral dosage unit composition
50 mg of the compound of Example 1 was mixed with 75 mg of lactose and 5 mg of magnesium stearate and pulverized to prepare capsules for oral administration. The resulting powder was screened and filled into hard gelatin capsules.
Example 86
Oral dosage unit composition
20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of Example 1 were mixed with a 10% gelatin solution and granulated to prepare tablets for oral administration. The wet granulation was screened, dried and mixed with 10 mg starch, 5 mg talc and 3 mg stearic acid and compressed with a tablet.
The foregoing description fully discloses methods for making and using the present invention. However, the present invention is not limited to the specific embodiments described above, but includes modifications thereof within the scope of the following claims. Various references to papers, patent documents and other publications cited herein are incorporated by reference herein in their entirety.

权利要求:
Claims (52)
[1" claim-type="Currently amended] Claims 1. A compound of formula (I) or (II) or (III) or (IV) or (V) or a pharmaceutically acceptable salt thereof.
(I)

&Lt;

(III)

(IV)

(V)

Wherein,
W is - (CHR ^g ) _b -V'- or phenyl;
A is a fibrinogen receptor antagonist template;
V 'is CONR ²¹ or NR ²¹ CO;
G is NR ^e , S or O;
R ^g is H, C _1-6 alkyl, Het-C _0-6 alkyl, C _3-7 cycloalkyl, -C _0-6 alkyl or Ar-C _0-6 alkyl;
R ²¹ is _{Het- (CH 2) 0-6 -U '} - (CH 2) 1-6 -, C 3-7 cycloalkyl, _{- (CH 2) 0-6 -U'} - (CH 2) 1-6 - or Ar- (CH ₂ ) _0-6- U '- (CH ₂ ) _1-6 -;
U 'is CONR ^f or NR ^f CO;
R ^f is H, C _1-6 alkyl or Ar-C _1-6 alkyl;
R ^e is H, C _1-6 alkyl, Ar-C _1-6 alkyl, Het-C _1-6 alkyl, C _3-7 cycloalkyl, -C _1-6 alkyl, (CH _{2) q} OH or (CH ₂ ) _k CO ₂ R ^g, and;
k is 0, 1 or 2;
q is 1 or 2;
b is 0, 1 or 2;
R ^b and R ^c are each H, C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, or C _3-6 cycloalkyl, -C _0-6 alkyl, halogen, CF _{3, ^{oR f, S (O) k}} R f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2 N (R f) selected from the _second or, or R ^b and R ^c is in combination with a halogen, CF _3, C _1-4 ^{alkyl, OR f, S (O)} k R f, COR f, CO 2 R f OH, NO 2, N (R f) 2, CO (NR f) _2, and CH ₂ N (R ^f) optionally a substitutent selected from the following three _{2-substituted} 5-membered or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic to form a cyclic ring, or methylenedioxy .
[2" claim-type="Currently amended] 3. The compound of claim 1, wherein the fibrinogen receptor antagonist template A is a compound of formula VI EMI5.1 or a pharmaceutically acceptable salt thereof.
&Lt; Formula (VI)

A ¹ through A ⁵ optionally form a saturated or unsaturated, optionally substituted 7-membered ring containing up to two heteroatoms selected from the group of O, S and N, said S and N being optionally oxidized Have;
D ¹ to D ^{4 form} optionally substituted six-membered rings optionally containing up to two nitrogen atoms;
R is R ^7, or = O, R ¹¹ or R ⁷ by at least one optionally substituted QC _1-4 alkyl, QC _2-4 alkenyl, wherein is one or more substituents selected from the group of QC _2-4 alkynyl ;
R ^* is H, QC _1-6 alkyl, QC _1-6 alkyl, oxo, QC _2-6 alkenyl, QC _3-4 oxo alkenyl, QC _3-4 alkynyl, oxo, QC _2-4 alkynyl, C _{3 6} cycloalkyl, Ar or Het, which are optionally substituted by one or more R &lt; ^{11 &} gt ;;
Q is H, C _3-6 cycloalkyl, Het or Ar;
R ⁷ is -COR ⁸ , -COCR ' ₂ R ⁹ , -C (S) R ⁸ , -S (O) _m OR', -S (O) _m NR'R " PO (OR ') ₂ , -B (OR') ₂ , -NO ₂ and Tet;
R ⁸ is -OR ', -NR'R ", -NR'SO ₂ R', -NR'OR ', -OCR' ₂ C (O) OR ', -OCR' ₂ OC (O) _{-OCR '2 C (O) NR} ' 2, CF 3 or AA, and;
R ⁹ is OR ', -CN, -S (O ) r R', S (O) m NR '2, -C (O) R'C (O) NR' 2 or -CO ₂ R ', and;
R ¹¹ is H, ^{halo, -OR 12, -CN, -NR'R 12} , -NO 2, -CF 3, CF 3 S (O) r-, -CO 2 R ', -CONR' 2, QC 0 _-6 alkyl -, QC _1-6 alkyl-oxo-, QC _2-6 alkenyl -, QC _2-6 alkynyl -, QC _0-6 alkyloxy -, QC _0-6 alkylamino-or QC _0-6 alkyl -S (O) r-;
R ¹² is -C (O) R ', -C (O) NR' ₂ , -C (O) OR ¹⁵ , -S (O) _m R 'or S (O) _m NR'₂;
R ¹³ is R ', -CF ₃ , -SR' or -OR ';
R ¹⁴ is R ', C (O) R', CN, NO ₂ , SO ₂ R 'or C (O) OR ¹⁵ ;
R ¹⁵ is H, C _1-6 alkyl or Ar-C _0-4 alkyl;
R 'is H, C _1-6 alkyl, C _3-7 cycloalkyl, -C _0-4 alkyl or Ar-C _0-4 alkyl;
R "is R ', -C (O) R', or -C (O) OR ¹⁵ ;
R "'is R" or AA2;
AA1 is an amino acid attached through an amino group and the carboxyl group is optionally protected, AA2 is an amino acid attached through a carboxyl group and the amino group is optionally protected;
m is 1 or 2;
n is from 0 to 3;
p is 0 or 1;
t is from 0 to 2;
[3" claim-type="Currently amended] 3. The method of claim 2,
A ¹ is CR ¹ R ^{1 '} , CR ¹ , NR ¹ , N, O or S (O) _x ;
A ² is CR ² R ^{2 '} , CR ² , NR ² ;
A ³ is CR ³ R ^{3 '} , CR ³ , NR ³ , N, O or S (O) _x ;
A ⁴ is CR ⁴ R ^{4 '} , CR ⁴ , NR ⁴ , or N;
A ⁵ is CR ⁵ R ^{5 '} , CR ⁵ , NR ⁵ , N, O or S (O) _x ;
D ¹ -D ⁴ is CH or N;
R ¹ and R ^{1 '} are R ^* or R, or together are = O;
R ² and R ^{2 '} are R ^* , R or = O;
R ³ and R ^{3 '} are R ^* , R or = O;
R ⁴ and R ^{4 '} are R ^* , R or = O;
R ⁵ and R ^{5 '} are R ^* , R or = O;
wherein x is 0,1 or 2.
[4" claim-type="Currently amended] The compound according to claim 2, wherein A ¹ is CR ¹ R ^{1 '} , CR ¹ , NR ¹ , N, O or S; A ² is CR ² R ^{2 '} , NR ² or CR ² ; A ³ is CR ³ R ^{3 '} ; A ⁴ is CR ⁴ R ^{4 '} , CR ⁴ , NR ⁴ or N; A ⁵ is CR ⁵ R ^{5 '} , CR ⁵ , NR ⁵ , N, O; D ¹ and D ⁴ are CH; D ² or D ³ is CH ⁶ ; R ² or R ⁴ is R; R ³ , R ^{3 '} and R ⁵ , R ^5' are ═O or R ^* , H.
[5" claim-type="Currently amended] The method of claim 2, wherein, A ¹ is ^{CHR 1, CR 1, NR "} , N or S; A ^'is; A ³ is CR ³ R ^{3' 2} is CR ² or CR ² R ^2, and; A ⁴ is CR ⁴ R ^{4 '} or NR ⁴ , A ⁵ is CR ⁵ R ^5' and D ¹ -D ⁴ is CH.
[6" claim-type="Currently amended] The compound according to claim 2, wherein A ¹ is CR ¹ , A ² is CR ² , A ³ is C═O, A ⁴ is NR ⁴ , and A ⁵ is CHR ⁵ .
[7" claim-type="Currently amended] A compound according to claim 2, wherein A ¹ is NR ¹ , A ² is CHCR ² , A ³ is CR ³ R ^{3 '} , A ⁴ is NR ⁴ and A ⁵ is C═O.
[8" claim-type="Currently amended] The compound according to claim 2, wherein A ¹ and A ⁴ are C═O, A ² is NR ² , A ³ is CHR ^{3 '} , and A ⁵ is NR ⁵ .
[9" claim-type="Currently amended] A compound according to claim 2, wherein A ¹ is NR ¹ , A ² is CHR ² , A ³ is C═O, A ⁴ is NR 'and A ⁵ is CHR ⁵ .
[10" claim-type="Currently amended] 3. The compound of claim 2, wherein R &lt; 1 &gt;
&Lt; Formula VIa &

(VIb)

<Formula VIc>

<Formula (VId)

<Formula VIe>

<Formula VIf>

<Formula VI>

(VI)

&Lt; Formula (VIII)

[11" claim-type="Currently amended] 3. The compound of claim 2, wherein R &lt; 1 &gt;

[12" claim-type="Currently amended] 12. The method of claim 11 wherein, R ¹ is H or C _1-4 alkyl; R ² , R ^{2 '} is H, -CH ₂ CO ₂ H; R ⁵ R ^{5 '} is H, H.
[13" claim-type="Currently amended] A compound of formula (XXI) or (XXII): or a pharmaceutically acceptable salt thereof.
&Lt; Formula (XXI)

(XXII)

Wherein,
B is - (CHR ^g ) _a -U- (CHR ^g ) _b -V- or phenyl or
ego;
A is a fibrinogen receptor antagonist template;
U and V is absent, or _{^{CO, CR g 2, C (}} = CR g 2), S (O) k, O, NR g, CR g OR g, CR g (OR k) CR g 2, CR g ^{_{2 CR g (OR k),}} C (O) CR g 2, CR g 2 C (O), CONR i NR i CO, OC (O), C (O) O, C (S) O, OC (S ^{), C (S) NR g} , NR g C (S), S (O) 2 NR g, NR g S (O) 2, N = N, NR g NR g, NR g CR g 2, NR g CR ^g ₂ , CR ^g ₂ O, OCR ^g ₂ , C≡C or CR ^g = CR ^g ;
G is NR ^e , S or O;
R ^g is H, C _1-6 alkyl, Het-C _0-6 alkyl, C _3-7 cycloalkyl, -C _0-6 alkyl or Ar-C _0-6 alkyl;
R ^k is R ^g , -C (O) R ^g, or -C (O) OR ^f ;
R ⁱ is H, C _1-6 alkyl, Het-C _0-6 alkyl, C _3-7 cycloalkyl, -C _0-6 alkyl, Ar-C _0-6 alkyl, Het- (CH _{2) 0-6} - _{U '- (CH 2) 1-6} -, C 3-7 cycloalkyl, _{- (CH 2) 0-6 -U'} - (CH 2) 1-6 - or Ar- (CH _{2) 0-6} -U '- (CH _{2) 1-6} - or a _{^{halogen, CN, NR g 2, oR}} g, SR g, CO 2 R g , and CO (R ^g) 1 to 3 groups selected from a C _1-6 substituted by ₂ Alkyl;
R ^f is H, C _1-6 alkyl or Ar-C _1-6 alkyl;
R ^e is H, C _1-6 alkyl, Ar-C _1-6 alkyl, Het-C _1-6 alkyl, C _3-7 cycloalkyl, -C _1-6 alkyl, (CH _{2) q} OH or (CH ₂ ) _k CO ₂ R ^g, and;
U 'are each CONR ^f or NR ^f CO;
k is 0, 1 or 2;
q is 1 or 2;
a is 0, 1 or 2;
b is 0, 1 or 2;
R ^b and R ^c are each H, C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, or C _3-6 cycloalkyl, -C _0-6 alkyl, halogen, CF _{3, ^{oR f, S (O) k}} R f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2 N (R f) selected from the _second or, or R ^b and R ^c is in combination with a halogen, CF _3, C _1-4 ^{alkyl, OR f, S (O)} k R f, COR f, CO 2 R f OH, NO 2, N (R f) 2, CO (NR f) _2, and CH ₂ N (R ^f) optionally a substitutent selected from the following three _{2-substituted} 5-membered or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic to form a cyclic ring, or methylenedioxy .
[14" claim-type="Currently amended] 14. The compound of claim 13, wherein the fibrinogen receptor antagonist template A is a compound of formula VI &lt; EMI ID = 27.1 &gt;
&Lt; Formula (VI)

A ¹ through A ⁵ optionally form a saturated or unsaturated, optionally substituted 7-membered ring containing up to two heteroatoms selected from the group of O, S and N, said S and N being optionally oxidized Have;
D ¹ to D ^{4 form} an optionally substituted 6-membered ring optionally containing up to two nitrogen atoms;
R is R ^7, or = O, R ¹¹ or R ⁷ by at least one optionally substituted QC _1-4 alkyl, QC _2-4 alkenyl, wherein is one or more substituents selected from the group of QC _2-4 alkynyl ;
R ^* is H, QC _1-6 alkyl, QC _1-6 alkyl, oxo, QC _2-6 alkenyl, QC _3-4 oxo alkenyl, QC _3-4 alkynyl, oxo, QC _2-4 alkynyl, C _{3 6} cycloalkyl, Ar or Het, which are optionally substituted by one or more R &lt; ^{11 &} gt ;;
Q is H, C _3-6 cycloalkyl, Het or Ar;
R ⁷ is -COR ⁸ , -COCR ' ₂ R ⁹ , -C (S) R ⁸ , -S (O) _m OR', -S (O) _m NR'R " PO (OR ') ₂ , -B (OR') ₂ , -NO ₂ and Tet;
R ⁸ is -OR ', -NR'R ", -NR'SO ₂ R', -NR'OR ', -OCR' ₂ C (O) OR ', -OCR' ₂ OC (O) _{-OCR '2 C (O) NR} ' 2, CF 3 or AA, and;
R ⁹ is OR ', -CN, -S (O ) r R', S (O) m NR '2, -C (O) R'C (O) NR' 2 or -CO ₂ R ', and;
R ¹¹ is H, ^{halo, -OR 12, -CN, -NR'R 12} , -NO 2, -CF 3, CF 3 S (O) r-, -CO 2 R ', -CONR' 2, QC 0 _-6 alkyl -, QC _1-6 alkyl-oxo-, QC _2-6 alkenyl -, QC _2-6 alkynyl -, QC _0-6 alkyloxy -, QC _0-6 alkylamino-or QC _0-6 alkyl -S (O) r-;
R ¹² is -C (O) R ', -C (O) NR' ₂ , -C (O) OR ¹⁵ , -S (O) _m R 'or S (O) _m NR'₂;
R ¹³ is R ', -CF ₃ , -SR' or -OR ';
R ¹⁴ is R ', C (O) R', CN, NO ₂ , SO ₂ R 'or C (O) OR ¹⁵ ;
R ¹⁵ is H, C _1-6 alkyl or Ar-C _0-4 alkyl;
R 'is H, C _1-6 alkyl, C _3-7 cycloalkyl, -C _0-4 alkyl or Ar-C _0-4 alkyl;
R "is R ', -C (O) R', or -C (O) OR ¹⁵ ;
R "'is R" or AA2;
AA1 is an amino acid attached through an amino group and the carboxyl group is optionally protected, AA2 is an amino acid attached through a carboxyl group and the amino group is optionally protected;
m is 1 or 2;
n is from 0 to 3;
p is 0 or 1;
t is from 0 to 2;
[15" claim-type="Currently amended] 15. The method of claim 14,
A ¹ is CR ¹ R ^{1 "} , CR ¹ , NR ¹ , N, O or S (O) _x ;
A ² is CR ² R ^{2 '} , CR ² , NR ² ;
A ³ is CR ³ R ^{3 '} , CR ³ , NR ³ , N, O or S (O) _x ;
A ⁴ is CR ⁴ R ^{4 '} , CR ⁴ , NR ⁴ , or N;
A ⁵ is CR ⁵ R ^{5 '} , CR ⁵ , NR ⁵ , N, O or S (O) _x ;
D ¹ -D ⁴ is CH or N;
R ¹ and R ^{1 '} are R ^* or R, or together are = O;
R ² and R ^{2 '} are R ^* , R or = O;
R ³ and R ^{3 '} are R ^* , R or = O;
R ⁴ and R ^{4 '} are R ^* , R or = O;
R ⁵ and R ^{5 '} are R ^* , R or = O;
wherein x is 0,1 or 2.
[16" claim-type="Currently amended] 15. The compound of claim 14, wherein A ¹ is CR ¹ R ^{1 '} , CR ¹ , NR ¹ , N, O, or S; A ² is CR ² R ^{2 '} , NR ² or CR ² ; A ³ is CR ³ R ^{3 '} ; A ⁴ is CR ⁴ R ^{4 '} , CR ⁴ , NR ⁴ or N; A ⁵ is CR ⁵ R ^{5 '} , CR ⁵ , NR ⁵ , N, O; D ¹ and D ⁴ are CH; D ² or D ³ is CH ⁶ ; R ² or R ⁴ is R; R ³ , R ^{3 '} and R ⁵ , R ^5' are ═O or R ^* , H.
[17" claim-type="Currently amended] 15. The method according to claim 14, wherein, A ¹ is ^{CHR 1, CR 1, NR "} , N or S; A ^'is; A ³ is CR ³ R ^{3' 2} is CR ² or CR ² R ^2, and; A ⁴ is CR ⁴ R ^{4 '} , or NR ⁴ , A ⁵ is CR ⁵ R ^5', and D ¹ -D ⁴ is CH.
[18" claim-type="Currently amended] A compound according to claim 14, wherein A ¹ is CR ¹ , A ² is CR ² , A ³ is C═O, A ⁴ is NR ⁴ and A ⁵ is CHR ⁵ .
[19" claim-type="Currently amended] 15. The method according to claim 14, wherein, A ¹ is a NR ^1, A ² is CHCR ² and, A ³ is CR ³ R ^{3 ',} and, A is ⁴ is NR ⁴ and A ⁵ is C = O compound.
[20" claim-type="Currently amended] 15. The method of claim 14, and A ¹ and A ⁴ is C = O, and A ² is NR ^2, A ³ is CHR ^{3 'and} A ⁵ is NR ⁵ compounds.
[21" claim-type="Currently amended] 15. The method of claim 14, and A ¹ is NR ^1, and A ² is CHR ^2, and A ³ is C = O, A ⁴ is NR ', and A ⁵ is CHR ⁵ in the compound.
[22" claim-type="Currently amended] 15. Compounds of formula VIa-VIi according to claim 14.
&Lt; Formula VIa &

(VIb)

<Formula VIc>

<Formula (VId)

<Formula VIe>

<Formula VIf>

<Formula VI>

(VI)

&Lt; Formula (VIII)

[23" claim-type="Currently amended] 15. The compound of claim 14, wherein R &lt; 1 &gt;

[24" claim-type="Currently amended] 24. The method of claim 23 wherein, R ¹ is H or C _1-4 alkyl; R ² , R ^{2 '} is H, -CH ₂ CO ₂ H; R ⁵ R ^{5 '} is H, H.
[25" claim-type="Currently amended] A compound selected from the group:
5 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -1H-benzimidazole-2-aminoacetic acid;
Methyl] amino] carbonyl] -4- (3,3-dimethylbutyl) - (2-methylbenzyl) 3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-7 - [[[(5-trifluoromethylbenzimidazol- ] -1H-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4,7-dimethoxybenzimidazol-2- yl) methyl] - methylamino] carbonyl] -Oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(3,3-dimethylbutyl) -3, 3, 4-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -4- -Oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-methylbenzimidazol-2-yl) methyl] methylamino] carbonyl] -4-methyl- -1,4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol-2-yl) methyl] -N- (4-aminobutyl) amino] carbonyl] -4- Methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol-2-yl) methyl] -N- (2- cyanomethyl) amino] carbonyl] -Methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -1H-l, 4-benzodiazepin-2-acetic acid;
4 - [[[3- (benzimidazol-2-yl) propyl] amino] carbonyl] piperidine-1-acetic acid;
4 - [[[3- (benzimidazol-2-yl) propyl] amino] carbonyl] phenylacetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5,7-dimethylbenzimidazol-2- yl) methyl] methylamino] carbonyl] -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
Methyl] amino] carbonyl] -4- [2- (3,4-methylenedioxy) benzyl] Oxyphenyl) ethyl] -3-oxo-1H-1, 4-benzodiazepin-2-acetic acid;
Methyl] amino] carbonyl] -4- (2-methoxyethyl) -3-oxo &lt; RTI ID = 0.0 & -1H-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] 4-benzodiazepin-2-acetamide;
Yl] methyl] amino] carbonyl] -2-methyl-1H-pyrazolo [3,4-d] pyrimidin- -4-methyl-3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] -3-oxo-1H-1,4-benzodiazepin- 2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[bis [(benzimidazol-2-yl) methyl] amino] carbonyl] -4- 4-benzodiazepin-2-acetic acid;
Methyl] methylamino] carbonyl] -4- (3,3-dimethylbutyl) -2,3,4,5-tetrahydro-7 - [[[ ) -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
Methyl) amino] carbonyl] -3-oxo-4- (2,2,2 &lt; RTI ID = 0.0 & -Trifluoroethyl) -lH-l, 4-benzodiazepin-2-acetic acid;
(2-phenylethyl) -lH-indol-2-yl) acetyl] amino] -5-oxo-4- 1,4-benzodiazepin-2-acetic acid;
Methyl] amino] carbonyl] -3-oxo-4- (2,2,2-trifluoroethyl) Trifluoroethyl) -1H-1,4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(5,6-difluorobenzimidazol-2-yl) methyl] methylamino] carbonyl] -Oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(2-phenylethyl) -2,3,4,5-tetrahydro-7 - [[bis [(benzimidazol-2-yl) methyl] amino] carbonyl] -1H-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] amino] carbonyl] Oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-4-methyl-7- [[[(4-nitrobenzimidazol-2-yl) methyl] methylamino] carbonyl] -1,4-benzodiazepin-2-acetic acid;
Methyl] amino] carbonyl] -3-oxo-4- (2-methylbenzyl) (2,2,2-trifluoroethyl) -1H-1,4-benzodiazepin-2-acetic acid;
() -4- [4 - [[[(1H-benzimidazol-2-yl) methyl] methylamino] carbonyl] phenyl] -3-phenylbutanoic acid;
(±) -3 - [[[4- (4-azabenzimidazol-2-yl) butanoyl] glycyl] amino] -4-pentenoic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[[1- (2-hydroxyethyl) benzimidazol-2- yl] methyl] amino] carbonyl] 3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
Methyl] amino] carbonyl] -4- (2-methoxybenzyl) -2,3,4,5-tetrahydro-7 - [[[ Ethoxyethyl) -3-oxo-lH-l, 4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aminobenzimidazol-2-yl) methyl] methylamino] carbonyl] -4-methyl- -1,4-benzodiazepin-2-acetic acid;
Methyl (3-methyl-3-oxo-1H-1 , 4-benzodiazepine-2-acetate;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] methylamino] carbonyl] 4-benzodiazepin-2-acetic acid, [(2,2-dimethyl-2-methoxyacetyl) oxy] methyl ester;
Ethyl] methylamino] carbonyl] -4-methyl-3-oxo-1 H-1, 2-benzothiazol- 4-Benzodiazepine- (2S) -acetic acid;
(±) -N- [2- (aminomethyl) -4 - [[[(4-aza-5-methylbenzimidazol-2-yl) methyl] methylamino] carbonyl] phenyl] aspartic acid;
(Methyl) amino] carbonyl] -1H-1, 2-dihydroxy- 4-benzodiazepin-2-acetic acid;
Yl) phenyl] -4-methyl-3-oxo-1H-1,4-benzodiazepin-2- Acetic acid;
() -4- [4 - [[[(Benzimidazol-2-yl) methyl] methylamino] carbonyl] phenyl] -3- (dimethylaminocarbonyl) butanoic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -3-oxo-4- [2- Yl) ethyl] -1H-1,4-benzodiazepine-2-acetate;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2-yl) methyl] methylamino] carbonyl] -1,4-benzodiazepin-2-acetic acid;
(2-hydroxybenzoyl) amino] &lt; RTI ID = 0.0 &gt; butyl] Amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepin-2-acetic acid;
(-) - 2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol- Benzoyl) amino] butyl] amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepin-2-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2- yl) methyl] amino] carbonyl] -Oxo-lH-l, 4-benzodiazepine-2-acetate;
Methyl] -N - [[[(+) - biotin oil] amino] butyl] amino] carbonyl ] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine- (2RS) -acetic acid;
Ethyl] methylamino] carbonyl] -4-methyl-3-oxo-1 H-1, 2-benzothiazol- 4-Benzodiazepine- (2S) -acetic acid;
Yl) methyl] methylamino] carbonyl] -4-methyl-3- (4-methoxyphenyl) Oxo-lH-l, 4-benzodiazepine-2S-acetic acid;
(S) -2,3,4,5-tetrahydro-7 - [[[(benzimidazol-2-yl) methyl] amino] carbonyl] -3-oxo-1H-1,4-benzodiazepine- 2S) -acetic acid;
(3-oxo-4- (2-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin- ) -1H-1,4-benzodiazepin-2-yl] methyl] tetrazole;
(S) -2,3,4,5-tetrahydro-7 - [[[(4-aza-5-methylbenzimidazol-2-yl) methyl] amino] carbonyl] 1,4-benzodiazepin-2-acetic acid;
Methyl-3-oxo-1H-1, 4-benzodiazepin-2-yl) propyl] Acetic acid;
(4-aminobutyl) amino] carbonyl] -3- (4-fluorobenzyl) Oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepine-2-acetic acid;
(Methyl) amino] carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine -Benzodiazepin-2- (N-hydroxy) acetamide;
Ethyl (±) -3 - [[[2- (benzimidazol-2-yl) ethyl] amino] succinol] amino-4-pentenoate;
() -3 - [[[2- (Benzimidazol-2-yl) ethyl] amino] succinol] amino-4-pentenoic acid;
(-) - 2,3,4,5-tetrahydro-7 - [[N - [(benzimidazol- -2-hydroxybenzoyl) amino] butyl] amino] carbonyl] -3-oxo-4- (2-phenylethyl) -1H-1,4-benzodiazepin-2-acetic acid;
Ethyl] amino] carbonyl] -4-methyl-3-oxo-1H-1,4-benzodiazepine - benzodiazepine- (2S) -acetic acid;
Ethyl] amino] carbonyl] -4-methyl-3-oxo-1H-1,4-benzoimidazo [ - benzodiazepine- (2S) -acetic acid;
Methyl] methylamino] carbonyl] -2,3,4,5-tetrahydro-4-methyl-3 (1H) -imidazo [ -Oxo-lH-l, 4-benzodiazepin-2-acetic acid;
Or a pharmaceutically acceptable salt thereof.
[26" claim-type="Currently amended] A compound selected from the group:
3 - [[3- [2- (benzimidazol-2-yl) ethyl] isooxazolin-5 (R, S) -yl] acetyl] amino-3 (R, S) -methylpropanoic acid;
Methyl] amino] carbonyl] -1-methyl-2,5-dioxo-1H-1,4-benzodiazepin- Benzodiazepine} -4-propanoic acid;
3- {4H-imidazo [1,2-a] [1,4] benzodiazepine-5 (6H) Methylamino] carbonyl]} - 4-propanoic acid;
4- [4- [2- (1H-benzimidazol-2-yl) ethyl] -1-piperazinyl] -1-piperidine acetic acid;
1-hydroxy-4- [4- [3- (1H-benzimidazol-2-yl) propyl] -1-piperazinyl] -cyclohexanoic acid;
N- [3- [1 - [[2- (2-benzimidazolyl) ethyl] carbonyl] piperidinyl] carbonyl] - [beta] -alanine;
2 - [(benzimidazol-2-yl) methyl] -5- [2- (carboxy-ethyl) amino] carbonyl] -2,3-dihydro-3-oxo-1-isoindole;
[3 (R) - [2- (Benzimidazol-2-yl) ethyl] -2-oxopiperidinyl] acetyl-3 (R) -methyl- [beta] -alanine;
4 - [[[[2- (benzimidazolyl) methyl] carbonyl] methylamino] acetyl] phenoxyacetic acid;
4 - [[[[2- (benzimidazolyl) methyl] carbonyl] methylamino] acetyl] - 1, 2-phenylenedioxydiacetic acid;
N- [3 - [[[(2-benzimidazolyl) methyl] carbonyl] amino] benzoyl] - - alanine;
[[1- [N - [[(2-benzimidazolyl) methyl] carbonyl] thyloyl] -4-piperidinyl] oxy] acetic acid;
(S) -4 - [[[(2-benzimidazolyl) methyl] carbonyl] glycyl] -3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid;
(3S, 5S) -5 - [[4 - [(2-Benzimidazolyl) methyl] phenyl] oxymethyl] -3-carboxymethyl-2-pyrrolidinone;
1 - [(2-benzimidazolyl) methyl] -3- [4- (2-carboxyethyl) phenyl] -4-methoxy-3-pyrrolin-2-one;
2- [6- (benzimidazol-2-yl) methylaminocarbonyl) -1,2,3,4-tetrahydroisoquinolinyl] acetic acid;
2- [6- (Benzimidazol-2-yl) methylaminocarbonyl) -1-oxo-1,2,3,4-tetrahydroisoquinolinyl] acetic acid;
2- [6 - ((Benzimidazol-2-yl) methylcarbonylamino) tetralin] acetic acid;
2- [6 - ((Benzimidazol-2-yl) methylaminocarbonyl) tetralin] acetic acid;
2- [5 - ((Benzimidazol-2-yl) methylcarbonylamino) -benzofuran] -propionic acid;
2- [5 - ((Benzimidazol-2-yl) methylcarbonylamino) -2,3-dihydro-benzofuran] -propionic acid;
2- [5- (6-aminopyridinyl-2-methylaminocarbonyl) benzofuran] -propionic acid;
2- [5 - ((Benzimidazol-2-yl) methylaminocarbonyl) -2,3-dihydro-benzofuran] -propionic acid; or
1 - [(1 H-benzimidazol-2-yl) methyl] -3- {4 - [(2- ethoxycarbonyl) ethyl]] phenyl} -3-oxo-imidazoline
Or a pharmaceutically acceptable salt thereof.
[27" claim-type="Currently amended] 26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 26.
[28" claim-type="Currently amended] A method of inhibiting a bitonectin receptor in a mammal comprising administering an effective amount of a compound according to formula I or II or III or IV or V defined in claim 1.
[29" claim-type="Currently amended] 29. The method of claim 28, wherein the compound inhibits the vitronectin receptor to a Ki in a bitronectin receptor that is ten times greater than Ki at the fibrinogen receptor.
[30" claim-type="Currently amended] 29. The method of claim 28, wherein the compound inhibits the vitronectin receptor to a Ki in a bitronectin receptor that is 30 times greater than Ki at the fibrinogen receptor.
[31" claim-type="Currently amended] 29. The method of claim 28, wherein the compound inhibits the vitronectin receptor to a Ki in a neurotransmitter that is 100 times greater than Ki at the fibrinogen receptor.
[32" claim-type="Currently amended] 29. The method of claim 28, wherein bone resorption is a factor.
[33" claim-type="Currently amended] 29. The method of claim 28, wherein the osteoporosis, inflammation, stenosis or atherosclerosis is treated.
[34" claim-type="Currently amended] A method of inhibiting a bitonectin receptor in a mammal, comprising administering an effective amount of a compound according to formula (XXI) or (XXII) as defined in claim 13.
[35" claim-type="Currently amended] 35. The method of claim 34, wherein the compound inhibits the vitronectin receptor to a Ki in a neurotransmitter that is ten times greater than Ki at the fibrinogen receptor.
[36" claim-type="Currently amended] 35. The method of claim 34, wherein the compound inhibits the vitronectin receptor to Ki in a bitronectin receptor that is 30 times greater than Ki in the fibrinogen receptor.
[37" claim-type="Currently amended] 35. The method of claim 34, wherein the compound inhibits the vitronectin receptor with a Ki in a neurotransmitter that is 100 times greater than Ki at the fibrinogen receptor.
[38" claim-type="Currently amended] 35. The method of claim 34, wherein bone resorption is a factor.
[39" claim-type="Currently amended] 35. The method of claim 34, wherein the method is for the treatment of osteoporosis, inflammation, stenosis or arteriosclerosis.
[40" claim-type="Currently amended] 26. A method of inhibiting a bitronectin receptor in a mammal comprising administering an effective amount of a compound according to claim 25.
[41" claim-type="Currently amended] 41. The method of claim 40, wherein the compound inhibits the vitronectin receptor to a Ki in a neurotransmitter that is ten times greater than Ki at the fibrinogen receptor.
[42" claim-type="Currently amended] 41. The method of claim 40, wherein the compound inhibits the vitronectin receptor to a Ki in a bitronectin receptor that is 30 times greater than Ki in a fibrinogen receptor.
[43" claim-type="Currently amended] 41. The method of claim 40, wherein the compound inhibits the vitronectin receptor to Ki in a neurotransmitter that is 100 times greater than Ki at the fibrinogen receptor.
[44" claim-type="Currently amended] 41. The method of claim 40, wherein bone resorption is a factor.
[45" claim-type="Currently amended] 41. The method of claim 40, wherein the method is for the treatment of osteoporosis, inflammation, stenosis or arteriosclerosis.
[46" claim-type="Currently amended] 26. Use of a compound according to any one of claims 1 to 26 for the manufacture of a medicament.
[47" claim-type="Currently amended] 26. The use of a compound according to any one of claims 1 to 26 for the manufacture of a medicament for inhibiting vitronectin in a mammal in need thereof.
[48" claim-type="Currently amended] 26. The use of a compound according to any one of claims 1 to 26 for the manufacture of a medicament for the treatment of a disease in which bone resorption is a factor.
[49" claim-type="Currently amended] 26. The use of a compound according to any one of claims 1 to 26 for the manufacture of a medicament for the treatment of osteoporosis, inflammation, stenosis or atherosclerosis.
[50" claim-type="Currently amended] (i) for a compound of formula (I) wherein R &lt; 1 &gt; and R &lt; 2 &gt; are as defined hereinbefore, with a compound of formula (Ib) or

L "-A
(Wherein,
R ^b , R ^c , R ^f and A are as defined in formula I with any reactive functional group protected;
L '"and L and may be a group that reacts to form an amide bond in the W part, or L' is phenyl substituted by -SnBu _3, L" is halo).
(ii) for a compound of formula (II): reacting a compound of formula (IIa): &lt; EMI ID = 31.1 &gt; with a compound of formula (Ib), followed by removal of any protecting group and optionally forming a pharmaceutically acceptable salt; or
<Formula IIa>

(Ib)
L "-A
(Wherein,
R^b, R^c, G And A is as defined in formula I with any reactive functional group protected;
L '"and L and may be a group that reacts to form an amide bond in the W part, or L' is phenyl substituted by -SnBu _3, L" is halo).
(iii) for a compound of formula (III): reacting a compound of formula (IIIa): &lt; EMI ID = 31.1 &gt; with a compound of formula (Ib), followed by removal of any protecting group and optionally forming a pharmaceutically acceptable salt; or

(Ib)
L "-A
(Wherein,
R ^b , R ^c , R ^e and A are as defined in formula I with any reactive functional group protected;
L 'and L "may be a group that reacts to form an amide bond in the W part, or L' is phenyl substituted by -SnBu ₃ L" is halo)
(iv) for a compound of formula (IV): wherein R 1 and R 2 are as defined above, with a compound of formula (Ib): wherein R 1 and R 2 are as hereinbefore defined; or

(Ib)
L "-A
(Wherein,
R ^g , R ^e , and A are as defined in formula I with any reactive functional group protected;
L '"and L and may be a group that reacts to form an amide bond in the W part, or L' is phenyl substituted by -SnBu _3, L" is halo).
(v) for a compound of formula (V): reacting a compound of formula (Va) wherein R &lt; 1 &gt;

(Ib)
L "-A
(Wherein,
R ^g , R ^e , and A are as defined in formula I with any reactive functional group protected;
L '"and L and may be a group that reacts to form an amide bond in the W part, or L' is phenyl substituted by -SnBu _3, L" is halo).
Lt; RTI ID = 0.0 &gt; III &lt; / RTI &gt; or IV or V, or a pharmaceutically acceptable salt thereof.
(I)

&Lt;

(III)

(IV)

(V)

Wherein,
W is - (CHR ^g ) _b -V'- or phenyl;
A is a fibrinogen receptor antagonist template;
V 'is CONR ²¹ or NR ²¹ CO;
G is NR ^e , S or O;
R ^g is H, C _1-6 alkyl, Het-C _0-6 alkyl, C _3-7 cycloalkyl, -C _0-6 alkyl or Ar-C _0-6 alkyl;
R ²¹ is _{Het- (CH 2) 0-6 -U '} - (CH 2) 1-6 -, C 3-7 cycloalkyl, _{- (CH 2) 0-6 -U'} - (CH 2) 1-6 - or Ar- (CH ₂ ) _0-6- U '- (CH ₂ ) _1-6 -;
U 'is CONR ^f or NR ^f CO;
R ^f is H, C _1-6 alkyl or Ar-C _1-6 alkyl;
R ^e is H, C _1-6 alkyl, Ar-C _1-6 alkyl, Het-C _1-6 alkyl, C _3-7 cycloalkyl, -C _1-6 alkyl, (CH _{2) q} OH or (CH ₂ ) _k CO ₂ R ^g, and;
k is 0, 1 or 2;
q is 1 or 2;
b is 0, 1 or 2;
R ^b and R ^c are each H, C _1-6 alkyl, Ar-C _0-6 alkyl, Het-C _0-6 alkyl, or C _3-6 cycloalkyl, -C _0-6 alkyl, halogen, CF _{3, ^{oR f, S (O) k}} R f, COR f, NO 2, N (R f) 2, CO (NR f) 2, CH 2 N (R f) selected from the _second or, or R ^b and R ^c is in combination with a halogen, CF _3, C _1-4 ^{alkyl, OR f, S (O)} k R f, COR f, CO 2 R f OH, NO 2, N (R f) 2, CO (NR f) _2, and CH ₂ N (R ^f) optionally a substitutent selected from the following three _{2-substituted} 5-membered or 6-membered aromatic or non-aromatic carbocyclic or heterocyclic to form a cyclic ring, or methylenedioxy .
[51" claim-type="Currently amended] Comprising the step of reacting a compound of formula (XXV): &lt; EMI ID = 31.1 &gt; with a compound of formula (XXVI), followed by removal of any protecting group and optionally forming a pharmaceutically acceptable salt.

L ⁴ -A
Wherein,
A is as defined in claim 13 with any reactive functional group protected;
L ³ and L ⁴ are groups which react to form a covalent bond at the B moiety.
&Lt; Formula (XXI)

Wherein,
A and B are as defined in claim 13.
[52" claim-type="Currently amended] Comprising the step of reacting a compound of formula (XXVII): &lt; EMI ID = 31.1 &gt; with a compound of formula (XXVIII), followed by removal of any protecting group and optionally forming a pharmaceutically acceptable salt.

L ⁶ -A
Wherein,
A and G are as defined above with the proviso that any reactive functional group is protected;
L ⁵ and L ⁶ are groups that react to form a covalent bond at the B moiety.
(XXII)

Wherein,
A, B and G are as defined in claim 13.

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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:
1995-12-29|Priority to US936695P

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1995-12-29|Priority to US60/009,366

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1996-12-20|Application filed by 스티븐 베네티아너, 스미스클라인 비참 코포레이션

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1999-10-25|Publication of KR19990076878A

优先权:

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申请号 | 申请日 | 专利标题

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US936695P| true| 1995-12-29|1995-12-29|

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US60/009,366|1995-12-29|