MXPA06009771A - Caspase inhibitors and uses thereof - Google Patents
Caspase inhibitors and uses thereofInfo
- Publication number
- MXPA06009771A MXPA06009771A MXPA/A/2006/009771A MXPA06009771A MXPA06009771A MX PA06009771 A MXPA06009771 A MX PA06009771A MX PA06009771 A MXPA06009771 A MX PA06009771A MX PA06009771 A MXPA06009771 A MX PA06009771A
- Authority
- MX
- Mexico
- Prior art keywords
- compound
- formula
- disease
- compound according
- carboxylic acid
- Prior art date
Links
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- 239000007921 spray Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000707 stereoselective Effects 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- GXDPEHGCHUDUFE-UHFFFAOYSA-N sulfanylmethanol Chemical compound OCS GXDPEHGCHUDUFE-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KMUQLNSVLPPTEO-GDVGLLTNSA-N tert-butyl (2S)-3-amino-2-hydroxybutanoate Chemical compound CC(N)[C@H](O)C(=O)OC(C)(C)C KMUQLNSVLPPTEO-GDVGLLTNSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960000103 thrombolytic agents Drugs 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical compound CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Abstract
The present invention provides a compound of formula (I):wherein the variables are as defined herein. The present invention also provides processes for preparing the compounds of formula (I), and intermediates thereof, pharmaceutical compositions comprising those compounds, and methods of using the compounds and compositions.
Description
CASPASA INHIBITORS AND USES OF THEM
FIELD OF THE INVENTION This invention relates to compounds, and compositions thereof, that are useful as caspase inhibitors. This invention also relates to the processes for preparing these compounds. This invention further relates to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions thereof for the treatment of diseases and disorders related to conditions caused by caspase.
BACKGROUND OF THE INVENTION Caspases are a family of cysteine protease enzymes that are the key suppliers in inflammation. Caspase-1 (ICE) processes pre-IL-lβ to produce the active form of IL-1β [WO 99/47545]. ICE has also been linked to the conversion of pro-IGIF to IGIF and / or to the production of IFN-? [Id.] Both IL-β and IFN-? they contribute to the pathology associated with inflammatory, infectious, and autoimmune diseases (see, for example, WO 99/47545; J.
Invest. Dermatology, 120 (1), pp. 164-167 (2003); Br. J. Derma tology, 141, p. 739-746 (1999); Science, 282, pp. 490-493 (1998); Schweiz. Med. Wochenschr., 130, pp. 1656-1661 (2000)]. Caspases are also key suppliers in the signaling pathways for apoptosis and cell disassembly [N.A. Thornberry, Chem. Biol. , 5, pp. R97-R103 (1998)). These signaling trajectories vary depending on the cell type and stimulus, although all apoptosis trajectories appear to converge on a common effector path that leads to the proteolysis of important proteins. Caspases are involved both in the effector phase of the signaling path and in the additional 5 'direction in its initiation. The caspases in the 5 'direction involved in the initiation events are activated and in turn activate other caspases that are' involved in the later stages of apoptosis. The utility of caspase inhibitors to treat a variety of disease states in mammals associated with an increase in cellular apoptosis has been demonstrated using peptide caspase inhibitors. For example, in rodent models, it has been shown that caspase inhibitors reduce the intensity of infarction and inhibit cardiomyocytic apoptosis after myocardial infarction, reduce the volume of the lesion and the neurological deficit resulting from stroke, to reduce Post-traumatic apoptosis and neurological deficit in traumatic brain injury are effective in the treatment of fulminant hepatic destruction and improve survival after endotoxic shock. [H. Yaoita et al., Circulation,
97, pp. 276-281 (1998); M. Endres et al., J. Cerebral
Blood Flow and Metabolism, 18, pp. 238-247, (1998);
Y. Cheng et al., J. Clin. Invest. , 101, pp. 1992-1999
(1998); A.G. Yakovlev et al., J Neuroscience, 17, pp. 7415-7424 (1997); I. Rodriquez et al., J. Exp. Med., 184, pp. 2067-2072 (1996); Grobmyer et al., Mol. Med., 5, 585 (1999). However, due to their peptide nature, these inhibitors are typically characterized by undesirable pharmacological properties, such as, for example, deficient cellular penetration and cellular activity, poor oral absorption, poor stability and rapid metabolism [J.J. Plattner and D.W. Norbeck, in Drug Discovery Technologies, C.R. Clark and W.H. Moos, Eds.
(Ellis Horwood, Chichester, England, 1990), pp. 92-126]. This has hindered its development into effective drugs. These and other studies with caspase peptide inhibitors have shown that a residue of aspartic acid is involved in a key interaction with the caspase enzyme [K.P. Wilson et al., Nature, 370, pp. 270-275 (1994); Lazebnik et al., Nature, 371, p. 346 (1994)]. Accordingly, peptidyl and peptidyl-free aspartic acid compounds are useful as caspase inhibitors. However, there is a need for compounds that have the ability to act as caspase inhibitors, in particular with selective activity against certain caspases.
BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound of the formula I:
where the variables are as defined in the present. The present invention also provides processes for preparing these compounds, compositions, pharmaceutical compositions, and methods for using these compounds and compositions to inhibit caspases. These compounds are in particular useful as selective caspase-l / capase-8 inhibitors.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of the formula I:
where :
"R is R3C (0) -, HC (O), R3S02-, R3OC (0), (R3) 2NC (0), (R3) (H) NC (O), R3C (0) C (0) - , R3 -, (R3) 2NC (0) C (O), (R3) (H) NC (O) C (O), or R3OC (O) C (O) -; R1 is H, aliphatic, cycloaliphatic, aryl, heterocyclyl, heteroaryl, cycloalkyl-aliphatic-, cycloalkenyl-aliphatic-, aryl-aliphatic-, heterocyclyl-aliphatic-, or heteroaryl-aliphatic-, wherein any hydrogen atom is optionally and independently replaced by R8 and any set of two Hydrogen atoms attached to the same atom are optionally and independently replaced by carbonyl; Ring A is:
wherein, in each ring, any hydrogen atom is optionally and independently replaced by R4 and any set of two hydrogen atoms attached to the same atom is optionally and independently replaced by carbonyl; R3 is aliphatic, cycloaliphatic, aryl, heterocyclyl, heteroaryl, cycloaliphatic-aliphatic-, aryl-aliphatic-, heterocyclyl-aliphatic-, or heteroaryl-aliphatic-; or two R3 groups attached thereto together with that atom form an aromatic or non-aromatic 3-10 membered ring; wherein any ring is optionally fused to an aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein up to 3 aliphatic carbon atoms can be replaced by a group selected from O, N, NR9, S, SO, and S02, wherein R3 is substituted with up to 6 substituents independently selected from R8; R4 is halogen, -OR9, -N02, -CN, -CF3, -OCF3, -R9, .1, 2-methylenedioxy, 1,2-ethylenedioxy, -N (R9) 2, -SR9, -SOR9, -S02R9 , -S02N (R9) 2, -S03R9, -C (0) R9, -C (0) C (0) R9, -C (O) C (0) OR9, -C (O) C (0) N (R9) 2, - C (O) CH2C (O) R9, -C (S) R9, -C (S) OR9, -C (0) OR9, -OC (0) R9, -C (0) N (R9) 2, -OC (0) N (R9) 2, -C (S) N (R9) 2, - (CH2) 0-2NHC (O) R9, -N (R9) N (R9) COR9, -N (R9) N (R9) C (O) OR9,
-N (R9) N (R9) CON (R9) 2, -N (R9) S02R9, • -N (R9) S02N (R9) 2, -N (R9) C (O) OR9, -N (R9) C (0) R9, -N (R9) C (S) R9,
-N (R9) C (O) N (R9) 2, -N (R9) C (S) N (R9) 2, -N (COR9) COR9, -N (OR9) R9, -C (= NH) N (R9) 2, - C (O) N (OR9) R9, -C (= NOR9) R9, -OP (O) (OR9) 2, -P (O) (R9) 2, -P (0) (OR9) 2, or - P (O) (H) (OR9); R2 is -C (R5) (R6) (R7), aryl, heteroaryl, or C3_7 cycloalkyl; R5 is H or a C? -6 straight or branched chain alkyl;
R5 is H or a straight or branched C6-6 alkyl; R7 is -CF3, -C3-7cycloalkyl, aryl, heteroaryl, heterocycle, or a straight or branched C6-6 alkyl, wherein each carbon atom of the alkyl is optionally and independently substituted with R10; OR R5 and R7 taken together with the carbon atom to which they are attached form a cycloaliphatic of 3-10 members; R8 and R8 'each are independently halogen, -OR9, -N02, -CN, -CF3, -0CF3, -R9, 1,2-methylenedioxy, 1,2-ethylenedioxy, -N (R9) 2, -SR9, -SOR9, -S02R9, -S02N (R9) 2, -S03R9, -C (0) R9, -C (0) C (0) R9, -C (O) C (0) OR9, -C (O) C (0) N (R9) 2, -C (O) CH2C (O) R9, -C (S) R9, -C (S) OR9, -C (0) OR9, -OC (0) R9, - C (0) N (R9) 2, -OC (0) N (R9) 2, -C (S) N (R9) 2, - (CH2) or-2NHC (0) R9, -N (R9) N (R9) COR9, -? (R9)? (R9) C (0) OR9,
-? (R9)? (R9) CO? (R9) 2, -? (R9) S02R9, -? (R9) S02? (R9) 2, -? (R9) C (O) OR9, -? (R9) C (0) R9, -? (R9) C (S) R9,
-? (R9) C (O)? (R9) 2, -? (R9) C (S)? (R9) 2, -? (COR9) COR9, -? (OR9) R9, -C (=? H)? (R9) 2, - C (O)? (OR9) R9, -C (=? OR9) R9, -OP (O) (OR9) 2, -P (0) (R9) 2, -P (0) (OR9) 2, and -P (O) (H) (OR9); R9 is hydrogen, aliphatic, cycloaliphatic, aryl, heterocyclyl, heteroaryl, cycloaliphatic-aliphatic-, aryl-aliphatic, heterocyclyl-aliphatic, or heteroaryl-aliphatic-; wherein any hydrogen atom is optionally and independently replaced by R8 and any set of two hydrogen atoms attached to the same atom is optionally and independently replaced by carbonyl; R10 is halogen, -OR11, -N02, -CN, -CF3, -OCF3, -R11, or -SR11; wherein R11 is C? _ -aliphatic-. The present invention also provides a compound of formula II:
II
where
R1 is H, aliphatic, cycloalkyl (for example, cyclopentyl), cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-aliphatic-cycloalkenyl-aliphatic-, aryl-aliphatic-, heterocyclyl-aliphatic-, or heteroaryl-aliphatic-, wherein hydrogen atom is optionally and independently replaced by R8 and any set of two hydrogen atoms attached to the same atom is optionally and independently replaced by carbonyl; The anil lo A is:
? • n / uv r JJLyJ. ? r ivwf JJU
wherein, in each ring, any hydrogen atom is optionally and independently replaced by R4 and any set of two hydrogen atoms attached to the same atom is optionally and independently replaced by carbonyl (or in an alternative embodiment, carbonyl or (C3-C6) ) Spirocycle;) R4 is halogen, -OR9, -N02, -CN, -CF3, -OCF3, -R9, 1, 2-methylenedioxy, 1,2-ethylenedioxy, -N (R9) 2, -SR9, -SOR9 , -S02R9, -S02N (R9) 2, -S03R9, -C (0) R9, -C (0) C (0) R9, -C (O) C (0) 0R9, -C (0) C ( 0) N (R9) 2, -C (O) CH2C (O) R9, -C (S) R9, -C (S) OR9, -C (0) 0R9, -0C (0) R9, -C ( 0) N (R9) 2, -0C (0) N (R9) 2, -C (S) N (R9) 2, - (CH2) or-2NHC (0) R9, -N (R9) N (R9) ) COR9, -N (R9) N (R9) C (0) OR9, -N (R9) N (R9) CON (R9) 2, -N (R9) S02R9, -N (R9) S02N (R9) 2 , -N (R9) C (O) OR9, -N (R9) C (O) R9, -N (R9) C (S) R9, -N (R9) C (O) N (R9) 2, - N (R9) C (S) N (R9) 2, -N (COR9) COR9, -N (OR9) R9,
- C (= NH) N (R9) 2, -C (0)? (OR9) R9, - C (= NOR9) R9, -OP (O) (OR9) 2, -P (0) (R9) 2 , -P (0) (OR9) 2, or -P (0) (H) (OR9); R2 is -C (R5) (R6) (R7), aryl, heteroaryl, or
-C3-7 cycloalkyl; R5 is H or a C .6 straight or branched chain alkyl; R6 is H or a C ?. straight or branched chain alkyl; R7 is -CF3, -C3-7 cycloalkyl, aryl, heteroaryl, heterocycle, or a straight or branched chain alkyl, wherein each carbon atom of the alkyl is optionally and independently substituted with R10; (or in an alternative embodiment, R5 and R7 taken together with the carbon atom to which they are attached form a cycloaliphatic of 3-10 members); R3 is phenyl, thiophene, or pyridine, wherein each ring is optionally substituted with up to 5 groups independently selected from R8 ', and wherein at least one position on the phenyl, thiophene, or pyridine adjacent to the bond x is replaced by R12, wherein R12 has no more than 5 straight chain atoms;
R8 and R8 are each independently halogen, -OR9, -N02, -CN, -CF3, -OCF3, -R9, 1,2-methylenedioxy, 1,2-ethylenedioxy, -N (R9) 2, -SR9, - SOR9, -S02R9, -S02N (R9) 2, -S03R9, -C (0) R9, -C (0) C (0) R9, -C (O) C (0) OR9, -C (0) C (0) N (R9) 2, -C (O) CH2C (O) R9, -C (S) R9, -C (S) OR9, -C (0) OR9, -OC (0) R9, -C (0) N (R9) 2, -OC (0) N (R9) 2, -C (S) N (R9) 2, - (CH2) 0-2NHC (O) R9, -N (R9) N ( R9) COR9, -N (R9) N (R9) C (O) OR9,
-N (R9) N (R9) CON (R9) 2, -? (R9) S02R9, -? (R9) S02? (R9) 2, -? (R9) C (O) OR9, -? (R9) C (0) R9, -? (R9) C (S) R9,
-? (R9) C (O)? (R9) 2, -? (R9) C (S)? (R9) 2, -? (COR9) COR9,
-? (OR9) R9, -C (=? H)? (R9) 2, - C (O)? (OR9) R9, -C (=? OR9) R9,
-OP (O) (OR9) 2, -P (O) (R9) 2, -P (O) (OR9) 2, and -P (O) (H) (OR9); R9 is hydrogen, aliphatic, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloaliphatic-aliphatic-, aryloaliphatic, heterocyclic-aliphatic, or heteroaryl-aliphatic;
(in certain embodiments, any hydrogen atom of R9 is optionally and independently replaced by R8 and any set of two hydrogen atoms attached to the same atom is optionally and independently replaced by carbonyl, with the proviso that if R9 is replaced with an R8 , wherein R8 comprises a substituent R9, then that substituent R9 is not substituted with R8);
R10 is halogen, - OR11, -N02, - CN, - CF3, -OCF3,
, 11 OR -SR 11 R is C? -4 - to the physical f? -; and R12 is halogen, -OR11, -N02, -CN, -CF3, -OCF3, -R11, -SR9. In the sense in which it is used in the definition of R12, "straight chain atoms" refers to atoms that are linearly linked, regardless of whether those atoms have also been bound or not in a branched form. According to this definition, an ethyl group and a trifluoromethoxy group each have three straight chain atoms, and a methyl group has two straight chain atoms. In the previous embodiment, R12 has no more than 5 straight chain atoms. In two different embodiments, R12 has no more than 4 straight-chain atoms and no more than 3 straight-chain atoms. Still in other embodiments, R12 has 2 straight chain atoms or 1 atom. In the sense in which it is used in the present, a position adjacent to the junction x refers to a position that is located next to the position in which x is joined. In an aryl ring, this position is often referred to as the "ortho position" or, in the case of a phenyl ring, it may be referred to as "position 2". By way of example, in the following structures, R12 is attached to the rings of phenyl, thiophene, and pyridine in "the position adjacent to the junction x".
In one embodiment of this invention, R is
R3C (0) In some embodiments, R3 is optionally substituted C6-? Or aryl or heteroaryl. In other embodiments R3 is phenyl optionally substituted. In still other embodiments, R3 is optionally substituted heteroaryl of 8-10 members (ie, quinoline, isoquinoline, or quinazoline). In still other embodiments, R3 is an optionally substituted 5-6 membered heteroaryl (ie, pyridyl, pyrimidyl, pyrazinyl, thiophenyl, furanyl, thiazolyl).
In some embodiments, R3 is optionally and independently substituted by the R8 'groups of 0-5. In one embodiment, the compound of this invention is represented by formula II:
II
wherein: a) R3 is phenyl, thiophene, or pyridine; b) each ring is optionally substituted with up to 5 groups independently selected from R8 '; and c) at least one position in the phenyl, thiophene, or pyridine adjacent to the bond x is replaced by R12, wherein R12 has no more than 5 straight chain atoms. Another embodiment of this invention provides a compound wherein Y is:
In one embodiment of this invention, R1 is substituted with up to 3 groups independently selected from carbonyl and R8. In another embodiment, R1 is C? -12aliphatic or C3. locicloalkyl, wherein each R1 is optionally substituted with 1-3 groups independently selected from R8. In yet another embodiment, R1 is a straight chain or C? _4 branched alkyl which is optionally substituted with 1-3 groups independently selected from R8. In one embodiment, R1 is an unsubstituted straight chain, or C? _4 branched alkyl (eg, ethyl, isopropyl, n-propyl, or n-butyl). In another embodiment, R1 is ethyl. In any of these embodiments, R8 is halogen, -OR9, -CN, -CF3, -OCF3, or -R9. In another embodiment where R8 is -R9, that R9 is benzyl. In another modality, Y is
In another embodiment, ring A is substituted with up to 3 groups (preferably, group 1) independently selected from carbonyl and R4.
In one embodiment, ring A is:
optionally substituted with R4. Still in another modality, ring A is
optionally substituted with R4. In another form of this embodiment, ring A is unsubstituted proline (ie, R4 is hydrogen). Still in another modality, ring A is:
In one embodiment, ring A is optionally substituted with R 4.
In any of these embodiments, R 4 is halogen, -OR 9, -CF 3, -OCF 3, -R 9, or -SR 9. In certain embodiments R4 is H. In one embodiment, R2 is a C3.4 branched alkyl group.
In another embodiment, R is H or -CH3, R6 is -CH3, and R7 is -CH3. In another embodiment, R12 is -OCF3, -OCH3, -CF3, -CH3 / -CH2CH3, -Cl, or -F. Still in another embodiment, R12 is -CF3, -CH3,
-Cl, or -F. Still in another embodiment, R12 is -CH3 / -Cl, or -F. In another embodiment, each R8 ', if present, is independently halogen, -OR9, -N02, -CN, -CF3, -0CF3, -R9, 1, 2-methylenedioxy, 1,2-ethylenedioxy, -N (R9 ) 2, -SR9, -SOR9, -S02R9, -S02N (R9) 2, -C (0) R9, -C (0) C (0) N (R9) 2, -C (0) N (R9) 2, -OC (0) N (R9) 2, - (CH2) 0-2NHC (O) R9, -N (R9) S02R9, -N (R9) S02N (R9) 2, -N (R9) C ( O) OR9, -N (R9) C (0) R9, or -N (R9) C (O) N (R9) 2. In another embodiment, R8 'is -NH2, -N (R9) 2, -N (R9) C (0) R9, -0CF3, -OR9, -CF3, -R9, -SR9, or halo. In this embodiment, halo is preferably Cl or F and R 9 is preferably C ?. straight or branched alkyl. According to one embodiment, this invention provides compounds of formula III:
III;
where the variables are as defined in any of the modalities of the present. In one form of this embodiment, the compound has the stereochemistry indicated below:
where the variables are as defined in any of the modalities of the present. In other forms of this embodiment, the compound has the stereochemistry indicated below:
where the variables are as defined in any of the modalities of the present. According to another embodiment, this invention provides a compound of formula IV:
IV;
where the variables are as defined in any of the modalities of the present. In one form of this embodiment, the compound has the stereochemistry indicated below:
where the variables are as defined in any of the modalities of the present. The embodiments herein may be combined to provide a compound according to this invention. According to one embodiment, the present invention provides a compound selected from the following Table 1:
Table 1
X-l 1-2 1-3 -16 1-17 1-18
-19-1-20 1-21
1-25 1-26
1-27 1-28
1-31 -29 1-30
1-34 1-35 1-36
1-37 1-38 1-39
1-40 1-41 1-42
1-43 1-44 1-45
1-46 1-47 1-48 2-49 1-50 1-51
1-52 1-53
? 1-62 & 1-73 According to another embodiment, the present invention provides a compound of formula II selected from the following Table 2: Table 2
11-4 II-5 XX-6 llt7 11-8 11-9
12-10 21-11 11-12
11-13 21-14 11-15 11-16 11-17 12-18
22-22 22-23 22-24
22-25 22-26 22-27
22-28 22-29 22-30
22-31 22-32 22-39 22-40 22-41
11-42 11-43 11-44
11-45 11-46 11-47
11-48 11-49 11-50 11-51 11-52 11-53
11-54 11-55
11-58 11-59
11-62 11-63 11-64 11-65
11-66
In certain embodiments of this invention, the definitions of the variables are selected from those represented in the compounds of Table 1 and / or Table 2. In the sense in which it is used herein, a specific number of atoms includes any number whole of them. For example, a group that has 1-4 atoms, could have 1, 2, 3, or 4 atoms. In the sense in which it is used herein, an aliphatic group includes straight and branched chain groups having the specific number of atoms. If the number of atoms is unspecified, the aliphatic group has 1 to 12 carbon atoms. As it could be understood, the aliphatic alkenyl and / or alkynyl groups have a minimum of 2 carbon atoms. Preferred aliphatic groups are alkyl groups (preferably having 1 to 6 atoms). The cycloalkyl and cycloalkenyl groups have between 3 and 10 carbon atoms and are monocyclic or bicyclic, including linearly fused, bridged, or spirocyclic. In the sense in which it is used herein, "aromatic group" or "aryl" refers to a ring system of 6-10 members that contains at least one aromatic ring. Examples of aromatic rings include phenyl and naphthyl. In the sense in which it is used herein, "heteroaryl" refers to a ring system having 5-10 members and 1, 2, or 3 heteroatoms independently selected from N, N (R9), O, S, SO , and S02. , wherein at least one ring is heteroaromatic (eg, pyridyl, thiophene, or thiazole). In the sense in which it is used herein, a "heterocycle" refers to a ring system having 3-10 members and 1, 2, or 3 heteroatoms independently selected from N, N (R9), 0, S, SO, and S02, where no ring is aromatic (for example, piperidine and morpholine).
Additional examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g. pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (for example 5-tetrazolyl), triazolyl (for example, 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (for example, 2-indolyl), pyrazolyl (for example, 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1,2,4-oxadiazolyl, 1, 2,3-thiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1, 2, 5-thiadiazolyl, purinyl, Pyrazinyl, 1, 3, 5- triazinyl, quinolinyl (e.g., 2 -quinolinyl, 3 -quimolinilo, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl). Additional examples of heterocyclic rings include 3 -LH-benzimidazol-2-one, 3- (1-alkyl) -benzizidazol-2 -one, 2 - tetrahydrofuranyl, 3 -tetrahidrofuranilo, 2 -tetrahidrotiofenilo, 3-tetrahydrothiophenyl, 2-morpholino , 3-morpholino, 4-morpholino, 2 -tiomorfolino, 3 -tiomorfolino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1- tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3 -tetrahidropiperazinilo, 1-piperidinyl, 2 -piperidinyl, 3 -piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2 -piperidinyl, 3-piperidinyl, 4 -piperidinyl, 2 -tiazolidinilo, 3-thiazolidinyl, 4- thiazolidinyl , 1- imidazolidinyl, 2-imidazolidinyl, 4 -imidazolidinilo, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1, 3-dihydro-imidazol-2-one. Each of the above aliphatic, aryl, cycloaliphatic, heteroaryl, and heterocyclyl can contain suitable substituents (preferably up to 5) independently selected from, for example, carbonyl and R8. Preferred substituents are halogen, -OR9, -N02, -CF3, -OCF3, -R9, oxo, -OR9, -O-benzyl, -O-phenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, -N (R9) 2, -C (0) R9, -COOR9 or -CON (R9) 2, wherein R9 is defined herein (and preferably is H, (C1-C6) -alkyl, or (C2-C6) ) -alkenyl and alkynyl), with (C 1 -C 6) -alkyl being preferred to a greater extent). It should be understood that this definition could include a perfluorinated alkyl group. It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms or in hydrated forms, all of these forms of the compounds are within the scope of the invention. Unless stated otherwise, the structures represented herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, the individual stereochemical isomers, as well as the enantiomeric and diastomeric mixtures of the present compounds are within the scope of the invention. Unless stated otherwise, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures herein except for the replacement of a hydrogen atom by one of deuterium or tritium, or the replacement of a carbon atom with a 13C- or 14C-enriched carbon atom remain within the scope of the invention. scope of this invention. The compounds of this invention can be obtained by any method, including general, synthetic methods, known to those skilled in the art for analogous compounds (see for example, WO 99/47545). For purposes of illustration, the following Schemes are provided for the synthesis of the compounds of the present invention. The following abbreviations are used: EDC is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HOBt is 1-hydroxybenzotriazole THF is tetrahydrofuran TFA is trifluoroacetic acid DCM is dichloromethane DMAP is 4-dimethylaminopyridine DIPEA is diisopropylethylamine DMF is dimethylformamide TFA is trifluoroacetic acid Z is benzyloxycarbonyl 1H NMR is nuclear magnetic resonance TLC is thin layer chromatography Scheme I. General scheme for the preparation of E and F
B
Scheme I represents a general route for preparing the compounds E and F set forth in this invention. The amino group of species A, obtained easily from the reduction of the α-carboxylic group of aspartic acid (protected with PGi as an ester), is coupled to the carboxylic acid entity of species B (N-protected with PG2) ) to provide the species C. PGX and PG2 are orthogonal protecting groups (ie, protecting groups where a protecting group can be removed selectively in the presence of another protective group.) Ideally, PGX should be able to be removed without removing PG2 and vice versa) . Here, the aspartate portion of the molecule is then manipulated in an oxidation / chelation / deprotection / cyclization sequence to provide D. Portion A of ring D then becomes functionally additional to provide E which forms part of the disclosed invention. The deprotection of the ketal provides the species F which represents the other part of the invention disclosed. In various embodiments of this invention, PG2 is a suitable amine protecting group, including, but not limited to, the amine protecting groups described in T.W. Greene & P.G.M Wutz, "Protective Groups in Organic Synthesis", 3rd. Edition, John Wiley & Sons, Inc., (1999 and other editions) ("Greene"). A "Z" (benzyloxycarbonyl) protecting group is a particularly N-protecting group useful for use in conjunction with this invention. In compounds where PG2 is protecting the nitrogen atom of a proline, PG is preferably Z. It is to be understood that the modified Z groups ("Z-type protecting groups") used in conjunction with the compounds and processes of this invention are also within the scope of this invention. For example, z could be substituted in the CH2 group or the phenyl group with R8 (preferably halo or C? -e straight or branched chain alkyl) to provide a Z-type protecting group. In various embodiments of this invention, PGi is a suitable carboxylic acid protecting group, including, but not limited to, the acidic protecting groups described in Greene. In certain embodiments, PGi is a C? -6 straight or branched chain alkyl group. A t-butyl group is a particularly useful acid protecting group for use in connection with this invention. In Scheme I, compound A is a residue of modified aspartic acid. In addition to compound A, other residues of modified aspartic acid have been reported, including the following:
wherein, PG3 and PG4 are suitable protecting groups. These modified aspartic acids can be prepared by methods known to those skilled practitioners. See, for example, the publication of US patent application 2002/0042376 (especially page 9, paragraph [0121] and pages 21-22, paragraph [0250] and the documents cited in paragraph [ 0123]) and U.S. Patent 6,235,899. See, also, C. Gros et al. "Stereochemical control in the preparation of a-amino N-methylthiazolidine Masked Aldehydes used for Peptide Aldehyde Synthesis" Tetrahedron, 58, pp. 2673-2680 (2002); K.T. Chapman, "Synthesis of a Potent Reversible Inhibitor of Interleukin- ß Converting Enzyme" Bioorg. Med. Chem. Letts. , 2, pp. 613-618 (1982); M. D. Mullican et al.
"The Synthesis and Evaluation of Peptidyl Aspartyl
Aldehydes as Inhibitors of ICE "'4, pp. 2359-2364
(1994); M.H. Chen, et al. "An Efficient
Stereoselective Synthesis of [3S (SS, 9S)] -3 - [[[9- (Benzoylamino) octahydro-6, 10-Dioxo-6H-pyridazino- (1,2-a) (1,2) -Diazepin-1 -yl] -carbonyl] amino] -4-oxobutanoic acid, an interleukin converting enzyme (ICE) Inhibitor "9, pp. 1587-1592 (1999). Therefore, Scheme I (and also the following Scheme III) could be modify to use these other aspartic acid residues.
Scheme II. Preparation of the compounds of the
Formulas I and II
Reagent and conditions: (a) R COOH, HOBt, DMAP, EDC, THF; (b) R3CONHCH (R2) COOH, HOBt, DMAP, EDC, THF; (c) 2M HCl, MeCN. Scheme II represents the formation of the compounds of formulas I and II, wherein Ring A is unsubstituted proline. Here, the cyclic acetal form of a compound of this invention is represented as the formula I and the aldehyde form is represented as the formula II. Compounds having a Ring A other than unsubstituted proline could be substituted in the methods depicted in Scheme I. Scheme II represents the routes used to prepare the compounds of Formulas I and II.
The compounds I can be prepared from the compounds 1 by condensation of the amino group at 1 with the carboxylic acid having a suitable (or derivative) functional group. In this step, standard coupling reagents have been represented to form the amide bonds; other conditions known in the art to form the amide bonds can also be used. As is known to those skilled practitioners, a carboxylic acid (-C (O) OH) can be coupled to the amine under the conditions suitable for the coupling of amines and carboxylic acids. Alternatively, in these couplings, a carboxylic acid derivative (-C (O) X) can be used in place of the carboxylic acid. It should be understood that in the context of the coupling of an amine and a carboxylic acid derivative, the derivative could activate the acid to facilitate coupling to an amine. Suitable groups X are essentially leaving groups and are known to those skilled practitioners. "March's Advanced Organic Chemistry", 5a. Ed., Ed .: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001. Typical conditions for the coupling of an amine and an acid include combining a suitable solvent, a carboxylic acid, a base, and a reagent for peptide coupling. Examples of suitable conditions are described in US2002 / 0042376 and WO 01/81330, all of which are incorporated herein by reference. In certain modalities, the conditions are as described in the Schemes and Examples herein. Examples of suitable derivatives include, but are not limited to, compounds of the formula RX wherein X is Cl, F, OC (= 0) R "(R" is aliphatic or aryl), SH, SR, SAr, or SeAr. In some modalities R is C (= 0). Suitable conditions for using these suitable derivatives are known in the art.
Scheme III. Preparation of compound 1
2. 3. 4. 5
7 8 9
1
Reagent and conditions: (a) Cbz-Pro-OH, EDC, HOBt, DMAP, DIPEA, THF; (b) Swern; (c) R ^ OH, sieves of 3Á, DCM, TsOH; (d) TFA, DCM; (e) H2, Pd (OH) 2, EtOAc, DMF, Et3N; (f) EDC, HOBt, Et3N, EtOAc, DMF; (g) H2, Pd / C, acid Citrate.
Scheme III represents a possible route for preparing compounds 7 and compounds 1 described in scheme I. Compound 2, easily obtained from the reduction of the α-carboxylic group of aspartic acid, is coupled to N-protected proline (or other ring, where Ring A is distinct from unsubstituted proline) to form 3. Here, proline is N-protected with a Z group
(benzyloxycarbonyl). The compounds 3 are then oxidized in the aldehydes 4 which are treated with acetyl in itself to provide the acetals 5. The acetals can be formed in the presence of R 1 -OH (or a suitable acid-forming reagent), a protic acid ( example, TsOH), or a Lewis acid, and a suitable solvent. Examples of suitable acid-forming reagents forming the compounds wherein R 1 is converted to ethyl can be considered ethanol equivalents and include, but are not limited to, triethyl orthoformate or a diethylacetal, such as, for example, a (CH 3) 2 C (OCH 2 CH 3) 2. Preferably, the solvent is CH2C12, toluene, or chlorobenzene. Suitable protic acids include, but are not limited to, TFA, p-TsOH. Suitable Lewis acids include, enunciatively, TiCl4, MgBr2 and ZnCl2. In Scheme III, the oxidation of compounds 3 to compounds 4 is represented as being carried out under Swern conditions. To prepare the compounds of this invention, other oxidation conditions may also be employed. Preferred oxidation conditions are those that are mild and relatively fast to minimize epimerization in the acid side chain of the modified aspartic acid residue. In one embodiment, the oxidation step is a TEMPO oxidation (see the following Example 1-1, Method C). Other oxidation conditions include a Dess-Martin oxidation and an oxidation with tetrapropylammonium perruthenate (TPAP). The aldehydes 4 can be isolated, but preferably they are taken directly to 5 without isolation. Deprotection of the tert-butyl ester (in 5) is accompanied by spontaneous cyclization of rings to provide a mixture of diastereoisomers that were separated by column chromatography to provide enantiomerically pure syn-ketals 6 and anti-ketals (not shown in this scheme ). The deprotection can be carried out under conditions of protic acid or Lewis acid in a suitable solvent. Suitable solvents include, but are not limited to, toluene, chlorobenzene, and DCM. Suitable protic acids include, but are not limited to, TFA, p-TsOH. Suitable Lewis acids include, but are not limited to, TiCl 4, MgBr 2, and ZnCl 2. For clarity of the scheme, only the synatals are represented in the next steps to form the compounds 7 and 1 although the same sequence can be used to form the anti-ketals. The compounds 6 are subjected to hydrogenolysis and the resulting compounds 7 are reacted with the Z-protected aminoacids, using conditions known in the art to prepare amide bonds, to provide the compound 9. The compounds 7 can be generated and used in if you If they are isolated, it is preferred to use compound 7 relatively shortly after generation. The compounds 9 are finally subjected to hydrogenolysis to provide compound 1 which can be used directly to prepare compounds I, as depicted in Scheme II.
Alternatively, compounds 7 can be used to prepare compounds I, as depicted in Scheme II. In this preparation, an amino acid residue and the desired N-terminal group are prepared in a single step (see, Scheme II, reaction (b)). As described in connection with Scheme I, derivatives of aspartic acid other than compounds 2 can be used to obtain the compounds of this invention.
Scheme IV. The preparation of the compounds of Formulas III and IV
17
Reagent and conditions: (a) ROH / HOBt / DMAP / EDC / THF or RC1 / Et3N / DCM; (b) RNHCH (R2) COOH, HOBt, DMAP, EDC, THF; (c) 2M HCl, MeCN.
Scheme IV represents the formation of the compounds of formula III and IV, wherein Ring A is 2-Aza-bicyclo [2.2.1] -heptan-3-carboxylic acid. Here, the cyclic acetal form of a compound of this invention is represented as the formula III and the aldehyde form is represented as the formula IV. Scheme IV represents the routes used to prepare the compounds of Formulas III and IV. Compounds III can be prepared from the compounds II by condensation of the amino group under the conditions to provide the desired R group, such as, for example, the carboxylic acid with suitable functional group (or derivative), sulfonic acid ( or derivative), chloroformate or carbamoyl chloride (or isocyanate), for example, under the condition of suitable reaction. In this step, standard coupling reagents have been represented to form the CO-NH bonds; to provide the desired compound comprising R-N other conditions known in the art to form the CO-NH (or alkyl-N, or S02-N) bonds can also be used. Alternatively, compounds I can be prepared from compounds 17 by condensation of the amino group at 17 with the carboxylic acid having a suitable functional group (or derivative), sulfonic acid (or derivative), chloroformate or carbamoyl chloride (or isocyanate) ). In this step, standard coupling reagents have been represented to form the CO-NH bonds; other conditions known in the art to form CO-NH bonds can also be used.
Scheme V. Preparation of Compound 11
16 17 18 19 11
Reagent and conditions: (a) EDC, HOBt, DMAP, DIPEA, THF; (b) Swern; (c) R1OH, sieves of 3Á, DCM, TsOH; (d) TFA, DCM; (e) H2, Pd (OH) 2, EtOAC, DMF, Et3N; (f) EDC, HOBt, Et3N, EtOAc, DMF; (g) H2, Pd / C, acid Citrate.
Scheme V represents a possible route for preparing compounds 17 and compounds 11 described in Scheme III. Compound 2, easily obtained from the reduction of the O-carboxylic group of aspartic acid, is coupled to the N-protected 2-aza-bicyclo [2.2.1] heptan-3-carboxylic acid (prepared as in Tetrahedron: Asymetry , 13, 2002, 25-28) to form 13. The compound 13 is then oxidized in the aldehyde 14 which is treated with acetal in itself to provide the acetals 15. The deprotection of the tert-butyl ester is accompanied by spontaneous cyclization of rings to provide a mixture of diastereoisomers that were separated by column chromatography to provide enantiomerically pure syn-ketals and anti-ketals (not shown in this scheme). Alternative Ring A groups are either commercially available, reported in the literature, or can be prepared according to methods known in the literature. For clarity of the scheme, only the synatals are represented in the next steps to form the compounds 17 and 11 although the same sequence can be used to form the anti-ketals. The compounds 16 are subjected to hydrogenolysis and the resulting compounds 17 are reacted with the Z-protected amino acids, using conditions known in the art to prepare the amide bonds, to provide the compounds 19. Alternatively, the compounds 17 can be used to prepare the compounds III, as represented in Scheme IV. The compounds 19 are finally subjected to hydrogenolysis to provide compound 11, which can be used directly to prepare compound III, as depicted in Scheme IV. The R3COOH used in Scheme II is either commercially available, reported in the literature, or prepared according to methods known in the literature. For compound 11-30, 2-chloro-3-methoxybenzoic acid was prepared as in J. Org. Chem, 59, 1994, 2939-2944. For compound 11-32, 2-chloro-3-trifluoromethoxybenzoic acid was prepared from 2-amino-3-trifluoromethoxybenzoic acid (prepared as in J. Org Chem, 68, 2003, 4693-4699) using a replacement Sandmeyer of the amino group by means of a chlorine, according to a method practically similar to the one reported in J. Org. Chem, 59, 1994, 2939-2944.
Accordingly, this invention also provides a process for preparing a compound of this invention. In one embodiment, a process for preparing a compound of formula I is provided:
where Y is
and the other variables are as defined in any of the modalities herein; which comprises reacting a compound of formula 1:
where the variables are as defined in any of the modalities of the present; and a compound of the formula RX, wherein X is OH or a suitable derivative (i.e., a leaving group), in the presence of the conditions for the coupling of an amine and an acid (when X is OH) or an amine and a suitable acid derivative (when X is not OH (ie, a leaving group, eg, Cl) to provide the compound of formula I. Another embodiment provides a process for preparing a compound of formula I:
where Y is
and the other variables are as defined in any of the modalities herein; which comprises reacting a compound of formula 7:
wherein the variables are as defined in any of the embodiments herein, and a compound of the formula RNHCH (R2) C (O) X, wherein X is OH or a suitable derivative, in the presence of conditions for coupling of an amine and an acid (when X is OH) or a suitable acid derivative (when 'X is not OH, for example, X is Cl) to provide the compound of formula I. Yet another embodiment of this invention provides a process to prepare a compound of formula IV:
IV
wherein the variables are as defined in any of the embodiments herein, which comprises reacting a compound of the formula I:
where Y is:
wherein R and R1 are each independently as defined in any of the embodiments herein, under the conditions of hydrolysis, to provide the compound of formula II. In certain modalities, R is R3C (= 0). Still in other modalities, when A is proline, R is R3C (= 0). The hydrolysis conditions for converting I to II are well known to those experienced practitioners (see, for example, Greene). These conditions include a suitable solvent (e.g., acetonitrile) and aqueous acid (e.g., 2M HCl). Another embodiment provides a process for preparing a compound of the formula 6-A: 6-A
wherein PG2 is a suitable nitrogen protecting group and R1 is as defined in any of the embodiments herein, which comprises reacting a compound of the formula 5-A:
-A
under the conditions suitable for ring cyclization, to provide the compound of the formula 6-A. Suitable conditions for ring cyclization include an acid and a suitable solvent; for example, TFA in DCM. Another embodiment provides a process for preparing a compound of the formula 5-A:
-A which comprises reacting a compound of the formula 4-A:
in the presence of R1-OH (or a suitable acetal-forming reagent), protic or Lewis acid (eg, TsOH), and a suitable solvent to provide the compound of the formula 5-A. Another embodiment provides a process for preparing a compound of the formula 4-A:
4-A
which comprises reacting a compound of the formula 3-A:
3-A under suitable oxidation conditions (eg, an oxidation Swern: Mancuso, A.J., Swern, D. Synthesis, 1981, 165-185) to provide the compound of the formula 4-A. Preferred oxidation conditions include TEMPO oxidation (see Example 1-1, Method C, below). Another embodiment provides a process for preparing a compound of the formula 3 -A:
comprising: reacting a compound of formula 2
with a compound of the formula 20-A:
under the conditions for the coupling of an amine and a carboxylic acid (when X is OH), or an amine and a suitable carboxylic acid (when X is not OH), to provide the compound of the formula 3-A. Another embodiment provides a process for preparing a compound of formula 6:
wherein PG2 is a suitable nitrogen protecting group and R1 is as defined in any of the embodiments herein, which comprises reacting a compound of formula 5:
under suitable cyclization conditions, to provide the compound of formula 6. Another embodiment provides a process for preparing a compound of formula 5:
which comprises reacting a compound of formula 4:
4
in the presence of R1-OH (or a suitable acetal-forming reagent), protic or Lewis acid (eg, TsOH), and a suitable solvent to provide the compound of formula 5. Preferably, the solvent is CH2C12, toluene, or chlorobenzene. Another embodiment provides a process for preparing a compound of formula 4:
which comprises reacting a compound of formula 3:
under suitable oxidation conditions (e.g., Swern oxidation) to provide the compound of formula 4. Preferred oxidation conditions include TEMPO oxidation (see Example 1-1, Method C, below). Another embodiment provides a process for preparing a compound of formula 3:
comprising: reacting a compound of formula 2
with a compound of formula 20
under the conditions for the coupling of an amine and a carboxylic acid (when X is OH), or an amine and a suitable carboxylic acid (when X is not OH), to provide the compound of formula 3. Another embodiment provides a process to prepare a compound of formula 16:
wherein PG2 is a suitable nitrogen protecting group and R1 is as defined in any of the embodiments herein, which comprises reacting a compound of formula 15:
fifteen
under suitable cyclization conditions, to provide the compound of formula 16.
Another embodiment provides a process for preparing a compound of formula 15:
which comprises reacting a compound of formula 14:
14
in the presence of R1-OH (or a suitable acetal-forming reagent), protic or Lewis acid (eg, TsOH), and a suitable solvent to provide the compound of formula 15. Another embodiment provides a process for preparing a compound of Formula 14:
which comprises reacting a compound of formula 13:
13
under suitable oxidation conditions (eg, Swern oxidation) to provide the compound of formula 14. Another embodiment provides a process for preparing a compound of formula 13:
13
which comprises reacting a compound of formula 2 with a compound of formula 21:
under the conditions for the coupling of an amine and a carboxylic acid (when X is OH), or an amine and a suitable carboxylic acid (when X is not OH), to provide the compound of formula 13. Another embodiment provides a process to prepare a compound of formula 22:
22
which comprises reacting a compound of formula 23:
in the presence of R ^ '-OH (or a suitable acetal-forming reagent), protic or Lewis acid (eg, TsOH), and a suitable solvent to provide the compound of formula 22. Acetal-forming equivalents include, enunciatively, triethyl orthoformate, a diethylacetal, such as, for example, a (CH3) 2C (OCH2CH3) 2 • Preferably, the solvent is CH2C12, toluene, or chlorobenzene.
Another embodiment provides a process for preparing a compound of formula 23 which comprises reacting a compound of formula 2:
2
under suitable oxidation conditions (Swern example) to provide the compound of formula 23. Another embodiment provides a process for preparing a compound of formula 5 -A
-A
wherein PGX is a suitable carboxylic acid protecting group, PG2 is a suitable nitrogen protecting group, and R1 is as defined in any of claims 1 or 5-9, comprising: reacting a compound of the formula 20- TO:
with a compound of formula 22
22
under the conditions for the coupling of an amine and a carboxylic acid (when X is OH), or an amine and a suitable carboxylic acid (when X is a suitable leaving group), to provide the compound of the formula 5-A. Another embodiment provides a process for preparing a compound of formula 5:
which comprises reacting a compound of the formula 20:
with a compound of formula 22
22
under the conditions for coupling an amine and a carboxylic acid (when X is OH), or an amine and a suitable carboxylic acid (when X is not OH), to provide the compound of formula 5. Another embodiment provides a process to prepare a compound of the formula 5 -A:
-A
which comprises reacting a compound of formula 21:
with a compound of formula 22
22
under the conditions for the coupling of an amine and a carboxylic acid (when X is OH), or an amine and a suitable carboxylic acid (when X is not OH), to provide the compound of the formula 5-A. In accordance with this invention, the processes can be used alone or in combination to provide a compound of this invention. Certain specific embodiments of this invention provide the processes for preparing compounds 4 from 3 (in embodiments where compounds 4 are isolated); 5 from 3 (in modalities where the compounds 4 are not isolated, although they are carried out directly, for example, generated in si tu); 5 from 4; and 6 from 5 in accordance with the methods set forth herein. In a preferred embodiment, the compounds
6 are prepared from the compounds 5; the compounds 5 are prepared from the compounds 4 (whether or not they are isolated); and the compounds 4 are prepared from 3. Preferably, the compounds 6 are used in the preparation of caspase inhibitors containing proline. These caspase inhibitors containing proline include, but are not limited to, those set forth in WO 95/35308, WO 99/47545, WO 01/81330, and WO 01/90063 (all of which are incorporated herein by reference). For example, compound IA (and stereoisomers thereof) of WO 01/90063 (which is specifically incorporated herein by reference) could be prepared as disclosed herein (see, for example, page 13). Undoubtedly, it should be understood that compounds containing proline could be represented by the
Formula I except that Ring A is pyrrolidine (ie, it is derived from proline).
The processes for converting compounds 6 to proline-containing caspase inhibitors are preferably as disclosed herein. The processes for preparing the compounds 3 are also preferably as set forth herein. However, other processes known to those skilled practitioners could be used to convert compounds 6 to caspase inhibitors containing proline and / or to prepare compound 3. Other embodiments of this invention provide compounds of formula 3 to 6, 3 -A to 6-A, and 13-16. One embodiment of this invention provides the compounds of formula 4A:
4A.
Another embodiment of this invention provides the compounds of formula 4:
Another embodiment of this invention provides these of the formula 14:
14.
One embodiment of this invention provides these of the formula 5-A:
-A.
Another embodiment of this invention provides these of the formula 5:
Another embodiment of this invention provides these of the formula 15:
.
One embodiment of this invention provides these of the formula 3-A:
3-A.
Another embodiment of this invention provides these of formula 3:
Another embodiment of this invention provides these of the formula 13: 13.
In all the above modalities, the variables are as defined in any of the modalities herein. In a preferred form of 3, PG2 is Z and PGX is a straight or branched chain C? _6 alkyl group (preferably a t-butyl group), either alone or in combination. As you might understand from experienced practitioners, certain process steps can be achieved in discrete steps or in yourself. For example, deprotection and subsequent reaction of an amine can be carried out in a stepwise manner (upon isolating the amine) or in a one-step procedure (without isolating the amine). In certain embodiments, the above processes are conducted as described herein (for example, in the schemes, examples, and the accompanying description). Compounds such as, for example, 3 could be used in the processes for preparing the proline-containing compounds, such as, for example, caspase inhibitors. The caspase inhibitors containing proline include, but are not limited to, those set forth in WO 95/35308, WO 99/47545, WO01 / 81330, and WO 01/90063 (all of which are incorporated herein by reference). For example, compound IA (and stereoisomers thereof) of WO 01/90063 (which are specifically incorporated herein by reference) could be prepared as disclosed herein (see, for example, page 13). The compounds used in the compositions and methods of this invention can also be modified by adding suitable functional groups to enhance the selective biological properties. These modifications are known in the art and include those that increase biological penetration in a given biological system (eg, blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter the metabolism and alter the rate of excretion. For example, a carboxylic acid group in a compound of this invention can be derived as, for example, an ester. Preferred esters could be those derived from: a straight or branched chain C6-alkyl, alkenyl, or alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with C6-? Or aryl, CF3, Cl, F, OMe, OEt, OCF3, CN, or NMe2; a C? -e-cycloalkyl, wherein 1-2 carbon atoms in cycloalkyl are optionally replaced with -0- or -NR9-. The compounds of this invention having a carbonyl group can be derived similarly, for example, as an acetal, ketal, oxime (= N0R9), hydrazine (= NN (R9) 2), thioacetal, or thioketal. Suitable derivatives of amines are known in the art and are also included within the scope of this invention. Certain of the above derivatives could include the protecting groups known to those experienced practitioners (see, for example, Greene). As would be recognized by an experienced practitioner, these protective groups can also be employed in the processes of this invention. The compounds of this invention can be analyzed for their ability to inhibit apoptosis, the release of IL-1β or directly the activity of caspase. The analyzes for each of the activities are known in the art. However, as would be recognized by an experienced practitioner, a prodrug compound of this invention should be active only in assays where the prodrug entity could be cleaved, typically in vivo analysis. Analyzes for caspase activity are described in WO 99/47545. According to another embodiment, the present invention provides a pharmaceutical composition comprising: a) a compound of the invention, as defined herein, or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable carrier, adjuvant or vehicle. It should be understood that the compounds and pharmaceutically acceptable salts thereof are included within this invention. If pharmaceutically acceptable salts of the compounds of this invention are used in these compositions, those salts are preferably derived from inorganic or organic acids and bases. These acid salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate , hydrochloride, hydrobromide, iodhirate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate,. Basic salts include ammonium salts, alkali metal salts, such as, for example, sodium and potassium salts, alkaline earth metal salts, such as, for example, calcium and magnesium salts, salts with organic bases, such as, for example, salts of dicyclohexylamine, N-methyl-D-glucamine, and salts with amino acids such as, for example, arginine, lysine, etc. Also, groups containing basic nitrogen can be quaternized with these agents as lower alkyl halides, such as for example, methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as, for example, dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as, for example, decyl chlorides, lauryl, myristyl and stearyl, bromides and iodides, aralkyl halides, such as, for example, bromides of benzyl and phenethyl and others. By this, soluble or dispersible products are obtained in water or oil. Pharmaceutically acceptable carriers that can be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as, for example, human serum albumin, buffer substances such as, for example, phosphates, glycine , sorbic acid, potassium sorbate, mixtures of partial glyceride of saturated vegetable fatty acids, water, salts or electrolytes, such as, for example, protamine sulfate, sodium monoacid phosphate, potassium monoacid phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool grease. According to a preferred embodiment, the compositions of this invention are formulated for the pharmaceutical administration to a patient, preferably a human being. These pharmaceutical compositions of the present invention can be administered orally, parenterally, by inhalation by spray, topical, rectal, nasal, buccal, vaginally or via an implanted reservoir. The term "parenteral", in the sense that is used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. The sterile injectable forms of the compositions of this invention can be aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed, sterile oils are conventionally employed as a solvent or suspending medium. For this purpose, any simple fixed oil including synthetic mono or di-glycerides can be employed. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectable solutions, such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents which are commonly used in the preparation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying or bioavailability enhancing agents that are commonly used in the manufacture of solids, liquids, or other pharmaceutically acceptable dosage forms, may also be used for the purposes of the formulation. The pharmaceutical compositions of this invention can be administered orally in any orally acceptable dosage form among which include, but are not limited to, capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. These materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention can also be administered topically, especially when the target of treatment includes easily accessible areas or organs for topical application, including eye, skin, or lower intestinal tract diseases. Suitable topical formulations are easily prepared for each of these areas or organs. Topical application to the lower intestinal tract can be carried out in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches can also be used. For topical applications, the pharmaceutical compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol compound, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, the pharmaceutical compositions can be formulated as micronized suspensions in sterile, isotonic saline solution, adjusted in pH, or, preferably, as solutions in sterile, isotonic saline solution, adjusted in pH, either with / without a conservative as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions can be formulated into an ointment such as petrolatum. In one embodiment, the compositions are as formulated in, for example, U.S. Patent 6,645,994 and / or U.S. Patent 6, 630, 473. The pharmaceutical compositions of this invention can also be administered by aerosol or nasal inhalation. These compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other agents conventional solubilizers or dispersants. The compounds and compositions described above are particularly useful in therapeutic applications that are related to a disease caused by IL-1, a disease caused by apoptosis, an inflammatory disease, an autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease (for example, bacterial infections, preferably ocular infections), a degenerative disease, a disease associated with cell death, a disease by excess daily alcohol intake, a disease caused by viruses, retinal disorders, uveitis, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, respiratory distress syndrome in adults, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, mia stenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, scarring, graft-versus-host disease, organ transplant rejection, organic apoptosis after burn injury, osteoporosis, leukemia and related disorders, myelodysplastic syndrome, bone disorder related to multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, hemorrhagic shock, sepsis, septic shock, burns, Shigellosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy's disease, prion disease, cerebral ischemia, epilepsy, myocardial ischemia, acute and chronic heart disease, myocardial infarction, congestive heart failure, atherosclerosis, graft for coronary artery bypass, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, traumatic brain injury, spinal cord injury, hepatitis B , hepatitis-C, hepatitis-G, yellow fever, dengue fever, Japanese encephalitis, various forms of liver disease, kidney disease, polycystic kidney disease, gastric and duodenal ulcer disease associated with H. pylori, HIV infection, tuberculosis, and meningitis, toxic epidermal necrolysis, pemphigus, and autoinflammatory diseases (av sometimes referred to as autoinflammatory syndromes due to fever) and related syndromes such as, for example, the Muckle-Wells Syndrome (MWS), Urticaria due to Family Cold (FCU), Familial Mediterranean Fever (FMF), Cutaneous and Chronic Neurological Articular Infantile Syndrome (CINCAS) , aka Inflammatory disease
Multisystemic of Emergence in Newborns
(TRAPS), and Hyper-IgD Periodic Fever Syndrome
(HIDS). The compounds and compositions are also useful for treating complications associated with grafts for coronary artery bypass. The compounds and compositions are also useful for lowering IGIF (also known as IL-18) or IFN-α production. The compounds and compositions are also useful in immunotherapy as a treatment against cancer. The compounds and compositions can also be used in methods for cell preservation. These methods could be useful for organ preservation, particularly those intended for transplants, or blood products.
The compounds of this invention are useful as dual inhibitors of caspase-1 and capase-8. Without being bound by theory, the R2 and R3 groups of the compounds of this invention appear to be related to this surprising activity. The groups with bridge A of the compounds of this
invention, such as for example, also appear to be related to this surprising activity. As such, the compounds and compositions of this invention in particular are useful for treating or preventing inflammatory conditions.
According to another embodiment, the compositions of this invention may further comprise another therapeutic agent (i.e., one or more additional agents). These agents include, but are not limited to, thrombolytic agents such as, for example, tissue plasminogen activator and streptokinase. When an additional agent is used, the additional agent can be administered either as a separate dosage form or as part of an individual dosage with the compounds or compositions of this invention. The amount of the compound present in the compositions of this invention should be sufficient to cause a discernible decrease in the severity of the disease or in caspase activity and / or cellular apoptosis, as measured by any of the assays known in the art. . Dosage levels between about 0.01 and 50 or about 100 mg / kg of body weight per day, preferably between 0.5 and 75 mg / kg of body weight per day and more preferably between about 1 and 25 or about 50 mg / kg of body weight per day of the compound of the active ingredient are useful in a monotherapy. Typically, a compound or composition of this invention will be administered between about 1 and 5 times a day or alternatively, as a continuous infusion. This administration can be used as a chronic or acute therapy. The amount of the active ingredient that can be combined with the carrier materials to produce an individual dosage form will vary, depending on the host treated and the particular mode of administration. A typical preparation will contain between about 5% and 95% of the active compound (w / w). Preferably, these preparations contain between about 20% and 80% of the active compound. When the compositions of this invention comprise a combination of a compound of this invention and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels between about 10% and 100%, and of greater preference between approximately 10% and 80% of the dosage normally administered in a monotherapy regimen. At the time of improving the condition of a patient, if necessary a maintenance dose of a compound, composition or combination of this invention can be administered. Accordingly, the dosage or frequency of administration, or both, can be reduced, as a function of the symptoms, at a level at which the improved condition is maintained when the symptoms have been alleviated to the desired level, the treatment should be discontinued. However, patients may require intermittent treatment on a long-term basis at the time of any recurrence of the symptoms of the disease. As the experienced practitioner will appreciate, lower or higher doses than mentioned above may be required. It should be understood that a specific dosage and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion , combination of drugs, severity and course of the particular disease, disposition of the patient to the disease that will be treated, and the judgment of the attending physician. The amount of the active ingredients will also depend on the particular compound and another therapeutic agent, if present, in the composition. In a preferred embodiment, the invention provides a method for the treatment of a patient, preferably a mammal, having one of the aforementioned diseases, comprising the step of administering to the patient said a compound or a pharmaceutically acceptable composition described above. In this embodiment, if the patient is also administered another therapeutic agent or caspase inhibitor, this can be delivered together with the compound of this invention in a single dosage form, or, as a separate dosage form. When administered as a separate dosage form, the other caspase inhibitor or agent may be administered before, at the same time, or after administration of a pharmaceutically acceptable composition comprising a compound of this invention. The compounds of this invention can also be incorporated into compositions for coating implantable medical devices, such as, for example, prostheses, artificial valves, vascular grafts, fasteners and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable medical device, comprising a compound of the present invention and a suitable carrier for coating the implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention and a suitable carrier for coating the implantable device.
Another aspect of the invention relates to inhibiting the activity of caspase in a biological sample, the method comprises contacting the biological sample with a compound of this invention, or a composition comprising the compound. The term "biological sample", in the sense in which it is used herein, includes, without limitation, cell cultures or extracts thereof; material subjected to biopsy obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof. The inhibition of caspase activity in a biological sample is useful for a variety of purposes that are known to one skilled in the art. Examples of these purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological specimens, and biological analyzes. The compounds of this invention are useful in methods for preserving cells, as may be necessary for organ transplantation or for the preservation of blood products. Similar uses have been reported for caspase inhibitors [Schierle et al., Nature Medicine, 5, 97 (1999)]. The method involves treating the cells or tissue that will be conserved with a solution comprising the caspase inhibitor. The amount of the caspase inhibitor needed will depend on the effectiveness of the inhibitor for the cell type determined and the time required to prevent the cells from experiencing apoptotic cell death. Without being bound by theory, it is believed that the cyclic acetal compounds of the applicant will be prodrugs. That is, the acetal portion is cleaved in vi to provide a corresponding acid-aldehyde compound. As would be recognized by an experienced practitioner, the chemical compounds can be metabolized in vi, for example, at a site other than the site for the cleavage of the prodrug. Any of these metabolites are included within the scope of this invention. In order that this invention be understood more fully, the following preparatory and test examples are established. These examples are for purposes of illustration only and should not be construed as limiting the scope of the invention in any way.
EXAMPLE 1-1 [(2R) -ethoxy-5-oxo-tetrahydrofuran- (3S) -yl] -amide of the acid. { S, S, S, R) - 1 - [(2S) - (3-methoxy-2-methyl-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) -carboxylic acid
METHOD A (S) -3-amino-4-hydroxy butyric acid tert-butyl ester
A solution of ter-butyl ester of acid
(S) -benzyloxycarbonylamino-4-hydroxy-butyric acid (prepared as described in Michel et al.,
Helvetica Chimica Acta 1999, 1960) (0.94g) in ethyl acetate (15 ml) was hydrogenated over palladium hydroxide / carbon (20% w / w, 160mg). The catalyst was removed via filtration through celite. Concentration of the filtrate in vacuo afforded the subtitle compound as a colorless oil (486mg, 91%); XH NMR (400MHz, CDC13) d 1.48 (9H, s), 1.95 (3H, brs), 2.28 (HH, dd), 2.46 (HH, dd), 3.29 (HH, brm), 3.42 (HH, m), 3.60 (ÍH, m).
METHOD B Benzyl ester of (ÍS) -2 - ((S) -2-tert-butoxycarbonyl-1-hydroxymethyl-ethylcarbamoyl) -pyrrolidine-1-carboxylic acid
To a stirred solution of (S) -3-amino-hydroxy-butyric acid tert-butyl ester (800 mg, 4.57 mmol) and Z-Pro-OH (1.14 g, 4.57 mmol) in THF (30 ml) was added 2 -hydroxybenzotriazole hydrated (741mg, 1.2eq,), DMAP (698mg, 1.25eq.), diisopropylethylamine (1.03ml, 1.3eq.) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 1.05g, 1.2eq) .). The resulting mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate. The mixture was then washed with water, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% ethyl acetate / petrol) to yield the subtitle compound as a colorless solid (1483g, 90%); MS ES (+) 407.3.
M ALL C Benzyl ester of (ÍS) -2 - ((S) -2-tert-butoxycarbonyl-1-formyl-ethylcarbamoyl) -pyrrolidine-1-carboxylic acid
A solution of benzyl ester of (1S) -2- ((S) -2-tert-butoxycarbonyl-1-hydroxymethyl-ethylcarbamoyl) -pyrrolidine-1-carboxylic acid (10 g) in DCM (100 ml) was cooled to 0 ° C under nitrogen. 2,2,6,6-tetramethylpiperidinyloxy (TEMPO, 38 mg) was then added followed by trichloroisocyanuric acid (6g) in portions over 30 minutes. The mixture was stirred at room temperature for 2 hours, then filtered through celite. The filtrate was washed with water, 1 M sodium thiosulfate solution and water. Drying over magnesium sulfate and concentration under reduced pressure afforded the subtitle compound as a pale yellow oil (9.92 g, 99%); XH NMR (400MHz, d-6 DMSO) d 1.38 (9H, d), 1.79-1.86 (3H, m), 2.08-2.23 (1H, m), 2.36-2.51 (ÍH, 2 X dd), 2.61 -2.86 (ÍH, 2 X dd), 3.88-3.46 (2H, m), 4.24-4.30 (2H, m), 5.05 (2H.quin), 7.28-7.37 (5H.m), 8.59-8.64 (ÍH, 2 xd), 9.21 (0.57H, s), 9.37 (0.43H, S).
METHOD D Benzyl ester of (IS) -2 - ((S) -1-tert-butoxycarbonylmethyl-2,2-diethyloxyethylcarbamoyl) -pyrrolidin-1-carboxylic acid
To a solution of benzyl ester of (SS) -2- ((S) -2-tert-butoxycarbonyl-l-formyl-ethylcarbamoyl) -pyrrolidine-1-carboxylic acid (4.98 g) in dichloromethane (70 ml) was added orthoformate of triethyl (6.2 mL) and p-toluenesulfonic acid monohydrate (47 mg). The resulting mixture was stirred at room temperature until there was no longer any aldehyde by TLC analysis. The mixture was concentrated in vacuo, redissolved in dichloromethane (35 mL). Then, saturated aqueous sodium bicarbonate solution (35 mL) was added and the organic phase was removed. This was washed with water and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. This gave the subtitle compound as a pale yellow oil (4.85 g, 82%); XH NMR (400MHz, d-6 DMSO) d
1. 04-1.11 (6H,), 1.35-1.37 (9H, m), 1.73-1.89 (3H, m), 2.01-2.49 (3H, m), 3.43-3.52 (6H, m), 4.05-4.29 (3H, m), 4.96-5.06 (2H, m), 7.27-7.38 (5H,), 7.80
(0.5H, d), 7.88 (0.5H, d).
METHOD E Benzyl ester of (ÍS) -2- ((2R, 3S) -2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -pyrrolidine-1-carboxylic acid benzyl ester (IS) - 2- ((2S, 3S) -2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -pyrrolidine-1-carboxylic acid
6-1 6.2
A solution of benzyl ester of (1S) -2- ((S) -1- tert-butoxycarbonylmethyl-2,2-diethoxy-ethylcarbamoyl) -pyrrolidine-1-carboxylic acid (4.85 g) in dichloromethane (25 ml) it was cooled to 0 ° C under nitrogen. Then trifluoroacetic acid (6 ml) was added and the mixture was stirred at 0 ° C for 15 minutes, then warmed to room temperature and stirred until the reaction was complete by TLC. The mixture was then diluted with dichloromethane (90 ml) and saturated aqueous sodium bicarbonate solution (130 ml) and stirred for 15 minutes. The organic phase was then removed and washed with 1: 1 saturated aqueous sodium bicarbonate / brine (100 ml), the combined aqueous washings were re-extracted with DCM (100 ml) and the combined organic layers were dried (magnesium sulfate). ), filtered and concentrated under reduced pressure. This provided the subtitle compound as a mixture of epimers in the ketal center (C2). The epimers were separated on silica gel, eluting with 30% acetone / petrol. Syn-isomer 6.1 (white solid); XH NMR (400MHz, d-6 DMSO) d 1.08-1.17 (3H, m), 1.78-2.01 (3H, m), 2.08-2.12 (ÍH, m), 2.37-2.57 (1H, 2 x dd), 2.61 -2.79 (ÍH, 2 x dd), 3.35-3.51 (2H, m), 3.55-3.68 (ÍH, m), 3.71-3.82 (ÍH, d), 4.20-4.32 (ÍH, m), 4.52-4.61 ( ÍH, m), 4.98-5.11 (2H, m), 5.53-5.58 (ÍH, m), 7.24-7.42 (5h, m), 8.25-8.31 (ÍH, m); MS ES + 377.3 (100%), ES-375.3 (10%); Anti-isomer 6.2 (colorless oil); 1H NMR (400MHz, d-6 DMSO) d 1.08-1.19 (3H, m), 1.78-1.89 (3H, m), 2.10-2.34 (HH, m), 2.92-3.07 (HH, 2 x dd), 3.36 -3.51 (3H, m), 3.62-3.78 (2H, m), 4.12-4.21 (2H, m), 4.97-5.12 (3H, m), 7.28-7.40 (5H, m), 8.51-8.58 (ÍH, m); MS ES + 377.4 (100%), ES-375.3 (10%).
Benzyl ester of (lS) -2 - ((2R, 3S) -2-methoxy-5-oxo-etrahydrofuran-3-ylcarbamoyl) -pyrrolidin-1-carboxylic acid benzyl ester (lS) -2- ((2S,
3S) -2-methoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -pyrrolidine-1-carboxylic acid 6.4
Prepared in a manner similar to that described in methods A-E, using the trimethylortoformate in step D, to produce the subtitle compound as a mixture of 6.3 and 6.4 epimers. The epimers were separated on silica gel eluting with 30% to 40% 2-Butanone / Petrol at 70% Acetone / Petrol. Syn-isomer 6.3 (viscous colorless oil); XH NMR (400MHz, d-6 DMSO) d 1.77-1.89 (3H, m), 2.07-2.12 (HH, m), 2.32-2.43 (HH, 2 X d), 2.55-2.61 (HH, 2 X d) , 2.71-2.81 (ÍH, 2 X d),
3. 39-3.62 (4H, m), 4.21-4.30 (HH, m), 4.57-4.64 (1H, m), 5.01-5.09 (2H, m), 5.42-5.47 (HH, m), 7.27-7.42 (5H , m), 8.24-8.31 (ÍH, m); Anti-isomer 6. 4 (white solid); XH NMR (400MHz, d-6 DMSO) d 1.79-1.90 (3H,), 2.09-2.21 (ÍH,), 2.23-41 (ÍH, 2 x d), 2.91-3.05
(ÍH, 2 x dd), 3.35-3.71 (5H, m), 4.09-4.21 (2H, m),
4. 98-5.19 (3H, m), 7.28-7.41 (5H, m), 8.51-8.58 (ÍH, m).
Benzyl ester of (lS) -2 - ((2R, 3S) -2-isopropoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -pyrrolidine-1-carboxylic acid ester 6.5 Benzyl ester of (lS) -2 - ((2S, 3S) -2-isopropoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -pyrrolidine-1-carboxylic acid 6.6
6. 5 6. €
Prepared in a manner similar to that described in Methods A-E, using triisopropylortoformate in step D, to provide the subtitle compound as a mixture of epimers 6.5 and 6.6. The epimers were separated on silica gel eluting with 30% to 40% 2-Butanone / Petrol. Syn-isomer 6.5 (colorless gum); 1H NMR (400MHz, d-6 DMSO) d 1.07-1.16 (6H, m), 1.81-1.86 (2H, m), 2.37-2.71 (2H, m), 3.35-3.53
(2H, m), 3.86-3.90 (1H, m), 4.18-4.24 (HH, m), 4.46- 4.55 (HH, m), 4.95-5.10 (2H, m), 5.63 (HH, d), 7.27 - 7.38 (5H, m), 8.22-8.30 (ÍH, m); MS ES + 391.3
(100%); Antisodium 6.6 (white solid); 1H NMR
(400MHz, d-6 DMSO) d 1.07-1.15 (6H, m), 1.78-1.82
(3H, m), 2.07-2.41 (2H, m), 2.87-3.01 (1H, m), 3.35- 3.50 (2H, m), 3.74-3.96 (ÍH, m), 4.07-4.18 (2H, m) ,
4. 95-5.11 (2H, m), 5.22 (HH, 2 x s), 7.24-7.39 (5H, m), 8.48-8.53 (HH, m); MS ES + 391.4 (100%).
Benzyl ester of the acid (IS) -2- ((2R, 3S) -2-propoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -pyrrolidine-1-carboxylic acid 6. 7 Benzyl ester of the acid (1S) - 2- ((2S,
3S) -2-propoxy-5-oxoetherahydro-furan-3-ylcarbamoyl) -pyrrolidine-1-carboxylic acid 6.8
6. 6.8 Prepared in a manner similar to that described in methods A-E, using tripropylortoformate in step D, to provide the subtitle compound as a mixture of epimers 6.7 and 6.8. The epimers were separated on silica gel eluting with 30% to 40% 2-Butanone / Petrol. Syn-isomer 6.7 (colorless gum); XH
NMR (400MHz, d-6 DMSO) d 0.84-0.93 (3H, m), 1.55 (2H, m), 1.81-1.89 (3H, m), 2.08 -2.22 (HH, m), 2.37-2.61 (HH, 2 x dd), 2.71-2.80 (HH, 2 x dd), 3.31-3.53 (2H, m), 3.60-3.69 (HH, m), 4.20-4.29 (HH, m), 4.52-4.61
(ÍH, m), 4.95-5.11 (2H, m), 5.50 (ÍH, m), 7.27-7.36
(5H, m), 8.27 (ÍH, m); Anti-isomer 6.8 (colorless oil); 1H NMR (400MHz, d-6 DMSO) d 0.82-0.90 (3H, m), 1.46-1.57 (2H, m), 1.77-1.89 (3H, m), 2.06- 2.41 (HH, m), 2.90-3.05 (1H, 2 x dd), 3.33-3.66 (5H, m), 4.11-4.20 (2H, m), 4.94-5.10 (3H, m), 7.28-7.37
(5H, m), 8.51 (ÍH, m).
Benzyl ester of (lS) -2 - ((2R, 3S) -2-butoxy-5-oxo-tetrahydrofuran-3-ylcarbamol .1) - pyrrolidine-1-carboxylic acid 6.9 Benzyl ester of the acid ) -2- ((2S,
3S) -2-butoxy-5-oxo-tetrahydro-furan- • 3 -ylcarbamoyl) -pyrrolidine-1-carboxylic acid 6.10
Prepared in a manner similar to that described in methods A-E, using tributylortoformate in step D, to provide the subtitle compound as a mixture of epimers 6.9 and 6.10. The epimers were separated on silica gel eluting with 30% to 40% 2-Butanone / Petrol. Syn-isomer 6.9 (colorless gum); 1H NMR (400MHz, d-6 DMSO) d 0.86-0.92 (3H, m), 1.28-1.37
(2H, m), 1.45-1.54 (2H, m), 1.79-1.88 (3H, m), 2.07-2.21 (HH, m), 2.35-2.78 (2H, m), 3.31-3.54 (2H, m) ,
3. 63-3.70 (HH, m), 4.21-4.29 (HH, m), 4.51-4.61 (HH, m), 4.95-5.09 (2H, m), 5.50 (HH, m), 7.27-7.37 (5H, m ), 8.25 (ÍH, m); Anti-isomer 6.10 (colorless oil); XH NMR (400MHz, d-6 DMSO) d 0.85-0.93 (3H, m), 1.26-1.36 (2H, m), 1.44-1.56 (2H, m), 1.77-1.90
(3H, m), 2.08-2.40 (ÍH, m), 2.89-3.05 (ÍH, 2 x dd),
3. 34-3.70 (5H, m), 4.08-4.19 (2H, m), 4.95-5.10 (3H, m), 7.28-7.39 (5H, m), 8.53 (1H, m).
METHOD F Benzyl ester of acid. { (S) -1- E (IR, 3S, 4S) -3- ((2R, 3S) • 2-ethoxy-5-oxo-tetrahydro-furan-3-alenbamoyl) -2-pyrrolidin-2 -carbonyl] -2, 2-dimethyl-propyl} -carbamic
To a solution of benzyl ester of (SS) -2- ((2R, 3S) -2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -pyrrolidine-1-carboxylic acid 6.1 (4.68 g) in acetate of ethyl (160ml) and DMF (25ml) was added triethylamine (2.5g) followed by palladium hydroxide / carbon (20% w / w, lg). The mixture was stirred under a hydrogen atmosphere until no starting material was present by TLC. The catalyst was removed by filtration through celite. To the filtrate was added (S) -2-benzyloxycarbonylamino-3, 3-dimethyl-butyric acid (4.93 g), hydroxybenzotriazole hydrate (2.01 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 2.85 g). . The resulting mixture was stirred overnight at room temperature. Then, saturated aqueous sodium bicarbonate solution (180ml) was added and the organic phase was removed. This was washed with saturated aqueous ammonium chloride (180 ml), then with brine (180 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product was purified on silica gel, eluting with 40-75% ethyl acetate / petrol. The subtitle compound was obtained as a white foam (4.02g, 66%); 2H NMR (400MHz, CDC13) d 0.97 (9H, s), 1.14 (3H, t), 1.79-1.94 (3H, m), 2.02-2.10 (HH, m), 2.44 (HH, dd), 2.75 (HH) , dd), 3.52-3.66 (2H,), 3.70-3.79 (2H, m), 4.22 (lH, d), 4.38-4.41 (HH, m), 4.48-4.58 (HH, m), 5.03 (2H, q), 5.56 (HH, d), 7.26 (HH, d), 7.29-7.40 (5H, m), 8.24 (HH, d); MS ES + 490.6 (100%), ES-488.8 (10%).
METHOD G ((2R) -ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (3, S, S, R) -1- [(2S) - (3-methoxy-2) -methyl-benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
To a solution of benzyl ester of the acid. { (S) -1- [(1R, 3S, 4S) -3- ((2R, 3S) -2-Ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -2-pyrrolidin-2 -carbonyl] -2 , 2-dimethyl-propyl} Carbamic acid (344mg) in ethyl acetate (20ml) was added palladium hydroxide / carbon (20% w / w, 74mg). The mixture was stirred under a hydrogen atmosphere until no starting material was present by TLC. The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure to provide the amine as a brown foam (260mg). A portion of this material (153mg) was dissolved in THF and 3-methoxy-2-methyl benzoic acid (146mg), diisopropylamine (191μl), hydroxybenzotriazole hydrate (77mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide were added. hydrochloride (EDC, 109mg). The resulting mixture was stirred at room temperature for 24 hours then diluted with saturated aqueous sodium bicarbonate. The organic phase was removed and washed with saturated aqueous ammonium chloride, then with brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product was purified on silica gel, eluting with ethyl acetate. This provided the subtitle compound as a white solid (138mg, 62%); the analytical data are summarized in Table 3. The compounds of formulas 1-2 to 1-58 have been prepared by methods practically similar to those described in Example 1-1.
EXAMPLE 1-2 [(2R) -Estaxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [(2S) - (2-methoxy) -benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-3 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (S, S, S, R) - 1 - [3 -me l - (2 S ) - (2-trifluoromethoxy-benzoylamino) -butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-4 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g, S, S, R) -1- [(2S) - (3-hydroxy) -2-methyl-benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-5 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [(2S) - (3-amino) - 2-methyl-benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-6 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [(2S) - (2, 6) -dichloro-benzoylamino) -3-methyl-butylril] -pyrrolidin- (2S) -carboxylic acid
EXAMPLE 1-7 (g, fl, fl. G) -N-. { (1S) - [(23) - ((2R) -Ethoxy-5-oxo-tetrahydrofuran- (3g) -ylcarbamoyl) -pyrrolidin-1-carbonyl] -2-methyl-propyl} -2-methyl-nicotinamide
Ottfrt EXAMPLE 1-8 (S, S, S, R) -N-. { (SS) - [(2S) - ((2R) -ethoxy-5 -oxo-tetrahydro furan- (3g) -ylcarbamoyl) -pyrrolidin-1-carbonyl] -2-methyl-propyl} -4-methyl-nicotinamide
EXAMPLE 1-9 [(2R) - Ethoxy-5-oxo-tetrahydrofuran- (3S) -yl] -amide of the acid (g, S, S, R) -l-. { 3-methyl- (2S) - [(3-ethylthiophene-2-carbonyl) -amino) -butyryl} -pyrrolidin- (2S) -carboxylic acid
EXAMPLE I -10 (S, S, S, R) -2,3-Dichloro-N- f (1S) - ((2S) - ((2R) -ethoxy-5-oxo-tetrahydro-furan- (3S) -carbamoyl) -pyrrolidin-1 'carbonyl] -2-methyl-propyl) -isonicotinamide
EXAMPLE I -11 (S, S, S, R) -3,5-Dichloro-Nf (1S) - [(2S) - ((2R) -et? Xi-5-oxo-tetrahydro-furan- (3S) -carbamoyl) -pyrrolidin-1 carbonyl] -2-methyl-propyl} - isonicotinamide
EXAMPLE 1-12 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amine of the acid (g, S, S, R) -1- [(2S) - (3-methoxy) -2-methyl-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-13 [(2R) - • Methoxy-5-oxo-tetrahydrofuran- (3S) -yl] -amine of (S, s. S, R) -1 - [(2S) - (3 -methoxy-2-methyl-benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-14 [(2R) -Isopropoxy-5 -oxo-tetrahydrofuran- (3S) -yl] -amide of the acid (g, S, S, R) -1- [(2S) - (3-methoxy) -2-methyl benzoylamino) -3-methyl-butyryl-pyrrolidin- (2S) -carroxylic acid
EXAMPLE 1-15 [5-Oxo- (2R) -propoxy-5-tetrahydro-furan- (3S) -yl] -amide of the acid (g, S, S, R) -1- [(2S) - (3 -methoxy-2-methyl-benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic EXAMPLE 1-16 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] - (S, S, S, R) -1 - [(2S) - (2-Chloro-benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid amide
EXAMPLE 1-17 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [3, 3-dimethyl- (2S) acid ) - (2-methyl-benzoylamino) -butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-18 [(2R) -Ethyo-5-oxo-tetrahydro-furan-3 (S) -yl] -amide of (S, S, S, R) -1- [3-methyl-2 (S ) - (2-trifluoromethyl-benzoylamino) -butyryl] -pyrrolidin- (2S) -carboxylic acid EXAMPLE 1-19 [(2R) -Metoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid ( g, S, S, R) -1- (S) - (2-chloro-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) -carboxylic acid
EXAMPLE 1-20 [(2R) - Isopropoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g, s, s, R) -1- [3, 3-dimethyl- (2S) - (2-trifluoromethyl-benzoyl-ino) -butyryl] -pyrrolidin- (2S) -carboxylic acid
EXAMPLE 1-21 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [(2S) - (2-Chloro) -benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid EXAMPLE I-22 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid ( S, S, S, R) -1- [3,3-dimethyl- (2S) - (2-trifluoromethyl-benzoylamino) -butyryl] -pyrrolidin- (2S) -carboxylic acid
EXAMPLE 1-23 [5-? Oxo- (2R) - Propoxy-tetrahydrofuran - (3S) -yl] -amide of the acid (= ', S g S, R) - 1 - E (2S) - ( 2-chloro-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidip L- (2S) -carboxylic acid
EXAMPLE 1-24 [(2R) -Butoxy -5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g, s. R) -1- [(2S) - (2- chloro-benzoylamino) -3,3-dimeti i-: butyryl] -pyrrolidin- (2S) -carboxylic EXAMPLE 1-25 [(2R) -Ethyoxy-5 -oxo-tetrahydro-furan-- (3S) - il] -amide of the acid (S, S, S, R) • -1-- [(2S) - (2-chloro-3-trifluoromethoxy-benzoylamino) -3,3-dimethyl-butyryl] -pyrreilidin - (2S) - carboxylic
EXAMPLE 1-26 [5-Oxo (2R) -propoxy-tetrahydro-furan- (3S) -yl] -amide of the acid (g, S, S, R) -1- [(2S) - (2-chloro- benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-27 [5-Oxo- (2S) -propoxy-tetrahydro-furan- (3S) -yl] -amide of the acid (g, S, S, S) -1 - [(2S) - (2-chloro) -benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid EXAMPLE 1-28 [(2S) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g, S , g, g) -1- [(2S) - (2-chloro-benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-29 [(2R) -Butoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [(2S) - (2-chloro) -benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-30 [(2S) -Butoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g, g, S, S) -1- [(2S) - (2-chloro) -benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid EXAMPLE 1-31 [(2R) -Isopropoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (S, S, S, R) - 1- [(2S) - (2-chloro-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) -carboxylic
EXAMPLE 1-32 [(2S) -Isopropoxy-5-oxo-tetrahydro-furan- (3S) -yl] amide of (S, S, S, S) -1- [(2S) - (2-chloro- benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-33 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g, g, g, .R) -1- [(2S) - (2- chloro-3-cyclopropyloxy-benzoxylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) carboxylic acid
EXAMPLE 1-34 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, 3, S, R) -1- [(2S) - (2-chloro) -3-methyl-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) -carboxylic acid
[(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [(2S) - (2-chloro-3-methoxy) -benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-36 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g, g, g, .R) -1 - [(2S) - (2 - chloro-3-ethyl-benzoylamino) -3, 3-dimethyl-butyryl] -pyrrolidin- (2S) -carboxylic acid
EXAMPLE 1-37 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [(2S) - (2-chloro) -4-methoxy-benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1 - 38 E (2R) -ethoxy-5-oxo-tetrahydro-furan-- (3S) -yl] -amide of (S, S, B, R) -1-- E (2S) - ( 2-Chloro-3-cyclopropylmethyl-1-benzoyl -lamino) -3,3-dimethyl-1-butyryl] -pyrrolidine- (2S) -carboxylic acid EXAMPLE 1-39 C (2R) -ethoxy-5 -oxo-- tetrahydro-furan-- (3S) -yl] -amide of the acid. { S, S, S, R) -1-- [(2S) - (2-chloro-3-hydroxy-benzoi -lamino) -3,3-dimethyl-butyryl] -pyrrolid, in- (2S) _ carboxxlic
EXAMPLE 1-40 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (SfS, S, R) -1- [(2S) - (2-chloro-4 -acetamido-benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-41 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- E (2S) - (2-chloro) - 3 -acetyl-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) carboxylic acid
EXAMPLE 1-42 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1 - [(2S) - (2-methyl) -3-acetamido-benzoxylamino) -3,3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-43 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g, S, S, R) -1- E (2S) - (2-chloro) -4-acetamido-benzoylamino) -3, 3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-44 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [(2S) - (2-fluoro) -4-acetamido-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-45 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, 3, S, R) -1- [(2S) - (2-fluoro) -4-acetamido-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) -carboxylic acid
EXAMPLE 1-46 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g, g, S, R) -1- [(2S) - (2-chloro) -4-isopropyloxy-benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid EXAMPLE 1-47 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide acid (g, 3, S, R) -1- [(2S) - (2-chloro-4-hydroxy-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) -carboxylic acid
EXAMPLE 1-48 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [(2S) - (2-chloro) -4-methoxymethyl-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1 - 4 9 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g,, 3, R) -1- [(2S) - (2-chloro) -4-isobutyrylamido-benzoylamino) -3, 3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-50 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, K) -1- [(2S) - (2-chloro) -4 - Cetamido-benzoylamino) -3-cyclohexyl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-51 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [(2S) - (2-chloro) -4-methoxycarbonylamino-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic EXAMPLE 1-52 [(2R) -Ethoxy-5 -oxo-tetrahydro-furan- (3S) -yl] - Amide of the acid (S, S, S, R) -1- [(2S) - (2-chloro-3-phenoxy-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) -carboxylic acid
EXAMPLE 1 - 53 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g, g, g, R) -1- [(2S) - (2-chloro -4-thiazolylamino-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) -carboxylic acid
* ^ 5 H 0 EXAMPLE - 54 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g,, S, R) -1- [(2S) - ( 3-amino-2-chloro-benzoylamino) -3-methyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-55 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- E (2S) - (2-chloro) -benzoylamino) -3-thiazol-4-yl-propionyl] -pyrrolidin- (2S) -carboxylic acid
EXAMPLE 1-56 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (S / S, S, R) -1 - [(2S) - (3-methoxy) -2-methyl-benzoylamino) -3-thiazol-4-yl-propionyl] -pyrrolidin- (2S) -carboxylic acid
EXAMPLE 1-57 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of the acid (g, S, S, R) -1- [(2S) - (2-chloro) - 3-methoxy-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine- (2S) -carboxylic acid
EXAMPLE 1-58 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of (S, S, S, R) -1- [(2S) - (2-chloro) -benzoylamino) -3,3-dimethyl-butyryl] -piperidine- (2S) -carboxylic acid
EXAMPLE 1-59 [2- (2S) - (3-methoxy-2-methyl-benzoylamino) -3 [2- (2R) -ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide, 3-dimethyl-butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic acid
METHOD H Benzyl ester of (IR, 3S, 4S) -3 ((S) -2- tert -butoxycarbonyl-1-hydroxymethyl-ethylcarbamoyl) -2-aza-bicyclo [2.2.1] heptan-2-carboxylic acid
To a stirred solution of (S) -3-amino-4-hydroxy-butyric acid tert-butylester (486 mg) and 2-benzyl ester of (IR, 3S, S) -2-aza-bicyclo [2.2.1] ] heptan-2,3-dicarboxylic acid (prepared as described in Tararov et al., Te tt Asmm, 2002, 13, 25-28) (767 mg) in THF (18 ml) was added 2-hydroxybenzotriazole hydrate (452) mg), DMAP (426 mg), diisopropylethylamine (631D1) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 641 mg). The resulting mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate. The mixture was then washed with water, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (60% ethyl acetate / petrol) to give the subtitle compound as a yellow oil (1.10 g, 91%); XH NMR (400 MHz, d-6 DMSO) d 1.13-1.25 (1H, m), 1.30-1.48 (9H, m), 1.49-1.88 (6H, m), 2.20-2.52 (2H, m), 3.09- 3.34 (2H, m), 3.64 (HH, d), 4.00-4.16 (2H, brm), 4.80 (HH, m), 4.90-5.15 (2H, m), 7.21-7.41 (5H, m), 7.50- 7.75 (ÍH, m); MS ES (+) 433.37.
METHOD I Benzyl ester of (IR, 3S, 4S) -3 - ((S) -2-tert-butoxycarbonyl-1-formyl-ethylcarbamoyl) -2-aza-bicyclo [2. 2 . 1] heptan-2-carboxylic acid
A solution of benzyl ester of (1R, 3S, 4S) -3 ((S) -2- tert -butoxycarbonyl-1-hydroxymethyl-ethylcarbamoyl) -2-aza-bicyclo [2.2.1] heptan-2-carboxylic acid ( 1.1 g) in DCM (10 ml) was cooled to 0 ° C under nitrogen. Then 2,2,6,6-tetramethylpiperidinyloxy (TEMPO, 4 mg) was added followed by trichloroisocyanuric acid (621 mg) in portions over 30 minutes. The mixture was stirred at room temperature for 1 hour, then filtered through celite. The filtrate was washed with water, 1M sodium thiosulfate solution and brine. It was dried over magnesium sulfate and concentrated under reduced pressure to provide the subtitle compound as a yellow oil (698 mg, 64%); XH NMR (400 MHz, d-6 DMSO) d 1.16-1.89 (16H, m), 2.30-2.80 (2H, m), 3.68-3.81 (1H, m), 4.19 (HH, brm), 4.39, (HH) , m), 4.91-5.16 (2H, m), 7.21-7.43 (5H, m), 8.45 (0.4H, d), 8.60 (0.6, d), 9.19 (0.6H, s), 9.37 (0.4H, s).
METHOD J Benzyl ester of the acid (IR, 3S, 4S) -3 - ((S) -1- er -butoxycarbonylmethyl- 2,2 -dietoxy-ethylcarbamoyl) -2-aza-bicyclo [2.2.1] heptan- 2 - carboxylic
To a solution of benzyl ester of (1R, 3S, 4S) -3- ((S) -2-er-butoxycarbonyl-1-formyl-ethylcarbamoyl) -2-aza-bicyclo [2.2.1] heptan- 2- carboxylic acid (698 mg) in dichloromethane (10 ml) was added triethyl orthoformate (720 mg) and p-toluenesulfonic acid monohydrate (6 mg). The resulting mixture is stirred at room temperature until no aldehyde is left by TLC analysis. Then, saturated aqueous sodium bicarbonate solution was added and the organic phase was removed. This was washed with water and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. This gave the subtitle compound as a light yellow oil (635 mg, 78%); XH NMR (400 MHz, d-6 DMSO) d 0.96-1.15 (6H, m), 1.26-1.84 (16H, m), 2.20-2.50 (2H, m), 3.40-3.81 (5H, m), 4.10- 4.28 (2H, m), 4.37 (HH, m), 4.88-5.14 (2H, m), 7.20-7.40 (5H, m), 7.65 (0.5H, d), 7.80 (0.5H, d).
METHOD K Benzyl ester of the acid (IR, 3S, 4S) -3 - ((2R, 3S) -2-ethoxy-5-oxo-tetrahydrofuran-3-carbamoyl) -2-azabicyclo [2.2.1] heptan- 2 -carboxylic
A solution of benzyl ester of (1R, 3S, 4S) -3- ((S) -1- er -butoxycarbonylmethyl-2,2-diethoxy-ethylcarbamoyl) -2-aza-bicyclo [2.2.1] heptan- 2 -carboxylic (635mg) in dichloromethane (3ml) was cooled to 0 ° C under nitrogen. Then trifluoroacetic acid (0.7 ml) was added and the mixture was stirred at 0 ° C for 15 minutes, then warmed to room temperature and stirred until the reaction was complete by TLC. The mixture was then diluted with dichloromethane (10 ml) and saturated aqueous sodium bicarbonate solution (14 ml). The organic phase was then removed and washed with 1: 1 saturated aqueous sodium bicarbonate / brine (8 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure. This provided the subtitle compound as a mixture of epimers in the ketal center. The epimers were separated on silica gel, eluting with 30% 2-butanone / petrol. Syn-isomer (oil) (115 mg, 23%); 1H NMR (400 MHz, d-6
DMSO) d 0.80-1.91 (10H, m), 2.35-2.79 (2H, m), 3.56
(HH, m), 3.66-3.80 (2H, m), 4.18 (HH, m), 4.59 (1H, m), 4.94-5.11 (2H, m), 5.53 (HH, d), 7.20-7.40 (5H , m), 8.18 (0.5H, d), 8.27 (0.5H, d); MS ES + 403.31 (100%), ES-401.37 (15%); Anti-isomer (oil) (103mg, 20%); 1 H NMR (400MHz, d-6 DMSO) d 0.80-1.85 (10H, m), 2.25-2.60 (HH, m), 2.95 (HH, m), 3.42 (HH, m), 3.5-3.75 (2H, m ), 4.88-5.15 (3H, m), 7.21-7.40 (5H, m), 8.50 (0.4H, d), 8.59 (0.6H, d).
METHOD L Benzyl ester of acid. { (S) -1- [(IR, 3S, 4S) -3 - ((2R, 3S) -2-Ethoxy-5-oxo-tetrahydro-furan-3-carbamoyl) -2-azabicyclo [2.2.1] heptan - 2 -carbonyl] -2, 2 -dimethyl-propyl} -carbamic
To a solution of benzyl ester of acid (1R), 3S, 4S) -3- ((2R, 3S) -2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -2-aza-bicyclo [2.2.1] heptan-2-carboxylic acid (5g) in ethyl acetate (160ml) and DMF (25ml) was added triethylamine (2.5g) followed by palladium hydroxide / carbon (20% w / w, lg) • The mixture was stirred under a hydrogen atmosphere until it was no longer no starting material by TLC analysis. The catalyst was removed by filtration through celite. To the filtrate was added (S) -2-benzyloxycarbonylamino-3, 3-dimethyl-butyric acid (4.93g), hydroxybenzotriazole hydrate (2.01g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC, 2.85g) . The resulting mixture was stirred at room temperature overnight. Then, saturated aqueous sodium bicarbonate solution (180 ml) was added and the organic phase was removed. This was washed with saturated aqueous ammonium chloride (180 ml), then with brine (180 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product was purified on silica gel, eluted with 40-75% ethyl acetate / petrol. The subtitle compound was obtained as a white foam (5.25g, 81%); 1H NMR (400MHz, d-6 DMSO) d 0.85-1.03 (10H, m), 1.07-1.20 (3H, t),
1. 30 (ÍH, m), 1.40 (ÍH, m), 1.50-1.80 (3H, m), 1.93
(ÍH, m), 2.40-2.50 (ÍH, m), 2.78 (ÍH, m), 3.60 (ÍH, m), 3.78 (ÍH, m), 3.89 (ÍH, s), 4.26 (1H, d), 4.52 (2H, m), 4.96-5.12 (2H, m), 5.56 (1H, d), 7.10 (1H, d), 7.24-7.40 (5H, m), 8.27 (1H, d); MS ES + 516.93 (100%), ES-515.05 (100%).
METHOD M ((2R, 3S) -2-Ethoxy-5-oxo-tetrahydro-furan-3-yl) -amide of the acid (IR, 3S, 4S) -2 - E (S) -2 - (3-methoxy) -2-methylbenzoylamino) -3,3-dimethyl-butyryl] -2-aza-bicycloE2.2.1] heptan-3-carboxylic acid
To a solution of benzyl ester of the acid. { (S) -l- [(1R, 3S, 4S) -3 - ((2R, 3S) -2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl) -2-azabicyclo [2.2.1] heptan- 2-carbonyl] -2, 2-dimethyl-propyl} -carbamic (370mg) in ethyl acetate (20ml) was added palladium hydroxide / carbon (20% w / w, 74mg). The mixture was stirred under a hydrogen atmosphere until no starting material was present by TLC analysis. The catalyst was removed by filtration through celite and the filtrate was concentrated under reduced pressure to provide the amine as a brown foam (272mg). A portion of this material (167mg) was dissolved in THF and 3-methoxy-2-methylbenzoic acid (146mg), diisopropylamine (191D1), hydroxybenzotriazole hydrate (77mg) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added.
(EDC, 109mg). The resulting mixture was stirred at room temperature for 24 hours, then diluted with saturated aqueous sodium bicarbonate. The organic phase was removed and washed with saturated aqueous ammonium chloride, then with brine, dried
(Magnesium sulfate), filtered and concentrated under reduced pressure. The crude product was purified on silica gel, eluted with ethyl acetate. This provided the subtitle compound as a white solid (121mg, 52%); 1H NMR (400MHz, CDC13) d 1.10 (9H, s), 1.28 (3H, t), 1.43-1.56 (HH, m), 1.79-1.86 (3H, m), 1.99 (HH, brd), 2.29 (3H , s), 2.30-2.37
(1H, m), 2.83 (1H, dd), 3.02 (HH, brs), 3.66-3.74 (1H, m), 3.87 (3H, s), 3.88-3.94 (HH, m), 4.16 (HH, brs ), 4.54 (1H, brs), 4.66-4.74 (HH, m), 4.97 (HH, d), 5.46 (HH, d), 6.44 (HH, brd), 6.93 (HH, d), 7.00
(ÍH, d), 7.22 (ÍH, t), 7.78 (ÍH, brd); IR (solid) cm "1 2960, 1791, 1624, 1505, 1438, 1261, 1115, 975; MS ES + 530; ES-528.
The compounds of formulas 1-60 to I-73 have been prepared by methods practically similar to those described in Example 1-59.
EXAMPLE 1-60 [2- (2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of 2 - [(2S) - (2-chloro-benzoylamino) -3,3-dimethyl- butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic
EXAMPLE 1-61 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of 2- [(2S) - (4-acetylamino-2-chloro-benzoylamino) -3 acid, 3-dimethyl-butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic acid
EXAMPLE 1-62 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of 2- E (2S) - (2-chloro-4-propionylamino-benzoylamino) -3, 3-dimethyl-butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic EXAMPLE 1-63 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- ( 3S) -yl] -2- [(2S) - (2-chloro-3-isobutyrylamino-benzoylamino) -3,3-dimethyl-butyryl] -2- (1S, 4R) -aza-bicyclic acid [2.2] .1] heptan- (3S) -carboxylic
EXAMPLE 1-64 [2- (2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of 2 - [(2S) - (2-fluoro-3-methoxy-benzoylamino) -3, 3-dimethyl-butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.13 heptan- (3S) -carboxylic acid
EXAMPLE 1-65 [2R-Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of 2 - [(2S) - (2-fluoro-3-methoxy-benzoylamino) -3- methyl-butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic acid
EXAMPLE 1-66 2 - [(2S) - (3-methoxy-2-methyl-benzoylamino) -3 [(2S) -ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide, 3-dimethyl-butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic acid
EXAMPLE 1-67 E (2S) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of 2 - [(2S) - (2-chloro-benzoylamino) -3,3-dimethyl- butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic
EXAMPLE 1-68 [(2R) -Ethyo-5-oxo-tetrahydro-furan- (3S) -yl] -amide of 2- [(2S) - (4-acetylamino-3-chloro-benzoylamino) -3 acid, 3-dimethyl-butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic acid
EXAMPLE 1-69 - [(2S) - (3-Chloro-4-propionylamino-benzoylamino) -3 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide, 3-dimethyl-butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic acid
EXAMPLE 1-70 [2- (2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of 2 - [(2S) - (isoquinolin-1-ylcarbonylamino) -3,3-dimethyl- butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic EXAMPLE 1-71 [(2R) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -il ] acid measurement 2-1 (2S) - (4-amino-3-chloro-benzoylamino) -3,3-dimethyl-butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic
EXAMPLE 1-72 [(2S) - (4-amino-3-chloro-benzoylamino) -3- [(2R) -ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide. methyl-butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic acid
EXAMPLE 1-73 [2- (2S) -Ethoxy-5-oxo-tetrahydro-furan- (3S) -yl] -amide of 2 - [(2S) - (isoquinolin-1-ylcarbonylamino) -3,3-dimethyl- butyryl] -2- (1S, 4R) -aza-bicyclo [2.2.1] heptan- (3S) -carboxylic
Table 3. Characterization data for the selected compounds of Formula I (by number of
EXAMPLE II-1 Acid (g, g, g, J.) - (3S) - (fl - [(2S) - (3-methoxy-2-methyl benzoylamino) -3-methyl-butyryl] pyrrolidin- (2S) - carbonyl.} - amino) -4 -oxo-butyrate
METHOD I ((S, S, S, R) -1- [2S) - (3-methoxy-2-methyl) [(2R) -ethoxy-5-oxo-tetrahydrofuran- (3S) -yl] amide was dissolved. -benzoylamino) -3-methyl-butyryl] pyrrolidine- (2S) -carboxylic acid (97.6 mg, 0.20 mmol) in a mixture of 2M HCl and MeCN (2 ml). The reaction mixture was stirred at room temperature for 2.5 hours. The resulting crude mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was co-evaporated with DCM / Petrol to give the title of the compound as a white solid (81.3mg, 88% yield). The compounds of formulas II-2 to II-61 were prepared by methods practically similar to those described in Example II-1.
EXAMPLE II -2 Acid (S, S, S) - (3S) - (fl- [(2S) - (2-chloro-benzoylamino) 3-methyl-butyryl] -pyrrolidin- (2S) -carbonyl.} - amino) -4-oxo-butyric
EXAMPLE II -3 Acid (S, S, S) - (3S) - (f 1- [3-methyl- (2S) - (2-methyl-benzoylamino) -butyryl] -pyrrolidin- (2S) -carbonyl. amino) -4 -oxo-butyric EXAMPLE II - 4 Acid (S, S, S) - (3S) - ((l- [(2S) - (2-methoxy-benzoylamino) 3-methyl-butyryl] -pyrrolidine - (2S) -carbonyl.}. -amino) -4-oxo-butyric
EXAMPLE II -5 Asid (g, g, g) - (3S) - ((l- [3-methyl- (28) - (2-trifluoromethoxy-benzoylamino) -butyryl] -pyrrolidin- (2S) -carbonyl. -amino) -4 -oxo-butyric
EXAMPLE II -6 Acid (S, S, S) - (3S) - (f 1 - [(2S) - (3-hydroxy-2-methyl-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) -carbonyl .}. -amino) -4-oxo-butyric EXAMPLE II -7 Acid (g, g, g) - (3S) - ( { l - [(2S) - (3-amino-2-methyl-benzoylamino ) -3-methyl-butyryl] -pyrrolidin- (2S) carbonyl.] - amino) -4-oxo-butyric
EXAMPLE II -8 Acid (g, g, g) - (3S) - (fl- [(2S) - (2,3-dichloro-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) carbonyl. . -amino) -4 -oxo-butyrate
EXAMPLE II -9 Acid (g, g, g) - (3S) - (fl- [(2S) - (2-chloro-3-trifluoromethyl-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) - carbonyl.} -amino) -4 -oxo-butyric
EXAMPLE 11-10 Acid (g, g, g) - (3S) - (fl - [(2S) - (3-chloro-2-methyl-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) carbonyl .}. -amino) -4 -oxo-butyric
EXAMPLE 11-11 Acid (g, g, g) - (3S) - (fl - [(2S) - (2,4-dichloro-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) carbonyl. - amino) -4 -oxo-butyric
EXAMPLE 11-12 Acid (8.8.8) - (3S) - (fl- [(2S) - (2, 5-dichloro-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) carbonyl. -amino) -4 -oxo-butyric
EXAMPLE II-13 Acid (S, 3, S) - (3S) - (f 1 - [(2S) - (2,6-dichloro-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) carbonyl. -amino) -4 -oxo-butyric
EXAMPLE -14 Acid (8.8.8) - (38) - ( { L-1 (28) - (2,6-methyl-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) carbonyl .}. -amino) -4 -oxo-butyric
EXAMPLE 11-15 Acid (8.38) -. { 33) -j (1-f 3 -methyl- (2S) - [(2-methyl-pyridin-3-carbonyl) -amino] -butyryl.} - pyrrolidin- (2S) carbonyl) -amino] -4- oxo-butyric
EXAMPLE 11-16 Acid (8,8,8) - (38) -l (1-f 3 -methyl- (2S) - [(4-methyl-pyridine-3-carbonyl) -amino] -butyryl. -pyrrolidin- (2S) sarbonyl) -amino] -4-oxo-butyric
EXAMPLE 11-17 Acid (S, S, S) - (3S) - [(1-f3-methyl- (2S) - [(3-methyl-2-phenyl-2-carbonyl) -amino] -butyryl} - pyrrolidin- (2S) sarbonyl) -amino] -4-oxo-butyryl
EXAMPLE 11-18 Acid (S, S, S) - (3S) - [(1-f (2S) - [(2,3-disloro-pyridin-4 -sarbonyl) -amino] -3-methyl-butyryl} -pyrrolidin- (2S) -sarbonyl) -amino] -4 -oxo-butyryrene
EXAMPLE 11-19 Asid (g, g, g) - (3S) - [(lf (2S) - [(3,5-disloro-pyridin-4-sarbonyl) -amino] -3-methyl-butyryl} - pyrrolidin- (2S) -sarbonyl) -amino] -4 -oxo-butyryl
EXAMPLE 11-20 Acid (S, S, S) - (3S) - (f 1- [(2S) - (3-methoxy-2-methyl-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- ( 2S) carbonyl.} -amino) -4-oxo-butyryr
EXAMPLE 11-21 Acid (S, S, S) -4 -oxo- (3S) - (f-E4, 4, 4-trifluoro- (2S) - (2-methyl-3-methoxy-benzoylamino) -butyryl ] -pyrrolidin- (2S) -carbonyl) -amino) -butyric
EXAMPLE 11-22 Assid (S, S, g) - (3S) - (fl - [(2S) -5- (methoxy-2-methyl-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) -carbonyl} -amino) -4 -oxo-butyric
EXAMPLE 11-23 Acid (g, g, g) - (3S) - (fl - [(2S) - (3-methoxy-2-methyl-benzoylamino) -3-thiazol-4-yl-propionyl] -pyrrolidin- (2S) -carbonyl.}. -amino) -4 -oxo-butyric
EXAMPLE 11-24 Acid (3,3,3) - (3S) - (1- [(2S) - (2-chloro-benzoylamino) 4, 4, 4 -trif luoro-butyryl] -pyrrolidin- (2S) - sarbonyl.}. -amino) -4 -oxo-butyris
EXAMPLE 11-25 Asid (S, S, S) - (3S) - (1- [(2S) - (2-chloro-benzoylamino) 3-thiazol-4-yl-propionyl] -pyrrolidin- (2S) -sarbonil .}. -amino) -4 -oxo-butyriso
EXAMPLE 11-26 Asid (S, 3.3) - (3S) - (fl- [3,3-dimethyl- (2S) - (2-methyl benzoylamino) -butyryl] -pyrrolidin- (2S) -sarbonyl. -amino) -4 -oxo-butyric
EXAMPLE 11-27 Asid (S, S, S) - (3S) - (f 1- [3-methyl- (2S) - (2-trifluoromethyl-benzoylamino) -butyryl] -pyrrolidin- (2S) -sarbonyl. -amino) -4-oxo-butyryrene
EXAMPLE 11-28 Asid (S, S, S) - (3S) - (f 1- [(2S) - (2-chloro-benzoylamino) 3,3-dimethyl-butyryl] -pyrrolidin- (2S) -sarbonyl} -amino) -4 - oxo - butyris
EXAMPLE 11-29 'Asid (S, S, S) - (3S) - (fl- [3, 3-dimethyl - (2S) - (2-trif luoromethyl-benzoylamino) -butyryl] -pyrrolidin- (2S) - sarbonyl.}. -amino) -4 -oxo-butyris
EXAMPLE 11-30 Asid (8, 8, 8) - (38) - (. {1- 1- (28) - (2-sloro-3-methoxy-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine - (2S) sarbonl.}. -amino) -4-oxo-butyric
EXAMPLE 11-31 Acid (S, S, S) - (3S) - (f 1- [(2S) - (2-fluoro-3-methoxy-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- ( 2S) carbonyl.} - amino) -4 -oxo-butyryl
EXAMPLE 11-32 Asid (S, S, S) - (3S) - (fl- [(2S) - (2-chloro-3-trifluoromethoxy-benzoylamino) -3,3-dimethyl-butyryl] pyrrolidin- (2S) -sarbonyl.}. -amino) -4 -oxo-butyriso
EXAMPLE 11-33 Asid (g, g, g) - (3S) - (fl - [(2S) - (2-chloro-3-sisloprop-yloxy-benzoylamino) -3,3-dimethyl-butyryl] pyrrolidin- (2S) ) -sarbonil.}. -amino) -4 -oxo-butyriso
EXAMPLE 11-34 Asid (g, g, g) - (3S) - (fl - [(2S) - (2-chloro-3-methyl-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) ) sarbonyl.} -amino) -4 -oxo-butyryl
EXAMPLE 11-35 Assid (S, S, S) - (3S) - (1- [(2S) - (2-Sollor-3-methoxybenzoylamino) -3-methyl-butyryl-pyrrolidin- (2S) sarbonyl. -amino) -4-oxo-butchriso
EXAMPLE 11-36 Asid (g, g, g) - (3S) - (fl - [(2S) - (2-chloro-3-ethyl-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) ) sarbonyl.} -amino) -4 -oxo-butyryl
EXAMPLE 11-37 Assid (g, g, g) - (3S) - (fl - [(2S) - (2-chloro-4-methoxybenzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) sarbonyl} -amino) -4 -oxo-butyriso
EXAMPLE 11-38 Asid (8,8,8) - (38) - (. {1- 1 (28) - (2-chloro-3-cyclopropylmethoxy-benzoylamino) -3,3-dimethyl-butyryl] pyrrolidin- (2S) -carbonyl.}. -amino) -4 -oxo-butyryl
EXAMPLE 11-39 Asid (8, 8, 8) - (38) - (. {1- 1- (28) - (2-Sloro-3-hydroxy-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidine - (2S) carbonyl.] - amino) -4-oxo-butyric
EXAMPLE 11-40 Assid (S, S, 3) - (3S) - (f 1- [(2S) - (2-Chloro-4-phenytoin-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) -sarbonyl.}. -amino) -4 -oxo-butyriso
EXAMPLE 11-41 Asid (S, S, 3) - (3S) - (1 - [(2S) - (2-Sulfo-3-asetamido-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) ) sarbonyl.} -amino) -4 -oxo-butyryl
EXAMPLE 11-42 Asid (S, S, S) - (3S) - (1- [(2S) - (2-methyl-3 -asetamido-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) carbonyl.} -amino) -4 -oxo-butyric
EXAMPLE 11-43 Acid (S, S, S) - (3S) - (f 1- [(2S) - (2-Sloro-4-acetamido-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- ( 2S) carbonyl.] -amino) -4-oxo-butyric
EXAMPLE 11-44 Acid (S, S, S) - (3S) - (f 1- [(2S) - (2-fluoro-4-acetamidobenzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S ) sarbonyl.} -amino) -4 -oxo-butyryl
EXAMPLE 11-45 Asid (S, S, S) - (3S) - (f 1- [(2S) - (2-fluoro-4 -asetamidobenzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) - sarbonyl.}. -amino) -4 -oxo-butyric
EXAMPLE 11-46 Asid (S, S, S) - (3S) - ((1- [(S) - (2-chloro-4-isopropyloxybenzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) - sarbonyl.}. -amino) -4 -oxo-butyris
EXAMPLE 11-47 Asid (S, S, S) - (3S) - (f 1- [(S) - (2-Sloro-4-hydroxy-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- ( 2S) sarbonyl.}. -amino) -4 -oxo-butyryl
EXAMPLE 11-48 Asid (S, S, S) - (3S) - (f 1- E (2S) - (2-Sulfo-4-methoxymethylbenzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S) ) -sarbonil.}. -amino) -4 -oxo-butyriso
EXAMPLE 11-49 Asid (S, 3, g) - (3S) - (fl-E (2S) - (2-chloro-4-isobutyrylamido-benzoylamino) -3,3-dimethyl-butyryl] pyrrolidin- (2S) -sarbonyl.}. -amino) -4 -oxo-butchriso
EXAMPLE 11-50 Asid (3, S, S) - (3S) - (f 1- (2S) - (2-Sloro-4 -asetamido-benzoylamino) -3-sislohexyl] -pyrrolidin- (2S) -carbonyl- amino) -4 -oxo-butyryl
EXAMPLE 11-51 Asid (8,8,8) - (38) - (l- [(28) - (2-Sulfo-4-methoxysarbonylamino-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- (2S ) -sarbonyl.}. -amino) -4-oxo-butyryrene
EXAMPLE 11-52 Asid (S, S, S) - (3S) - (f 1- E (2S) - (2-Sloro-3-phenoxy-benzoylamino) -3,3-dimethyl-butyryl] -pyrrolidin- ( 2S) sarbonyl.}. -amino) -4 -oxo-butyryl
EXAMPLE 11-53 Assid (S, S, S) - (33) - (1- (2S) - (2-sloro-6-amino-benzoylamino) -3-methyl-butyryl] -pyrrolidin- (2S) sarbonyl} -amino) -4 -oxo-butyriso
EXAMPLE 11-54 Asid (S, S, S) - (3S) - (f 1- [(2S) - (2-sloro-benzoylamino) -3,3-dimethyl-butyryl] -piperidin- (2S) -sarbonil .}. -amino) 4 -oxo-butyriso
EXAMPLE 1 - 55 Asido (3S) - (f2- [(2S) - (3-methoxy-2-methyl-benzoyl -lamino) -3,3-dimethyl-butyryl] -2- (IS, r4R) -aza- bisislo [2.2 .1] heptan- (3S) -carbillonyl}. -amino) -4-oxo-butyric
EXAMPLE 11-56 Asid (3S) - (f2 - [(2S) - (2-sloro-benzoylamino) -3,3-dimethyl-butyryl] -2- (1S, 4R) -aza-bisislo [2.2.1] I have tan- (3S) -sarbonyl.}. -amino) -4 -oxo-butyris
EXAMPLE 11-57 Asido (3S) "(f2-E (2S) - (4-acetylamino-2-chloro-benzoylamino) -3,3-dimethyl-butyryl] -2 - (1S, 4R) -aza-bisislo [2. 2.1] heptan- os) -sarbonyl.}. - amino) -4 -oxo-butyryl
EXAMPLE 11-58 Asid (3S) - (. {2- E (2S) - (2-sloro-4-propionylamino-benzollamino) -3,3-di? Methyl-butyryl] -2- (IS, 4R) -aza-bisislo [2. 2.1] heptan - (3S) -carbonyl.}. -amino) -4-oxo-butyric
EXAMPLE 11-59 Acid (3S) - (f 2- [(2S) - (2-chloro-3-isobutyrylamino-benzoylamino) -3,3-dimethyl-butyryl] -2- (1S, 4R) -aza-bismol [2.2.1] heptan- (3S) -sarbonyl.}. -amino) -4 -oxo-butyryl
EXAMPLE 11-60 Asid (3S) - (f2 - [(2S) - (2-f luoro -3-methoxy-benzoylamino) -3,3-dimethyl-butyryl] -2- (1S, 4R) -aza-bisislo [2.2.1] heptan- (3S) -sarbonyl.}. -amino) -4 -oxo-butyryl
EXAMPLE 11-61 Acid (3S) - (2- [(2S) - (2-f luoro-3-methoxy-benzoylamino) -3-methyl-butyryl] -2- (1S, 4R) -aza-bisislo [2.2 .1] heptan- (3S) -sarbonyl.}. -amino) -4 -oxo-butyryl
EXAMPLE 11-62 Asid (3S) - (f2- [(2S) - (4-acetylamino-3-chloro-benzoylamino) -3,3-dimethyl-butyryl] -2- (1S, 4R) -aza-bisislo [ 2.2.1] heptan- (3S) -sarbonyl.}. -amino) -4 -oxo-butyryl
EXAMPLE 11-63 Asid (3S) - < . { 2- E (2S) - (3-chloro-4-propionyl-ino-benzoylamino) -3,3-di-methyl-butyryl] -2- (SS, 4R) -aza-bisyclo [2. 2.1] heptan - (3S) -carbonyl} -amino) -4 -oxo-butyric
EXAMPLE 11-64 Asid (3S) - (f 2- E (2S) - (isoquinolin-1-ylcarbonylamino) 3, 3-dimethyl-butyryl] -2- (1S, 4R) -aza-bisislo [2.2.1] heptan- (3S) -sarbonyl.}. -amino) -4-oxo-butyryl
EXAMPLE 11-65 Asid (3S) - (f2 - [(2S) - (4-amino-3-sloro-benzoylamino) 3, 3-dimethyl-butyryl] -2- (1S, 4R) -aza-bisislo [2.2 .1] heptan- (3S) -sarbonyl.}. -amino) -4-oxo-butyryrene
EXAMPLE 11-66 Asid (3S) - (f2-E (2S) - (4-amino-3-sloro-benzoylamino) -3-methyl-butyryl] -2- (1S, 4R) -aza-bisislo [2.2. 1] heptan- (3S) -sarbonyl.}. -amino) -4 -oxo-butyryl
Characterization data for compounds II-1 through 11-66 are summarized in the following Table 4 and include HPLC, LC / MS data (observed) and 1 H NMR. The 1R NMR data was obtained at 400 MHz, and found to be consistent with the structure.
Table 4. Cost-face data for the selected packages of Formula II (According to the number of the package)
EXAMPLE III Biological Methods The compounds of this invention can be tested using the methods described below. Table 5 lists the inhibition data of the enzyme caspase-1 and caspase-8 for compounds II-1-II-25. In the Table, compounds with a Ki of < 10 are assigned category A, compounds with a Ki of 10-20 are assigned category B, and compounds with a Ki of 21-30 are assigned category C.
IN VITRO ANALYSIS Inhibition of enzymes The Ki values for the test compounds with caspase-1 and caspase-8 were obtained by the method of Margolin et al. (J. Biol. Chem., 272 pp. 7223-7228 (1997)). Other caspases can be analyzed in a similar manner (see, for example, WO 99/47545). Analyzes were performed in 10 mM Tris (Sigma Corp, St. Louis MO) pH 7.5, 1 mM Dithiothreitol, (DTT, Research Organic Inc., Cleveland, OH) and 0.1% CHAPS (Pierce, Rockford IL) at 37 ° C. For caspase-3, an 8% glycerol solution was added to the assay buffer solution to improve the stability of the enzyme. An aliquot of 65 μL of the buffer solution for analysis and an aliquot of 5μL of the appropriate dilutions of the inhibitor in DMSO were pipetted into a 96-well plate, treated with 10 μL of caspase, then diluted in buffer for analysis (protein active 0.5-40 nM by means of active site assessment). A DMSO containing the control but not the compound was included for each determination. The plates were then incubated for 15 minutes at 37 ° C, before the addition of the appropriate substrate (20 μL, final concentration 1-4 x KM, volume for final analysis of 100 μL) to initiate the reaction. Reaction rates were measured at 37 ° C either by following the time dependent increase in absorbance at
405 nM (for pNA substrates) or in fluorescence
(Ex 390, Em 460) (for AMC substrates). The velocities obtained were plotted against the concentration of the inhibitor and the data adapted to the Morrison precise binding equation for competitive inhibitors (Morrison, J.F., Biochem. Biophys. Acta, 185 pp. 269-286 (1969)). The substrates used for the individual analyzes were as follows:
Caspasa-1 Suc-YVAD-pNA (Bachem, King of
Prussia, PA) (final concentration in the 80 μM analysis); Caspasa-8 Ac-DEVD-pNA (Bachem, King of
Prussia, PA) (final concentration in the 80 μM analysis);
Table 5: Inhibition data for caspase-1 (Cl) and caspase-8 (c8). Compound Ki Cl (nM) Ki C8 (nM)
CELL ANALYSIS PBMC Analysis IL-lβ with a mixed population of human peripheral blood mononuclear cells (PBMC) or adherent mononucleoside enriched cells The processing of pre-IL-lβ by ICE can be measured in cell culture using a variety of cellular sources. Human PBMC obtained from healthy donors provide a mixed population of lymphocyte and mononuclear cell subtypes that produce a spectrum of interleukins and cytokines in response to many classes of physiological stimulants. Adherent mononuclear cells from PBMCs provide an enriched source of normal monocytes for selective studies of cytokine production by activated cells.
Experimental procedure; An initial dilution series of the test compound in DMSO or ethanol is prepared, with a subsequent dilution in RPMI-10% FBS medium
(containing 2 mM L-glutamine, 10 mM HEPES, 50 U and 50 ug / ml pen / strep) respectively for drug production at 4x the final test concentration containing 0.4% DMSO or 0.4% ethanol. The final concentration of DMSO is 0.1% for all dilutions of the drug. An assessment of the concentration in square brackets shows the apparent K for a test compound determined in an ICE inhibition analysis generally used for the selection of the primary compound. In general, 5-6 dilutions of the compound were tested and the cellular component of the analysis was performed in duplicate, with ELISA determinations in duplicate on each cell culture supernatant.
Isolation of PBMC and IL-1 analysis Cells with buffy coat isolated from human blood in pinta (yield 40-45 ml of final volumetric plasma plus cells) are diluted with media to 80 ml and tubes for LeukoPREP separation (Becton Dickinson ) each were coated with 10 ml of cell suspension. After 15 min of centrifugation at 1500-1800 xg, the plasma / media layer is aspirated and then the cell mononuclear layer is collected with a Pasteur pipette and transferred to a 15 ml conical tube for centrifugation (Corning). The medium is added to bring the volume to 15 ml, gently mixing the cells by inversion and centrifugation at 300 xg for 15 min. The PBMC granules were resuspended in a small volume of media, cells were counted and adjusted to 6 x 10 6 cells / ml. For cell analysis, 1.0 ml of the cell suspension was added to each well of a 24-well flat-bottomed tissue culture plate (Corning), 0.5 ml of test compound dilution and 0.5 ml of LPS solution (Sigma # L-3012, 20 ng / ml of the solution prepared in complete RPMl medium, final concentration of LPS 5 ng / ml). Additions of 0.5 ml of the test compound and LPS were usually sufficient to mix the contents of the cavities. Three control mixtures were run per experiment, either with LPS alone, vehicle solvent control, and / or additional means to adjust the final culture volume to 2.0 ml. The cell cultures were incubated for 16-18 hr at 37 ° C in the presence of 5% C02. At the end of the incubation period, the cells were harvested and transferred to conical tubes for 15 ml centrifugation. After centrifugation for 10 min at 200 xg, the supernatants were harvested and transferred to 1.5 ml Eppendorf tubes. It can be seen that the cell granules can be used for a biochemical evaluation of the content of pre-IL-1β and / or mature IL-1β in cytosol extracts by Western blot or ELISA with specific pre-IL-β antisera.
Isolation of adherent mononucleosis cells: The PBMCs were isolated and prepared as described above. The medium (1.0 ml) was added first to the cavities followed by 0.5 ml of the PBMC suspension. After one hour of incubation, the plates were shaken gently and the non-adherent cells were aspirated from each cavity. The wells were then gently washed three times with 1.0 ml of media and finally resuspended in 1.0 ml of media. Enrichment for adherent cells generally provides 2.5-3.0 x 105 cells per well. The addition of the test compounds, LPS, the conditions for cell incubation and the processing of the supernatants proceeded as described above.
ELISA; Quantikine equipment (R & D Systems) can be used for the measurement of mature IL-lß. The analyzes were carried out in accordance with the manufacturer's instructions. Mature IL-1β levels of approximately 1-3 ng / ml were observed in both PBMC and positive controls of adherent mononuclear cells. The ELISA analyzes were performed in 1: 5, 1:10 and 1:20 dilutions of the supernatants of the LPS-positive controls to select the optimal dilution for the supernatants in the test panel. The inhibitory potency of the compounds can be represented by an IC50 value, which is the concentration of the inhibitor in which 50% of mature IL-1β is detected in the supernatant compared to the positive controls. The experienced practitioner will understand that the values obtained in cellular analyzes may depend on multiple factors. The values do not necessarily represent fine quantitative results. Selected compounds of this invention have been tested for the inhibition of IL-1β release from PBMC with IC50 values between 300 nM and 4 μM.
Whole blood analysis for the production of IL-lß The IC50 values of the whole blood analysis for the compounds of this invention can be obtained using the method described below: End; The whole blood test is a simple method to measure the production of IL-lß (or other cytokines) and the activity of potential inhibitors. The complexity of this system of analysis, with its total complement of lymphoid and inflammatory cell types, the spectrum of plasma proteins and red blood cells is an ideal representation of the physiological conditions of human beings. Materials; Pyrogen-free syringes (~ 30 ce) Sterile pyrogen-free vacuum tubes containing lyophilized Na2EDTA (4.5 mg / 10 ml tube) Human whole blood sample (-30-50 ce) 1.5 ml Eppendorf tubes Concentrated solutions of the compound test (~ 25mM in DMSO or other solvent) Endotoxin-free sodium chloride solution (0.9%) and HBSS Lipopolysaccharide (Sigma; Cat. # L-3012) concentrated solution at lmg / ml in HBSS ELISA kit for IL-lß (R & D Systems; Cat. # DLB50) ELISA kit for TNFa (R & D Systems; Cat. # DTA50) Bath with water or incubator
Experimental procedure for the analysis of whole blood; Set of incubator or water bath at 30 ° C. Aliquot of 0.25ml of blood in 1.5 ml Eppendorf tubes. Remark: Be sure to invert the tubes of the whole blood sample after every two aliquots. Differences in replicates can result if the cells settle and are not suspended evenly. The use of a pipette for positive displacement will also minimize the differences between replicated aliquots. Preparation of dilutions of drugs in sterile, pyrogen-free saline solution by serial dilution. A series of dilutions with the K¿ evident in brackets for a test compound determined in an analysis for ICE inhibition for the selection of the primary compound. For the extremely hydrophobic compounds, prepare the dilutions of the compounds in fresh plasma obtained from the same blood donor or in 5% DMSO containing PBS to enhance the solubility. Add 25 μl of the dilution of the test compound or vehicle control and shake the sample gently. Then add 5.0 μl of the LPS solution (250 ng / ml concentrate, freshly prepared: 5.0 ng / ml final concentration of LPS), and mix again. Incubate the tubes at 30 ° C in a bath with water for 16-18 hr with occasional mixing. Alternatively, the tubes can be placed in a rotating assembly at 4 rpm during the same incubation period. This analysis could be prepared in duplicate or triplicate with the following controls: negative control - without LPS; positive control - without the test inhibitor; vehicle control - higher concentration of DMSO or the solvent of the compound used in the experiment. Additional saline was added to all the control tubes to normalize the volumes for the test samples with both control and experimental whole blood. After the incubation period, the whole blood samples are centrifuged for 10 minutes at ~2000 rpm in a microcentrifuge, the plasma is transferred to a fresh microcentrifuge tube and centrifuged at 1000 x g to the residual granule platelets if necessary. Plasma samples can be stored at -70 ° C before analysis for cytokine levels by ELISA. ELISA: Quantikine equipment from R &D Systems (614 McKinley Place N.E. Minneapolis, MN 55713) can be used for the measurement of IL-lß and TNF-a. The analyzes were carried out in accordance with the manufacturer's instructions. IL-1β levels of -1-5 ng / ml can be observed in positive controls among a variety of individuals. A 1: 200 plating dilution for all samples in general is sufficient for the experiments so that the ELISA results lie in the linear variation of the standard ELISA curves. It may be necessary to optimize the standard dilutions if differences are observed in the whole blood analysis. Nerad, J.L. et al., J. Leukocyte Biol., 52, pp. 687-692 (1992). Selected compounds of this invention have been tested for the inhibition of IL-1β release from whole blood with IC 50 values between 1 μM and 40 μM.
IN VIVO ANALYSIS The compounds of this invention can be tested in in vitro assays such as those described in WO 99/47545. WO 99/47545 and all other documents cited herein are incorporated herein by reference. While various embodiments of this invention have been described, it is evident that the basic examples may be altered to provide other embodiments utilizing the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention will be defined by the appended claims rather than the specific embodiments that have been represented by way of example above.
Claims (51)
- EIVINDICATIONS A compound of the formula I where : R1 is H, d-? 2alif attic, C3-10cycloaliphatic, Cs-ioaryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C3-? 0 cycloalkyl) - (C? -? 2alif attic) -, cycloalkenyl- (C? _12alif attic) -, (C6-? A -rilo) - (C? _ a2alif ático) -, (heterocyclyl of 5-10 mimbros) - (C? _ 12alif ático) -, or (heteroaryl of 5-10 members) - (Ci-12alif ático) -, in wherein any hydrogen atom is optionally and independently replaced by R8 and any set of two hydrogen atoms attached to the same atom is optionally and independently replaced by carbonyl; Ring A is: wherein, in each ring, any hydrogen atom is optionally and independently replaced by R4 and any set of two hydrogen atoms attached to the same atom is optionally and independently replaced by carbonyl; when Ring A is; so R is R3C (0) -, HC (0), R3S02-, R3OC (0), (R3) 2NC (0), (R3) (H) NC (0), R3C (0) C (0) -, R3 -, (R3) 2NC (O) C (O), (R3) (H) NC (O) C (O), or R3OC (O) C (O) -; and R3 is C? -? 2aliphatic, C3-? 0cycloaliphatic, C6-10aryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C3_? 0cycloaliphatic) - (C? -? 2aliphatic) -, (Ce- [Alpha] -aryl) - (C? -? 2aliphatic) -, (5-10 membered heterocyclyl) - (C? -12aliphatic) -, or (5-10 membered heteroaryl) - (C? -? 2aliphatic) -; or two R3 groups attached to the same atom together with that atom form an aromatic or non-aromatic 3-10 membered ring; wherein any ring is optionally fused to a Cs. ? 0aryl, 5-10 membered heteroaryl, C3. locicloalkyl, or 5-10 membered heterocyclyl; where up to 3 atoms of. aliphatic carbon can be replaced by a selected group of O, N, NR9, S, SO, and S02, wherein R3 is substituted with up to 6 substituents independently selected from R8; when Ring A is then is R C (O) -, as shown in the formula I I II and R3 is phenyl, thiophene, or pyridine, wherein each ring is optionally substituted with up to 5 groups independently selected from R8 ', and wherein at least one position on the phenyl, thiophene, or pyridine adjacent to the bond x is replaced by R12 , wherein R12 has no more than 5 straight chain atoms; R4 is halogen, -OR9, -N02, -CN, -CF3, -OCF3 / -R9, 1, 2-methylenedioxy, 1,2-ethylenedioxy, -N (R9) 2, -SR9, -SOR9, -S02R9, -S02N (R9) 2, -S03R9, -C (0) R9, -C (0) C (0) R 9, -C (O) C (0) OR 9, -C (O) C (0) N (R 9) 2, - C (O) CH 2 C (O) R 9, - C (S ) R9, -C (S) 0R9, -C (0) 0R9, -OC (0) R9, -C (0) N (R9) 2, -OC (0) N (R9) 2, -C (S) ) N (R9) 2, - (CH2) 0-2NHC (O) R9, -N (R9) N (R9) COR9, -N (R9) N (R9) C (O) OR9, -N (R9) N (R9) CON (R9) 2, -N (R9) S02R9, -N (R9) S02N (R9) 2, -N (R9) C (0) OR9, -N (R9) C (0) R9, -N (R9) C (S) R9, -N (R9) C (0) N (R9) 2, -N (R9) C (S) N (R9) 2, -N (COR9) COR9, -N (OR9) R9, -C (= NH) N (R9) 2, - C (O) N (OR9) R9, -C (= NOR9) R9, -OP (O) (OR9) 2, -P (O) (R9) 2, -P (0) (OR9) 2, or - P (O) (H) (OR9); R2 is -C (R5) (R6) (R7), C6-? 0aryl, 5-10 membered heteroaryl, or C3.7 cycloalkyl; R5 is H or a C? -6 straight or branched chain alkyl; R6 is H or a straight or branched chain C6-6 alkyl; R7 is -CF3, -C3-7cycloalkyl, C6-10aryl, 5-10 membered heteroaryl, heterocycle, or a straight or branched chain C6-6 alkyl, wherein each alkyl carbon atom is optionally and independently replaced with R10; OR R? and R7 taken together with the carbon atom to which they are attached form a cycloaliphatic of 3-10 members; R8 and R8 'each are independently halogen, -OR9, -N02, -CN, -CF3, -OCF3, -R9, 1,2-methylenedioxy, 1,2-ethylenedioxy, -N (R9) 2, -SR9, -SOR9, -S02R9, -S02N (R9) 2, -S03R9, -C (0) R9, -C (0) C (0) R9, -C (O) C (0) OR 9, -C (O) C (0) N (R 9) 2, -C (O) CH 2 C (O) R 9, -C (S) R 9, -C (S) OR 9 , -C (0) OR9, -OC (0) R9, -C (0) N (R9) 2, -0C (0) N (R9) 2, -C (S) N (R9) 2, - ( CH2) 0- NHC (O) R9, -N (R9) N (R9) COR9, -N (R9) N (R9) C (O) OR9, -N (R9) N (R9) CON (R9) 2, -N (R9) S02R9, -N (R9) S02N (R9) 2, -? (R9) C (O) OR9, -? (R9) C (O) R9, -? (R9) C (S) R9, -? (R9) C (0)? (R9) 2, -? (R9) C (S)? (R9) 2, -? (COR9) COR9, -? (OR9) R9, -C (=? H)? (R9) 2, - C (O)? (OR9) R9, -C (=? OR9) R9, -OP (O) (OR9) 2, -P (0) (R9) 2, -P (0) (OR9) 2, and -P (O) (H) (OR9); R9 is hydrogen, C? _? 2aliphatic, C3. xocycloaliphatic, C6-? oaryl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl, (C3. xcycloaliphatic) - (C? -12aliphatic) -, (C6-? 0aryl) - (C? _12aliphatic), (5-10 membered heterocyclyl) - (Ci-1 aliphatic-, or heteroaryl- (C-? aliphatic) -; wherein any hydrogen atom is optionally and independently replaced by R8 and any set of two hydrogen atoms attached to the the same atom is optionally and independently replaced by carbonyl, R10 is halogen, -OR11, -? 02, -C ?, -CF3, -OCF3, -R11, or -SR11, wherein R11 is C? -4-aliphatic-. , 10 is halogen, -OR-NO 1 i -CN, -CF3 / • OCF3 / R, 11, or -SR .11; wherein R is C? 4-aliphatic-, 11 is halogen, -OR • N02, -CN, -CF3, -OCF3,
- 2. The compound according to claim 1 wherein R is R3C (0) -; and R3 is C6-βaryl or 5-10 membered heteroaryl, wherein any hydrogen atom of R3 is optionally and independently replaced by R8 '.
- 3. A compound of formula II II wherein R is phenyl, thiophene, or pyridine, wherein each ring is optionally substituted with up to 5 groups independently selected from R8 ', and wherein at least one position on the phenyl, thiophene, or pyridine adjacent to the bond x is replaced by R12, wherein R12 has no more than 5 straight chain atoms;
- 4. The compound according to any of claims 1-3 wherein Y is
- 5. The compound according to claim 4, wherein R1 is C-12aliphatic or C3-10cycloalkyl, wherein each group is optionally substituted with 1-3 groups independently selected from R8.
- 6. The compound according to claim 5, wherein R 1 is a straight or branched chain C 1-4 alkyl which is optionally substituted with 1-3 groups independently selected from R 8.
- 7. The compound according to claim 6 wherein R1 is a straight or branched chain C? _4 unsubstituted alkyl.
- 8. The compound according to claim 7, wherein R 1 is ethyl, isopropyl, n-propyl, or n-butyl.
- 9. The compound according to claim 8, wherein R 1 is ethyl.
- 10. The compound according to any of claims 4-9 wherein R8 is halogen, -OR9, -CN, -CF3, -OCF3, or -R9.
- 11. The compound according to claim 10, wherein R8 is benzyl.
- 12. The compound according to any of claims 1-3 wherein Y is
- 13. The compound according to any of claims 1-12 wherein Ring A is:
- 14. The compound according to claim 13 wherein Ring A is: optionally substituted by R 4.
- 15. The compound according to any of claims 1-12 wherein Ring A is: optionally substituted by R4.
- 16. The compound according to claim 15, wherein Ring A is: optionally substituted by R4
- 17. The compound according to any of claims 13-16 wherein R 4 is halogen, -OR 9, -CF3 / -0CF3, -R9, or -SR9
- 18. The compound according to claim 17, wherein R 4 is H.
- 19. The compound according to any of claims 1-18 wherein R2 is a C3-branched alkyl group.
- 20. The compound according to any of claims 1-19 wherein R5 is H or -CH3, R6 is -CH3, and R7 is -CH3.
- 21. The compound according to any of claims 1-20 wherein R12 has no more than 4 straight chain atoms.
- 22. The compound according to claim 21 wherein R12 has no more than 3 straight chain atoms.
- 23. The compound according to claim 22, wherein R12 is -0CF3, -OCH3, -CF3, -CH3, -CH2CH3, -Cl, or -F.
- 24. The compound according to claim 23, wherein R12 is -CF3, -CH3, -Cl, or -F.
- 25. The compound according to claim 24, wherein R12 is -CH3, -Cl, or -F.
- 26. The compound according to any of claims 1-25 wherein each R8 'is independently halogen, -OR9, -N02, -CN, -CF3, 0CF3, -R9, 1, 2-methylenedioxy, 1,2-ethylenedioxy, -N (R9) 2, -SR9, -SOR9, -S02R9, -S02N (R9) 2, -C (0) R9, C (0) C (0) N (R9) 2, -C (0) N (R9) 2, -OC (O) N (R9) 2, - (CH2) 0-2NHC (0) R9, -N (R9) S02R9, -N (R9) S02N (R9) 2, -N (R9) C (O) OR9, -N (R9) C (0) R9, or -? (R9) C (0)? ( R9) 2.
- 27. The compound according to claim 26 wherein each R8 'is independently -? H2, -? (R9) 2, -? (R9) C (O) R9, -OCF3, -OR9, -CF3, -R9, -SR9, or halo.
- 28. A compound selected from
- 29. A pharmaceutical composition comprising: a) a compound according to any of claims 1-28; and b) a pharmaceutically acceptable carrier, adjuvant or vehicle.
- 30. A method of treating a disease in a patient, wherein the disease is a disease caused by IL-1, a disease caused by apoptosis, an inflammatory disease, an autoimmune disease, a destructive bone disorder, a proliferative disorder, an infectious disease, a degenerative disease, a disease associated with cell death, a disease by excessive daily alcohol intake, a disease caused by viruses, retinal disorders, uveitis, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, respiratory distress syndrome in adults, glomerulonephritis, arthritis rheumatoid, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, scarring, disease of graft against host, rejection of organ transplantation, organic apoptosis after a burn injury, osteoporosis, leukemia and related disorders, myelodysplastic syndrome, bone disorder related to multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, sarcoma Kaposi, multiple myeloma, hemorrhagic shock, sepsis, septic shock, burns, Shigellosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy's disease, prion disease, cerebral ischemia, epilepsy, myocardial ischemia, acute heart disease and chronic, myocardial infarction, congestive heart failure, atherosclerosis, graft for coronary artery bypass, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, HIV-related encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, injury traumatic brain ica, spinal cord injury, hepatitis B, hepatitis C, hepatitis G, yellow fever, dengue fever, Japanese encephalitis, various forms of liver disease, kidney disease, polycystic kidney disease, gastric ulcer disease and duodenal associated with H. pylori, HIV infection, tuberculosis, meningitis, toxic epidermal necrolysis, pemphigus, Muckle-Wells Syndrome, Urticaria due to Family Cold, Familial Mediterranean Fever, Childhood Chronic Neurological Cutaneous and Articular Syndrome, Multisystem Inflammatory Disease of Emergence in Newborns, Syndrome Newspaper associated with TNFR1, or Hyper-IgD Periodic Fever Syndrome; the method comprises the step of administering the compound to the patient according to any of claims 1-28 or a pharmaceutical composition according to claim 29.
- 31. A method for inhibiting a function caused by caspase in a patient comprises the step of administering to the patient a compound according to any of claims 1-28 or a pharmaceutical composition according to claim 29.
- 32. The method to decrease the production of IGIF or IFN-? in a patient, comprising administering to the patient a compound according to any of claims 1-28 or a pharmaceutical composition according to claim 29.
- 33. A method for preserving cells, said method comprises the step of bathing the cells in a composition of the compound according to any of claims 1-28 or a pharmaceutically acceptable derivative thereof.
- 34. The method according to claim 33, wherein the cells are in: a) an organ intended for transplantation; or b) a blood product.
- 35. A method for the treatment of cancer using immunotherapy, wherein the immunotherapy comprises as a component thereof a compound according to any of claims 1-28.
- 36. The method according to any of claims 30-35 wherein the composition comprises an additional therapeutic agent.
- 37. A process for preparing a compound of formula I: where Y is: and the other variables are as defined in any of claims 2-11 or 13-27; which comprises reacting a compound of formula 1: wherein the variables are as defined in any of claims 2-11 or 13-27; and a compound of the formula RX, wherein X is OH or a suitable derivative or leaving group, in the presence of the conditions for the coupling of an amine and an acid (when X is OH) or a suitable acid derivative (when X is a suitable leaving group) to provide the compound of formula I.
- 38. A process for preparing a compound of formula I: where Y is: and the other variables are as defined in any of claims 1-11 or 13-27; which comprises reacting a compound of the formula 7-A: 7-A wherein the variables are as defined in any of claims 1, 5-9; and a compound of the formula RNHCH (R2) C (O) X, wherein X is OH or a suitable derivative or leaving group, in the presence of conditions for the coupling of an amine and an acid (when X is OH) or the suitable acid derivative (when X is not OH) to provide the compound of formula I.
- 39. A process for preparing a compound of formula IV: IV wherein the variables are as defined in any of claims 1-3 or 12-27, which comprises reacting a compound of the formula I: where Y is wherein Rx is as defined in any of claims 1 or 5-9, under hydrolysis conditions, to provide the compound of the formula II.
- 40. A process for preparing a compound of the formula 3-A: PG2- * © e, OA HSTSI 3-A, wherein PGx is a suitable protecting group of carboxylic acid; PG2 is a suitable nitrogen protecting group; and ring A is as defined in claim 1; comprising: reacting a compound of the formula 2-A: 2-A and a compound of the formula 20-A: 20 A wherein X is OH or a suitable leaving group, under the conditions for the coupling of an amine and a carboxylic acid (when X is OH) or an amine and a suitable carboxylic acid (when X is a suitable leaving group) to provide the composed of the formula 3-A.
- 41. A process for preparing a compound of formula 3: wherein PGX is a suitable protecting group of carboxylic acid and PG2 is a suitable nitrogen protecting group; comprising: reacting a compound of the formula 2-A: 2-A with a compound of formula 20 under the conditions for the coupling of an amine and a carboxylic acid (when X is OH), or an amine and a suitable carboxylic acid (when X is a suitable leaving group), to provide the compound of the formula 3.
- 42. A process for preparing a compound of formula 13: 13 wherein PG is a suitable protective group of carboxylic acid and PG2 is a suitable nitrogen protecting group; comprising: reacting a compound of formula 2: with a compound of formula 21 under the conditions for the coupling of an amine and a carboxylic acid (when X is OH), or an amine and a suitable carboxylic acid (when X is a suitable leaving group), to provide the compound of the formula 13.
- 43. A compound of the formula 5-A: 5-A wherein PGx is a suitable carboxylic acid protecting group; PG2 is a suitable nitrogen protecting group; and R1 is as defined in any of claims 1 or claims 5-9.
- 44. A compound of formula 5: wherein Z is a type Z protective group and PGx and R1 are as defined in claim 40.
- 45. A compound of the formula 15: 15, wherein PGx is a suitable protective group of carboxylic acid and PG2 is a suitable nitrogen protecting group.
- 46. A compound of the formula 3 -A: 3-A, wherein PGx, PG2, and R1 are as defined in claim 43.
- 47. A compound of formula 3 3, wherein Z is a type Z protective group and PGx is as defined in claim 43.
- 48. A compound of formula 13 13, wherein PGx, and PG2 are as defined in claim 43.
- 49. A compound of the formula 4A: 4A, wherein PGx and PG2 are as defined in claim 43.
- 50 A compound of formula 4 4, wherein Z is a type Z protective group and PGx is as defined in claim 43.
- 51. A compound of formula 14: 14, wherein PGx and PG2 are as defined in claim 43.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/548,610 | 2004-02-27 | ||
| US60/629,661 | 2004-11-19 | ||
| US60/629,743 | 2004-11-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA06009771A true MXPA06009771A (en) | 2007-04-20 |
Family
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