Aromatic sulfonyl alpha-hydroxy hydroxamic acid compounds

专利摘要:
In particular, the aromatic sulfonyl alpha-hydroxy hydroxysamic acid compound and the aromatic sulfonyl alpha-hydroxy hydroxysamic acid compound that inhibit the interstitial metalloprotease activity, MMP to the host with a disease associated with pathological interstitial metalloprotease activity A method of treatment comprising administering in an amount effective for inhibition is disclosed.
公开号:KR20000075955A
申请号:KR1019997008037
申请日:1998-03-04
公开日:2000-12-26
发明作者:프레스코스존엔.；보엠테리엘.；미쉬크브렌트브이.；헤인츠로버트엠.；맥도날드조셉제이.；데크레센조게리에이.；하워드수잔시.
申请人:죤 에이치. 뷰센；몬산토컴퍼니；
IPC主号:

专利说明:

Aromatic sulfonyl alpha-hydroxy hydroxysamic acid compound {AROMATIC SULFONYL ALPHA-HYDROXY HYDROXAMIC ACID COMPOUNDS}
Connective tissue, extracellular cytoplasmic structures and basement membranes are essential components of all mammals. These components are biological substances that provide strength, differentiation, adhesion, and in some cases elasticity to biological systems, including humans and other mammals. Connective tissue components include, for example, collagen, elastin, proteoglycans, fibronectin, and laminin. These biochemicals are, for example, constituents or components of skin, bone, teeth, tendons, cartilage, basement membranes, blood vessels, corneas and vitreous fluids.
Under normal conditions, the connective tissue replacement and / or repair process is controlled and in equilibrium. Loss of balance for some cause leads to a number of morbid conditions. Inhibition of enzymes that cause loss of equilibrium not only provides a regulatory mechanism for this tissue breakdown, but also eventually provides a treatment for these diseases.
Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from tissue cells and / or invasive inflammation or tumor cells present therein. The main species of enzyme involved in this action is zinc metalloproteinases (metalloproteinases, or MMPs).
Metalloprotease enzymes are divided into classes with several members with several different names commonly used. Examples include: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); Collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 ( MMP-10; EC 3.4.24.22), proteoglycanase, matrilysine (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), Gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelase (MMP-12, HME, human macrophage elastase) and Membrane MMP (MMP-14). MMP is an abbreviation or acronym that refers to the term, Matrix Metalloprotease, and is numbered to distinguish between specific members of the MMP group.
Uncontrolled degradation of connective tissue by metalloproteases is a hallmark of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; Corneal ulcer, epidermal or gastric ulcer; Tumor metastasis, invasion or angiogenesis; Periodontal disease; Proteinuria; Multiple sclerosis; Alzheimer's disease; Coronary thrombosis and bone disease. Damage to the wound healing process may also occur. This results in inadequate wound healing, leaving inadequate repair, adhesion and wound traces. These latter injuries can lead to malformations and / or permanent disability when accompanied by postoperative attachment.
Interstitial metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF), and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. For example, TNF-α is a cytokine currently thought to be produced initially as a 28 kD intracellular molecule. It is released in the form of an active, 17 kD that can mediate a number of detrimental actions in vitro and in the body. For example, TNF can cause inflammation, rheumatoid arthritis, autoimmune diseases, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infections, meningitis, fever, psoriasis, reperfusion injury after ischemia, congestive Cardiovascular / pulmonary outcomes such as heart failure, bleeding, coagulation, peroxic alveolar damage, radiation damage and infection, sepsis and acute reactions observed in the presence of shock, such as septic shock and hemodynamic shock, or Can contribute to the results. Chronic release of active TNF can cause cachexia and anorexia. TNF can be fatal.
TNF-α convertase is a metalloprotease involved in the production of active TNF-α. Inhibition of TNF-α convertase inhibits the production of active TNF-α. Compounds that inhibit two MMP activities are disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824. There is still a need for effective MMP and TNF-α convertase inhibitors. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al., Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 (1994)).
MMPs are also involved in other biochemical processes in mammals at the same time. Is involved in the inactive protease inhibitor (α ₁ -PI) - ovulation, postpartum uterine atrophy, if possible, control of conception, APP (β- amyloid precursor protein, β-Amyloid Precursor Protein) to the amyloid plaque cutting and α ₁ of . Inhibition of these metalloproteases can modulate fertilization and treat or prevent Alzheimer's disease. In addition, maintenance or increase in levels of biochemicals or serine protease inhibitors, such as endogenous or administered α ₁ -PI, may be used to treat aging-related diseases such as emphysema, lung-related diseases, infectious diseases and loss of elasticity and elasticity of the skin or organs. And aid in prevention.
Inhibition of selected MMPs may also be desirable for other diseases. Treatment of cancer and / or inhibition of metastasis and / or inhibition of angiogenesis may include stromelysin (MMP-3), gelatinase (MMP-2), gelatinase B (MMP-9) or collagenase III (MMP). Selective inhibition of -13) is an example of an approach to the treatment of diseases that are the most important enzymes or enzymes to inhibit, in particular when compared to collagenase I (MMP-1). Drugs that do not inhibit collagenase I may have a superior therapeutic profile. Osteoarthritis, which is thought to be caused at least in part by MMP-13 released from cells such as stimulated chondrocytes in the inflamed joint, is a drug that involves the inhibition of MMP-13. It can be best treated by administration of. For example, Mitchell et al., J. Clin. Invest., 97: 761-768 (1996) and Reboul et al., J. Clin. See Invest., 97: 2011-2019 (1996).
Inhibitors of metalloproteases are known. Examples include tissue inhibitors of metalloproteinases (TIMPs), natural biochemicals such as α ₂ -macroglobulin and analogs or derivatives thereof. These are high molecular weight protein molecules that form inert complexes with metalloproteases. Numerous smaller peptide- pseudo compounds have been described that inhibit metalloproteases. Mercaptoamide peptidyl derivatives show inhibition of ACE in vitro and in vivo. Angiotensin converting enzyme (ACE) helps to produce angiotensin II, a potent booster in mammals, thus lowering blood pressure by inhibiting ACE enzymes.
Amide or peptidyl amide based metalloproteases (MMP) inhibitors containing thiol groups are described, for example, in WO95 / 12389, WO96 / 11209 and U.S. Known as shown at 4,595,700. MMP inhibitors comprising a hydroxyxamate group are described in Schwartz et al., Progr. Med. Chem., 29: 271-334 (1992) and Rasmussen et al., Pharmacol. Ther., 75 (1): 69-75 (1997) and Denis et al., Invest. WO 95/29892, WO 97/24117, WO 97/49679 and EP 0 780 386, peptidyl backbones, which disclose carbonaceous compounds with those disclosed in the paper by New Drugs, 15 (3): 175-185 (1997) Or in a number of published patent applications, such as WO 90/05719, WO 93/20047, WO 95/09841 and 96/06074, which disclose hydroxyxamates having a peptido pseudo backbone.
One possible problem with known MMP inhibitors is that these compounds often exhibit the same or similar inhibitory effects on each of the MMP enzymes. For example, the peptido doctor hydroxamate, known as batimastat, has about 1 to about 20 nanomoles (nM) for MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9, respectively. It is reported that the IC ₅₀ value of Another peptidohydroxamate, Marimastat, is another broad-spectrum MMP inhibitor with an enzyme inhibition spectrum very similar to Batimastat, except that it has an IC ₅₀ value of 230 nM for MMP-3. Has been reported. Rasmussen et al., Pharmacol. Ther., 75 (1): 69-75 (1997).
Substitute markers for biological activity as a result of meta-analysis of data from Phase I / II studies using marimastat in patients with advanced, rapid, refractory solid tumor cancers (colon cancer, pancreatic cancer, ovarian cancer, prostate cancer) The increase in tumor-specific antigen used as was shown to decrease with respect to dosage. Although marimastat showed some efficacy with these markers, side effects of toxicity were identified. The most common drug-related toxicity of marimastat in these clinical trials was musculoskeletal pain and stiffness, often beginning in small joints of the hand and spreading to the arms and shoulders. You can continue treatment by reducing your dose after you stop taking it for one to three weeks. Rasmussen et al., Pharmacol. Ther., 75 (1): 69-75 (1997). It is believed that the absence of specificity of the inhibitory effect between MMPs may be responsible for this side effect.
In view of the importance of hydroxyxamate MMP inhibitory compounds in the treatment of some diseases and the absence of enzyme specificity manifested by two more potent drugs in current clinical trials, if hydroxyxamate with greater enzymatic specificity is found, It can be a big advantage. In particular, hydroxyxamate inhibitors exhibit strong inhibitory activity against one or more of MMP-2, MMP-9, or MMP-13 associated with some pathological conditions, while at the same time relatively present in MMP-1, which is relatively everywhere and not yet associated with any pathological conditions. It would be a further advantage to show limited inhibition. The following disclosure describes a class of hydroxyxamate MMP inhibitors that exhibit this desirable activity.
FIELD OF THE INVENTION The present invention relates to proteinase (protease) inhibitors and, more particularly, to aromatic sulfonyl alpha-hydroxy hydroxamic acid compounds useful as inhibitors for interstitial metalloproteinases, compositions of these compounds, Intermediates for synthesizing these compounds, methods for preparing the compounds, and methods for treating pathological conditions associated with pathological interstitial metalloproteinase activity.
Brief description of the invention
The present invention, among other things, inhibits interstitial metalloprotease (MMP) activity, in particular inhibits the activity of one or more of MMP-2, MMP-9, or MMP-13, while at the same time having almost no activity against MMP-1. A class of molecules not represented, and methods of treating mammals with diseases associated with pathological activity.
In summary, one embodiment of the present invention relates to an aromatic sulfonyl alpha-hydroxy hydroxysamic acid compound. This compound has the structure corresponding to the following Chemical Formula 1.
Where
R ² is hydrido, C ₁ -C ₄ hydrocarbyl, hydroxy-C ₁ -C ₄ hydrocarbyl, C ₁ -C ₄ hydrocarbyloxy, halo-C ₁ -C ₄ hydrocarbyl, C _1- C ₄ hydrocarbyloxymethyl, aminomethyl, (NC ₁ -C ₃ hydrocarbyl) aminomethyl, (N, N-di-C ₁ -C ₃ hydrocarbyl) aminomethyl, (N-morpholi No) methyl, (N-pyrrolidino) methyl, or (N-thiomorpholino) methyl group. R ² is preferably a hydrido, hydroxy, hydroxymethyl, methoxymethyl or methyl-N-morpholinyl group.
R ¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical directly bonded to the SO ₂ -group shown in the formula, which is longer than the length of the approximately fully unfolded hexyl group and is approximately fully unfolded It is a substituent having a length shorter than the length of. In addition, R ¹ represents the center of the SO ₂ -bonded 1-position and 3,4-bond of the axial or 5-membered ring radical connected through the SO ₂ -bonded 1-position and 4-position of the 6-membered ring radical. A three-dimensional volume is defined when rotated about a connecting axis, and the widest width transverse to the axis of rotation is from about one furanyl ring to about two phenyl rings.
R ¹ preferably contains a single aromatic or heteroaromatic ring which is itself substituted with another substituent R ³ . R ¹ most preferably contains a phenyl ring Ph, which itself has a substituent R ³ in the 4-position. R ³ is preferably phenyl, phenoxy, which may itself be substituted with a substituent containing a single atom at its meta- or para-position or at both positions, or the longest chain of up to 8 atoms excluding hydrogen, Phenylazo, thiophenoxy, anilino, benzamido, nicotinamido, isnicotinamido, picolinoamido or ureidophenyl groups.
Also contemplated are methods of treating host mammals with diseases related to pathological interstitial metalloprotease activity. This method consists in administering an enzymatically effective amount of a compound described above to a mammalian host having such a disease. Particular expectation is the use of repeated administration.
Some of the benefits and advantages of the present invention include compounds and compositions that are effective as inhibitors of interstitial metalloprotease activity and that are effective in inhibiting metalloproteases associated with diseases and disorders involving uncontrolled degradation of connective tissue. There is an offer.
More specifically, the benefits of the present invention include metalloproteases, in particular, rheumatoid arthritis, osteoarthritis, septic arthritis, corneal ulcers, epidermal or gastric ulcers, tumor metastasis, invasion or angiogenesis, periodontitis disease, Provided are compounds and compositions effective for inhibiting MMP-13 and / or MMP-2 related to pathological conditions such as proteinuria, multiple sclerosis, Alzheimer's disease, coronary thrombosis and bone disease.
An advantage of the present invention is the provision of a method of making such a composition. Another benefit is the provision of methods for the treatment of pathological conditions associated with abnormal interstitial metalloprotease activity.
Another advantage of the present invention is the selective inhibition of metalloproteases, such as MMP-13 and MMP-2, which are associated with such diseases, thereby inhibiting other proteases, such as MMP-1, which are essential or desirable for normal body function. The side effects resulting from the provision of compounds, compositions and methods that are effective in minimizing and treating the pathological condition.
Further advantages and advantages of the invention will be apparent to those skilled in the art from the following disclosure.
Detailed Description of the Preferred Embodiments
According to the present invention, certain aromatic sulfonyl alpha-hydroxy hydroxamic acids (hydroxyxamates) of interstitial metalloproteases ("MMPs") are thought to be involved in uncontrolled or pathological degradation of connective tissue. It was found to be effective for inhibition. In particular, these constant aromatic sulfonyl alpha-hydroxy hydroxamic acids are collagenase III (MMP-13) and also gelatin, which, if present or produced in abnormal amounts or concentrations, are particularly detrimental to tissue and thus may exhibit pathological activity. It has been shown to be effective for the inhibition of Aze A (MMP-2).
Moreover, many of these aromatic sulfonyl alpha-hydroxy hydroxamic acids inhibit MMP-13 as well as other MMPs associated with pathological conditions, without undue inhibition of other collagenases essential for normal body function such as tissue replacement and repair. Edo was found to be optional. More specifically, it has been found that particularly preferred aromatic sulfonyl alpha-hydroxy hydroxamic acid is particularly active for the inhibition of MMP-13 and MMP-2, while having a limited or minimal effect on MMP-1. This point is discussed in detail later and is shown in the Table of Inhibitions later.
This compound corresponds to the following general formula (1).
(Formula 1)

Where
R ² is also Hi give, C ₁ -C ₄ hydrocarbyl, hydroxy -C _1- C ₄ hydrocarbyl, C ₁ -C ₄ hydrocarbyl oxy, halo -C ₁ -C ₄ hydrocarbyl, C ₁ -C ₄ hydrocarbyloxymethyl, aminomethyl (NH ₂ CH _2- ), (NC ₁ -C ₃ hydrocarbyl) aminomethyl, (N, N-di-C ₁ -C ₃ hydrocarbyl) amino Methyl [(NC ₁ -C ₃ hydrocarbyl), (NC ₁ -C ₃ hydrocarbyl) aminomethyl], (N-morpholino) methyl (OC ₄ H ₈ NCH _2- ), (N-pyrroli Dino) methyl (C ₄ H ₈ NCH _2- ), or (N-thiomorpholino) methyl (SC ₄ H ₈ NCH _2- ) groups. In a particularly preferred embodiment, the R ² substituent is methyl, hydroxymethyl, (N-morpholino) methyl or methoxymethyl group.
R ¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical directly bonded to the SO ₂ -group shown in the formula, which is longer than the length of the approximately fully unfolded hexyl group and is approximately fully unfolded It has a length that is shorter than the length of. In addition, R ¹ is a 6-membered ring radical SO ₂ - the center of the bonded 1-position and the 3,4-bond - SO ₂ in the bonded 1-position and a-axis or five-membered ring radical connected through the 4-position A three-dimensional volume is defined when rotated about a connecting axis, and the widest width transverse to the axis of rotation is from about one furanyl ring to about two phenyl rings.
As mentioned above, the R ¹ substituent contains a 5 or 6 membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the SO ₂ -group shown in the formula. R ¹ substituents have length, width and substitution requirements discussed in detail below. However, it should be noted here that the monocyclic or condensed cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radicals themselves are not long enough to meet the requirements of length. Thus, cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radicals must themselves be substituted.
And may form part of the R ¹ substituents and the substituted 5 or 6 membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radicals, as discussed herein, may be phenyl, 2-, 3-, or 4-pyridine. Dill, 2-naphthyl, 2-pyrazinyl, 2- or 5-pyrimidinyl, 2- or 3-benzo (b) thienyl, 8-purinyl, 2- or 3-furyl, 2- or 3- Pyrrolyl, 2-imidazolyl, cyclopentyl, cyclohexyl, 2- or 3-piperidinyl, 2- or 3-morpholinyl, 2- or 3-tetrahydropyranyl, 2-imidazolidinyl, 2- or 3-pyrazolidinyl and the like. Phenyl radicals are particularly preferred and are used here by way of example.
When present along the longest atomic chain of the R ¹ substituent, including its own substituents, the R ¹ substituent is longer than the length of the fully unfolded saturated chain of 6 carbon atoms (hexyl group); That is, it has a total length corresponding to the length of heptyl chain or more and shorter than the length of the fully unfolding saturated chain of about 20 carbon atoms (ecosilyl group). Preferably, the length corresponds to the length of the fully unfolded saturated chain of about 8 to 18 carbon atoms, but more atoms may exist as actual ring structures or substituents. The requirements of this length are discussed further below.
More generally, and aside from the specific moiety structured, the R ¹ substituent (radical, group or moiety) has a length corresponding to the length of the fully unfolded heptyl group or more. These R ¹ substituents also have a length shorter than the length of the fully unfolded eicosyl group. That is, R ¹ is a substituent that is longer than the length of the saturated saturated 6 carbon chain and shorter than the length of the saturated saturated 18 carbon chain, more preferably, longer than the length of the octyl group and shorter than the length of the palmityl group. The chain length of the radical is measured along the longest straight atomic chain in the radical, if necessary, following the skeletal atoms of the ring. Each atom in the chain, for example carbon, oxygen or nitrogen, is assumed to be carbon for computational convenience.
These lengths can be purchased, if necessary, by using published bond angles, bond lengths and atomic radii for drawing and measuring chains, or by commercially available values in accordance with published values of known bond angles, lengths and atomic radii. It can be easily measured by the building model using the kit. Although the above-mentioned measurement mode is preferred, the length of radicals (substituents) also has the bond length of all valences of saturated carbon, unsaturated and aromatic bonds have the same length as saturated bonds, and the bond angles of unsaturated bonds are saturated bonds. It may be measured somewhat inaccurately by assuming the same coupling angle as. For example, using this mode of measurement, a 4-phenyl or 4-pyridyl group has a length of four carbon chains as in a propoxy group, while a biphenyl group has a length of about eight carbon chains.
In addition, R ¹ substituent, 6- SO ₂ radical on the ring-bonded 1-position and the 3,4-bond-bonded 1-position and SO ₂ of a shaft or a 5-membered ring radical connected through the 4-position The three-dimensional volume is defined when rotated around the connecting axis, with the widest width having a width of approximately one furanyl ring to approximately two phenyl rings in the transverse direction with respect to the axis of rotation.
When using the criteria of this width or volume, and condensed ring systems such as naphthyl or one purine radical is SO _2, as described above - substituted at the numbered connections from a suitable position-SO ₂ in the connection region to the 1-position It is thought to be a 6 or 5 membered ring. Thus, when a 2-naphthyl substituent or 8-purinyl substituent is examined using the rotational width criterion, it is an R ¹ radical of the appropriate size with respect to the width. In other words, 1-naphthyl groups or 7- or 9-purinyl groups are excluded because they are too large in rotation.
As a result of the requirements of these lengths and widths, 4- (phenyl) phenyl [biphenyl], 4- (4'-methoxyphenyl) phenyl, 4- (phenoxy) phenyl, 4- (thiophenyl) phenyl [4 -(Phenylthio) phenyl], 4- (phenylazo) phenyl 4- (ureidophenyl) phenyl, 4- (anilino) phenyl, 4- (nicotinamido) phenyl, 4- (isonicotinamido) phenyl R ¹ substituents such as 4- (picolinamido) phenyl and 4- (benzamido) phenyl are particularly preferred R ¹ substituents, of which 4- (phenoxy) phenyl and 4- (thiophenyl) phenyl Most preferred.
The SO ₂ -bonded cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is a 5 or 6 membered monocyclic ring and is itself substituted with one other substituent, R ³ . The SO ₂ -bonded monocyclic cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is substituted with 4 at the 6-membered ring and 3 at the 5-membered ring with R ³ . R ³ is bonded a cycloalkyl hydrocarbyl, heterocycloalkyl, aryl or heteroaryl radical is preferably a phenyl group, and therefore, SO ₂ - R ¹ is preferred to be the R ³ bonded at the 4-position of the bonded phenyl (Ph) radical Preferably PhR ³ and R ³ may itself be optionally substituted as discussed later. Substitution at the 2-position of the SO ₂ -bonded monocyclic cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical appears to significantly reduce the inhibitory effect on the MMP enzyme and is therefore excluded from this compound.
Expected R ³ substituents are hydrocarbyl or hydrocarbyloxy groups [eg, C ₃ -C ₁₄ hydrocarbyl or OC ₂ -C ₁₄ hydrocarbyl], phenyl groups, phenoxy groups [-OC ₆ H ₅ ], thiope Oxysulfuric acid [henylsulfanyl; -SC ₆ H ₅ ], anilino group [-NHC ₆ H ₅ ], phenylazo group [-N ₂ C ₆ H ₅ ], ureidophenyl group [aniline carbonylamino; -NHC (O) NH-C ₆ H ₅ ], Benzamido group [-NHC (O) C ₆ H ₅ ], nicotinamido group [3-NHC (O) C ₅ H ₄ N], isnicotinamido group [4-NHC (O) C ₅ H ₄ N ], Or a monocyclic cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group or other substituent having a chain length of 3 to about 14 carbon atoms, such as picolinamido group [2-NHC (O) C ₅ H ₄ N] Can be As discussed above in connection with the discussion of R ¹ , the most preferred R ³ substituents are preferably phenoxy and thiophenoxy groups, which themselves are free of substituents. Additionally expected R ³ substituents are heterocyclo, heterocyclohydrocarbyl, arylhydrocarbyl, arylheterocyclohydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydro Carbyl, aryloxyhydrocarbyl, hydrocarboylhydrocarbyl, arylhydrocarbylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbyl Bilthioaryl, arylthiohydrocarbyl, heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, arylhydrocarbylamino, heteroaryl Hydrocarbylamino, or heteroarylthio groups.
Expected R ³ substituents may also be substituted with a single atom or with one or more substituents at the meta- or para-position of the 6-membered ring or at both positions with a substituent comprising the longest chain up to 10 atoms except hydrogen May itself be substituted. Illustrative substituents include halo, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, aryl Thio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarby Bill, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, aryl Hydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocycle, heteroaryl, hydroxycarbonylhydride Carbyloxy, alkoxycarbonylalkoxy, hydrocarbyl oil, arylcarbonyl, arylhydrocarbyl oil, hydrocarbonyloxy, arylhydrocarbonyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbyl Bilthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonyl hydrocarbyl, hydrocarbylhydroxycarbonyl hydrocarbylthio, Hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbon Carbonylamino, arylhydrocarbonylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonyl Furnace, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclo Hydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted aminohydrocarbyl groups, provided that the substituent (s) on nitrogen are hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarby Selected from the group consisting of biloxycarbonyl, hydrocarbyloxycarbonyl and hydrocarbonyl, or two substituents attached to nitrogen and nitrogen form a 5-8 membered heterocycle or heteroarylcyclic group) .
Thus, initial studies indicate that the R ¹ substituents can vary widely so long as the SO ₂ -bonded R ¹ substituents discussed herein meet the requirements of length, substitution and width (volume at rotation).
Particularly preferred R ³ substituents of the SO ₂ -linked Ph group are unsubstituted or substituted (optionally substituted) monocyclics themselves at the para position in the 6-membered ring and at the 3-position in the 5-membered ring. Aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo, ureidophenyl, nicotinamido, isnicotinamido, picolinamido, anilino or benzamido groups. Here, substituents containing a chain of one to about ten atoms other than a single atom such as a halogen moiety or hydrogen such as a C ₁ -C ₁₀ hydrocarbyl, C ₁ -C ₉ hydrocarbyloxy or carboxyethyl group can be used. have.
Examples of particularly preferred PhR ³ (particularly preferred R ¹ ) substituents are biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl, 4-benzamidophenyl, 4-ureidophenyl, 4-anilinophenyl, 4-nicotinamido, 4-isonicotinamido and 4-picolinamido. Particularly preferred R ³ groups by way of example include six-membered aromatic rings and include phenyl groups, phenoxy groups, thiophenoxy groups, phenylazo groups, ureidophenyl groups, alinino groups, nicotinamido groups, isonicotinamido groups, picolineamido groups And benzamido groups.
More particularly, particularly preferred sulfonyl butanehydroxyxamate compounds are themselves halogen, C ₁ -C ₉ hydrocarbyloxy (-OC ₁ -C ₉ hydrocarbyl) groups, C ₁ -C ₁₀ hydrocarbyl groups, Di-C ₁ -C ₉ hydrocarbylamino [-N (C ₁ -C ₉ hydrocarbyl) (C ₁ -C ₉ hydrocarbyl)] group, carboxyl C ₁ -C ₈ hydrocarbyl (C ₁ -C ₈ hydrocarbyl-CO ₂ H) group, C ₁ -C ₄ hydrocarbyloxy carbonyl C ₁ -C ₄ hydrocarbyl [C ₁ -C ₄ hydrocarbyl-O- (CO) -C ₁ -C ₄ hydrocarbyl] group, C ₁ -C ₄ hydrocarbyloxycarbonyl C ₁ -C ₄ hydrocarbyl [C ₁ -C ₄ hydrocarbyl (CO) -OC ₁ -C ₄ hydrocarbyl] Group and C ₁ -C ₈ hydrocarbyl carboxamido [—NH (CO) —C ₁ -C ₈ hydrocarbyl] group with a substituent selected from the group consisting of meta- or para- or both positions C ₁ -C substituted or substituted with two methyl or methylenedioxy groups ₂ alkylenedioxy groups meta- and para-positions is substituted with a phenyl group, a phenoxy group, thiophenoxy group, a phenyl azo group, urethane Ido group, anilino group, nicotine amido group, iso nicotine amido, picoline amido group or benzamide It has an R ³ substituent which is an amido group.
Since the present SO ₂ -bonded cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radicals are preferably substituted by themselves with a six-membered aromatic ring, the two nomenclature systems are used together for ease of understanding the position of substitution. do. The first system uses the position number for the ring directly attached to the SO ₂ group, and the second system uses one or more of a six membered ring bonded to a SO ₂ -bonded cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical. Use ortho, meta or para for the position of the substituents. When the R ³ substituent is not a six-membered ring, the substituents are numbered from the position bonded to the aromatic or heteroaromatic ring. Regular chemical nomenclature is used to refer to individual compounds.
Thus, the 1-position of the aforementioned SO ₂ -bonded cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical is the position at which the SO ₂ group is bonded to the ring. The 4- and 3-positions of the rings discussed herein are numbered from the substituent linkage positions at the SO ₂ -linking site as compared to the canonical ring numbering positions used in heteroaryl nomenclature.
In a particularly preferred embodiment, R ¹ contains a phenyl group (Ph) bonded to another substituent R ³ at its own 4 position, so that R ¹ becomes PhR ³ , and the compound of formula (2) In which R ² is as defined above and R ³ is as defined below.
Particularly preferred R ³ substituents of the SO ₂ -linked Ph group are unsubstituted or monocyclic substituted (optionally substituted) at the para-position when in 6-membered ring and at 3-position when in 5-membered ring. Aryl, heteroaryl, phenoxy, thiophenoxy, phenylazo, ureidophenyl, nicotinamido, isnicotinamido, picolinamido, anilino or benzamido groups. Here, a single atom such as a halogen moiety is used or a substituent containing a chain of 1 to about 10 atoms in addition to hydrogen, such as C ₁ -C ₁₀ hydrocarbyl, C ₁ -C ₉ hydrocarbyloxy or carboxyethyl group, is used. Can be.
Examples of particularly preferred substituted R ¹ PhR ³ substituents include biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl, 4-benzamidophenyl, 4-ureidophenyl, 4-anilinophenyl, 4- Nicotinamido, 4-isonicotinamido, and 4-picolinamido are mentioned. Particularly preferred R ³ groups contain 6-membered aromatic rings and examples thereof include phenyl group, phenoxy group, thiophenoxy group, phenylazo group, ureidophenyl group, alinino group, nicotinamido group, isnicotinamido group, picolineamido group and Benzamido group is mentioned
In one embodiment of the particularly preferred aromatic sulfonyl alpha-hydroxy hydroxyxamate compound, the R ³ substituent is, in its meta or para-position or both positions, halogen, C ₁ -C ₉ hydrocarbyloxy (- OC ₁ -C ₉ hydrocarbyl) group, C ₁ -C ₁₀ hydrocarbyl group, di-C ₁ -C ₉ hydrocarbylamino [-N- (C ₁ -C ₉ hydrocarbyl) (C ₁ -C ₉ hydrocarbyl)] group, a carboxyl C ₁ -C ₈ hydrocarbyl (C _1- C ₈ hydrocarbyl -CO ₂ H) group, a C ₁ -C ₄ hydrocarbyl oxycarbonyl C ₁ -C ₄ Hydrocarbyl [C ₁ -C ₄ hydrocarbyl-O- (CO) -C ₁ -C ₄ hydrocarbyl] groups, C ₁ -C ₄ hydrocarbyloxycarbonyl C ₁ -C ₄ hydrocarbyl [ C ₁ -C ₄ hydrocarbyl (CO) -OC ₁ -C ₄ hydrocarbyl] group and C ₁ -C ₈ hydrocarbyl carboxamide [-NH (CO) -C ₁ -C ₈ hydrocarbyl] Optionally substituted with a portion selected from the group consisting of groups, or And para-upon by the two methyl groups at the location or methylenedioxy group and a group such as C ₁ -C ₂ alkylenedioxy-substituted phenyl, phenoxy, thiophenoxy or a Reno time not. These compounds generally exhibit good activity for MMP-2, MMP-9 and MMP-13 (IC ₅₀ value about 0.1-60 nM), while substantially less activity for MMP-1 (IC ₅₀ value about 1000 to > 10,000 nM). Phenoxy or thiophenoxy unsubstituted as R ³ substituent is preferred at present.
In another embodiment of the particularly preferred aromatic sulfonyl alpha-hydroxy hydroxyxamate compound, the R ³ substituent is benzamido, nicotinamido, isnicotinamido, picolinamido or ureidophenyl, wherein the substituent ring (Benzamido, nicotinamido, isnicotinamido, picolinamido or ureidophenyl groups) are either unsubstituted or (optionally) substituted in their meta or para-position. Preferred substituent moieties on this substituent ring are halogen, nitro, C ₁ -C ₈ hydrocarbyl, C ₁ -C ₇ hydrocarbyloxy, C ₁ -C ₂ alkylenedioxy, amino, NC ₂ -C ₄ -hydroxy From the group consisting of alkylamino [eg -NH (C ₄ H ₈ OH)] and N, NC ₂ -C ₄ -hydroxyalkylamino [eg -N (C ₂ H ₄ OH) ₂ ] Is selected. Some of these compounds show at least 100,000-fold differences in in vitro inhibitory activity against MMP-2 and MMP-1, and still show about 2 to about 100-fold improvement in MMP-2 over MMP-13, but still have MMP. Maintain nanomolar activity for -2. These compounds exhibited about 10 to about 100 fold difference in activity between MMP-2 and MMP-9. Such compounds illustrate one aspect of the inhibitory activity and selectivity of some of the compounds.
Since the present SO ₂ -bonded aryl or heteroaryl radicals themselves are preferably substituted with a six-membered aromatic ring, the two nomenclature systems are used together for ease of understanding the position of substitution. The first system uses the position number for the ring directly attached to the SO ₂ group and the second system uses ortho, meta for the position of one or more substituents of the 6 membered ring bonded to the SO ₂ -bonded aryl or heteroaryl radical. Or use para. When the R ³ substituent is not a six-membered ring, the substituents are numbered from the position bonded to the aromatic or heteroaromatic ring. Regular chemical nomenclature is used to refer to individual compounds.
Thus, the 1-position of the aforementioned SO ₂ -bonded aryl or heteroaryl radical is the position at which the SO ₂ group is bonded to the ring. The 4- and 3-positions of the rings discussed herein are numbered from the substituent linkage positions at the SO ₂ -linking site as compared to the canonical ring numbering positions used in heteroaryl nomenclature.
The length, width and number of the aromatic rings present in the R ¹ substituents attached to the SO ₂ group are generally believed to play an important role in the overall activity of the compound against the MMP enzyme. Identity of the R ¹ substituents may also play an important role in the activity of the present compounds on specific MMP enzymes. In addition, the substitution at the alpha-position to the hydroxamic acid group, ie, on the carbon atom between the hydroxamic acid group and the methylene-SO ₂ group, appears to play an important role in the specificity of the compound as an inhibitor of certain MMP enzymes.
For example, the compound of Example 8 wherein the SO ₂ -bonded aryl group is a 4-methoxyphenyl substituent having a length of about 6 carbon chains (hexyl group) [N, 2-dihydroxy-3-[(4- Methoxyphenyl) sulfonyl) propanamide] was found to be relatively inactive as an inhibitor of MMP-1 and only slightly better for MMP-13. This lack of activity was likewise substituted with the compound of Example 9 [N, 2-dihydroxy-3-[(4-phenoxyphenyl)) having a longer R ¹ group (about 9 carbon chains) substituted at the alpha-position Phonyl) propanamide]. This comparative activity can be seen in Table 51 below.
Examples of compounds 14-35 contains an PhhR ³ of R ¹ containing amido [C (O) NH-] functionality as part of the group R ^1. These R ¹ groups slightly reduce the activity of the present compounds on MMP-13 depending on the total length of R ¹ , while substantially eliminating all activity on MMP-1, thus providing excellent specificity for distinguishing these two enzymes. . This phenomenon is part of the ureido [-NHC (O) NH-] bond, whether the R ³ group contains an aromatic moiety or an aliphatic moiety bound to an amido group and whether the amido group is present as a -C (O) NH- bond. It seems to exist or remain as. Therefore, the compound containing the R ¹ substituent containing an amido group seems to be bound to the minimum by the binding by MMP-1. These data are also shown in Table 51 below.
These data in Table 51 also show the relative importance of the substituents having two aromatic rings as well as the relative importance of the total length of the R ¹ substituents. Thus, the compound of Example 24, wherein the R ¹ group is about 18 carbon chains in length [4- (heptyloxy) -N- [4-[[(2-hydroxy-3- (hydroxyamino) -2-methyl -3-oxopropyl] sulfonyl] phenyl] benzamide] shows greater efficacy than can be measured by assays for MMP-13 and MMP-2, and can be measured by assays for MMP-1 Showed lower activity than the compounds of Examples 16 and 17, wherein the R ¹ groups were of approximately the same length {N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3- Oxopropyl] sulfonyl] phenyl] benzamide and N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -3-methylbutane The data in Table 51 for Amide} show that compounds having two aromatic rings are more active.
In addition, the R ¹ substituent preferably contains a thioether bond when present in the thiophenoxy R ³ group. This is preferred by comparing the activity of Table 51 of other, similarly substituted compounds in that a thioether group is present or absent in the R ¹ group as in the compounds of Examples 2 and 13 or 9 and 12 have.
The interstitial compounds contain asymmetric carbon atoms in the alpha-position such that d and l or R and S enantiomers of each compound are present. Particularly preferred stereoconfigurations for the present enantiomeric compounds are shown in the following formulas (3) and (4).
As is typical in stereochemical illustrations, the dashed line in the above formula represents a bond extending down the face of the page, and the wedge shaped line represents the bond extending over the face of the page. When the R ² group is methyl, the compound of formula 3 or 4 has an S stereoconfiguration.
X-ray crystallographic data of the complex of the compound bound to MMP-8, an enzyme very similar to MMP-13, showed that between the alpha-hydroxy and sulfonyl groups of the compound having the stereoconfiguration shown in Formula 3 or 4 It can be seen that intramolecular hydrogen bonds are formed. It was unexpected that such hydrogen bonds were observed. The structure of the bound inhibitor (Example 1A) seems to enable intramolecular hydrogen bonding only to this stereoisomer. From the opposite compound, this hydrogen bond cannot be formed while maintaining (a) the orientation of the hydroxyxamate group to the metal ion of the enzyme and (b) the position of the R ¹ group in the binding pocket of the enzyme. This may explain the better binding of the compounds to MMP-13, -2 and -9 compared to the reversed compound (compound of Example 1B) (see Table 51 for enzyme data).
Intramolecular hydrogen bonds are well known to those skilled in the art. The S stereoisomer of Example 1A is preferred, but both configurations allow for this advantageous intramolecular interaction. The benefits of such intramolecular hydrogen bonding in medicine have been reported by several research groups (see, eg, Smith, et al. J. Med. Chem. (1994) 37 (2), 215-218 and Leone-Bay). et al. J. Med. Chem. (1996) 39 (13), 2571-2578).
The data shown in Table 51 illustrate that the binding of the compounds of this batch to MMP-12, -2 and -9 is better than that of the opposite batch of compounds (compounds of Example 1B). The binding of both compounds to MMP-1 was within about factor 10. However, since the binding of the compound of Example 1A to MMP-13 is better, the ratio of inhibition of MMP-1 to inhibition of MMP-13 is such that the compound of the stereoconfiguration (compound of Example 1A) It was about 2 times larger than the compound. The benefits of these intramolecular hydrogen bonds in medicine have been reported by several research groups (eg, Smith, et al. J. Med. Chem. (1994) 37 (2), 215-218 and Leone). Bay et al. J. Med. Chem. (1996) 39 (13), 2571-2578).
The term "hydrocarbyl" is used herein as a short term term that includes an alicyclic group or radical containing only carbon and hydrogen as well as straight or branched chain aliphatic. Thus, alkyl, alkenyl and alkynyl groups are included, whereas, strictly speaking, aromatic hydrocarbons such as phenyl and naphthyl groups, which are also hydrocarbyl groups, are referred to herein as aryl groups or radicals as discussed below. Where specific aliphatic hydrocarbyl substituents are intended, those groups, ie C ₁ -C ₄ alkyl, methyl or dodecenyl, are mentioned. Exemplary hydrocarbyl groups contain 1 to about 12 carbon atoms, preferably 1 to about 10 carbon atoms. Particularly preferred hydrocarbyl groups are alkyl groups.
The use of the term "hydrocarbyl" follows the usual chemical suffix nomenclature, but does not always follow the usual practice of removing the ending "work" and adding the appropriate suffix, with the potential for similar names for one or more substituents. Hydrocarbylethers therefore mean "hydrocarbyloxy" groups rather than "hydrocarboxy" groups, since it may be more appropriate to follow the usual rules for chemical nomenclature, while -C (O) 0-. A hydrocarbyl group containing a functional group means a hydrocarbonyl group since there is no ambiguity in the use of the suffix, as will be appreciated by those skilled in the art, substituents that cannot exist as such as a C ₁ alkenyl group are referred to in the term “hydrocarbyl”. It shall not be included.
As mentioned above, particularly preferred hydrocarbyl groups are alkyl groups. As a result, generalized but more preferred substituents may be mentioned by substituting "alkyl" for "hydrocarbyl" of any of the substituents listed herein.
Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Examples of suitable alkenyl radicals are ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3- Butenyl, dessenyl, etc. are mentioned. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decinyl, 1-butynyl, 2-butynyl, 3-butynyl and the like.
The term “carbonyl”, alone or in combination, refers to the group —C (═O) —, wherein the other two bonds (atoms) are independently substituted. The term "thiol" or "sulfhydryl" alone or in combination means a -SH group. The term "thio" or "thia", alone or in combination, refers to a thiaether group, ie an ether group in which ether oxygen is substituted with a sulfur atom.
The term "amino", alone or in combination, refers to an amine or -NH ₂ group, while the term monosubstituted amino, alone or in combination, means a substituted amine -N (H) (substituent) group in which one hydrogen atom is substituted with a substituent. In addition, di-substituted amine means -N (substituent) ₂ in which two hydrogen atoms of an amino group are substituted by the substituent selected independently. Amines, amino groups and amides can be represented as primary (I °), secondary (II °) or tertiary (III °) or unsubstituted, monosubstituted or disubstituted depending on the degree of substitution of amino nitrogen. to be. Quaternary amine (IV °) means nitrogen with four substituents (-N ⁺ (substituents) ₄ ) that are positively charged and have a counterion, and N-oxide means that one substituent is oxygen (-N ⁺ (substituent) ₃ -O ^-) is expressed as. The charge is replenished internally.
The term "cyano", alone or in combination, refers to a -C- triple bond-N (-CN) group. The term "azido", alone or in combination, refers to an -N-double bond-N-double bond-N (-N = N = N) group.
The term "hydroxyl", alone or in combination, refers to an -OH group. The term "nitro" alone or in combination means a -NO ₂ group.
The term “azo”, alone or in combination, refers to the group —N═N—, wherein the bonds at the terminal positions are independently substituted. The term "hydrazino", alone or in combination, refers to the group -NH-NH-, wherein the remaining two bonds (atoms) are independently substituted. The hydrogen atom of the hydrazino group may be independently substituted with a substituent and the nitrogen atom may form an acid addition salt or may be quaternized.
The term “sulfonyl”, alone or in combination, refers to the group —S (═O) ₂ —, wherein the other two bonds (atoms) may be independently substituted. The term “sulfoxide”, alone or in combination, refers to the group —S (═O) ₁ — where the remaining two bonds (atoms) may be independently substituted. The term "sulfonylamide", alone or in combination, refers to the group -S (= 0) ₂ -N = wherein the remaining three bonds (atoms) are independently substituted. The term “sulfinamido”, alone or in combination, refers to the group —S (═O) ₁ N═where the remaining three bonds (atoms) are independently substituted. The term "sulfenamide", alone or in combination, refers to the group -SN = wherein the remaining three bonds (atoms) are independently substituted.
The term "hydrocarbyloxy", alone or in combination, refers to a hydrocarbylether radical, wherein the term hydrocarbyl is as defined above. Examples of suitable hydrocarbylether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. The term "cyclohydrocarbyl", alone or in combination, refers to a cyclic hydrocarbyl radical containing 3 to about 8 carbon atoms, preferably about 3 to about 6 carbon atoms. Examples of such cyclohydrocarbyl radicals include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctynyl and the like. The term "cyclohydrocarbylhydrocarbyl" means a hydrocarbyl radical, also as defined above, substituted with cyclohydrocarbyl as defined above.
The term "aryl", alone or in combination, refers to phenyl, p-tolyl, 4-methoxyphenyl, 4-hydroxyphenyl, 4- (tert-butoxy) phenyl, 4-fluorophenyl, 4-chlorophenyl, A phenyl or naphthyl radical, optionally including one or more substituents selected from hydrocarbyl, hydrocarbyloxy, halogen, hydroxy, amino, nitro and the like, such as 4-hydroxyphenyl and the like. The term "arylhydrocarbyl", alone or in combination, refers to a hydrocarbyl radical as defined above in which one hydrogen atom is substituted with an aryl radical as defined above, such as benzyl, 2-phenylethyl, and the like. do. The term "arylhydrocarbyloxycarbonyl", alone or in combination, refers to a radical of the formula -C (O) -0-arylhydrocarbyl, wherein the term "arylhydrocarbyl" has the meaning given above. An example of an arylhydrocarbyloxycarbonyl radical is benzyloxycarbonyl. The term "aryloxy" means a radical of the formula aryl-O-, wherein the term aryl has the meaning given above. The term "aromatic ring" such as substituted aromatic ring sulfonamide, substituted aromatic ring sulfinamide or substituted aromatic ring sulfenamide refers in combination to aryl or heteroaryl as defined above.
The term "hydrocarbyl oil" or "hydrocarbylcarbonyl", alone or in combination, refers to an acyl radical derived from hydrocarbylcarboxylic acid, examples of which include acetyl, propionyl, acryloyl, Butyryl, valeryl, 4-methyl valeryl, etc. are mentioned. The term "cyclohydrocarbonylcarbonyl" refers to an acyl group derived from a monocyclic or crosslinked cyclohydrocarbylcarboxylic acid, such as cyclopropanecarbonyl, cyclohexenecarbonyl, adamantanecarbonyl, and the like, or an example Optionally substituted with hydrocarbylylamino groups such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl Acyl group derived from benz condensed monocyclic cyclohydrocarbylcarboxylic acid. The term "arylhydrocarbyl oil" or "arylhydrocarbylcarbonyl" refers to phenylacetyl, 3-phenylpropenyl (cinnamoyl), 4-phenylbutyryl, (2-naphthyl) acetyl, 4-chlorohydrocinna Acyl radicals derived from aryl substituted hydrocarbylcarboxylic acids, such as moyl, 4-aminocinnamoyl, 4-methoxycinnamoyl, and the like.
The term "aroyl" or "arylcarbonyl" refers to an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals are benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4- (benzyloxycarbonyl) benzoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl, 6- (benzyloxycarbonyl)- 2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3- (benzyloxy And optionally substituted benzoic acid or naphthoic acid, which is an aromatic carboxylic acid such as formamido) -2-naphthoyl and the like.
Heterocyclyl (heterocyclo) or heterocyclohydrocarbyl moieties such as heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylhydrocarbyloxycarbonyl or heterocyclohydrocarbyl groups are nitrogen, oxygen and sulfur atoms. Saturated or partially saturated monocyclic, bicyclic or tricyclic heterocycles containing 1 to 4 heteroatoms selected from the group consisting of halogen, alkyl, alkoxy, oxo groups and the like on one or more carbon atoms Hydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyl oil, aryl or arylhydrocarbyl, or tertiary nitrogen atom (i.e., =) on and / or on a secondary nitrogen atom (i.e., -NH-). It is optionally substituted with an oxy group on N-) and attached via a carbon atom. Tertiary nitrogen atoms with three substituents can also form N-oxide [= N (O)-] groups. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl and the like.
Heteroaryl moieties such as heteroaroyl, heteroaryloxycarbonyl or heteroarylhydrocarbylyl (heteroarylhydrocarbylcarbonyl) groups contain heteroatoms as defined above in connection with the definition of heterocyclyl And optionally substituted aromatic monocyclic, bicyclic or tricyclic heterocycles. A "heteroaryl" group is an aromatic heterocyclic ring substituent which may contain 1, 2, 3 or 4 atoms other than carbon in the ring. These heteroatoms may be nitrogen, sulfur or oxygen. Heteroaryl groups may contain a single 5 or 6 membered ring or a condensed ring system containing two 6 or 6 membered rings and a 6 membered ring. Examples of heteroaryl groups include six-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl and pyridazinyl; 1,3,5-, 1,2,4- or 1,2,3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3 5-membered ring substituents such as 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl groups; 6/5 membered condensed ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, furinyl and anthranylyl groups: and 1,2-, 1,4-, 2,3 And 6 / 6-membered condensed rings such as 2,1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and 1,4-benzoxazinyl groups.
The term "cyclohydrocarbylhydrocarbyloxycarbonyl" means an acyl group derived from cyclohydrocarbylhydrocarbyloxycarboxylic acid of the formula cyclohydrocarbylhydrocarbyl-O-COOH, wherein cyclohydrocarbyl Hydrocarbyl has the meaning given above. The term "aryloxyhydrocarbyl oil" means an acyl radical of the formula aryl-O-hydrocarbyl oil, wherein aryl and hydrocarbyl oil have the meanings given above. The term "heterocyclyloxycarbonyl" refers to an acyl group derived from heterocyclyl-O-COOH, wherein heterocyclyl has the meaning given above. The term “heterocyclylhydrocarbyl oil” is an acyl radical derived from a heterocyclyl substituted hydrocarbylcarboxylic acid where heterocyclyl has the meaning given above. The term "heterocyclylhydrocarbyloxycarbonyl" is an acyl radical derived from heterocyclyl substituted hydrocarbyl-O-COOH, where heterocyclyl has the meaning given above. The term "heteroaryloxycarbonyl" refers to an acyl radical derived from a carboxylic acid represented by heteroaryl-O-COOH, wherein heteroaryl has the meaning given above.
The term "aminocarbonyl", alone or in combination, refers to an amino substituted carbonyl (carbamoyl) group derived from an amino substituted carboxylic acid wherein the amino group is hydrogen, hydrocarbyl, aryl, aralkyl, cyclo Primary, secondary or tertiary amino groups containing substituents selected from hydrocarbyl, cyclohydrocarbylhydrocarbyl radicals and the like. The term "aminohydrocarbyl oil" means an acyl group derived from an amino substituted hydrocarbylcarboxylic acid, wherein the amino group is hydrogen, alkyl, aryl, aralkyl, cyclohydrocarbyl, cyclohydrocarbylhydrocarbyl radical Primary, secondary or tertiary amino groups independently selected from the like.
The term "halogen" means fluorine, chlorine, bromine or iodine. The term "halohydrocarbyl" means a hydrocarbyl radical having the meaning as defined above wherein at least one hydrogen is replaced by halogen. Examples of such halohydrocarbyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like. The term "perfluorohydrocarbyl" means a hydrocarbyl group in which each hydrogen is substituted with a fluorine atom. Examples of such perfluorohydrocarbyl groups include perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl in addition to the above trifluoromethyl.
Tables 1 to 50 below show some of the present aromatic sulfonyl alpha-hydroxy hydroxysamic acid compounds as structural formulas illustrating substituents. Each group of compounds is illustrated by the general formula, followed by a series of preferred moieties or groups that constitute various substituents that may be attached at the positions clearly indicated in this general structure. The substituent symbol, for example, R ¹ is as shown in each table. One bond (straight) is shown with substituents to indicate each attachment site in the exemplified compounds. Such systems are well known in the chemical information technology field and are widely used in scientific papers and presentations.












Treatment method
Also contemplated are methods of treating host mammals with diseases associated with pathological interstitial metalloprotease activity. This method consists in administering the aforementioned compounds to a mammalian host with such a disease in an amount effective to inhibit MMP enzymes. Particularly expected is to administer a plurality of repetitions.
The compounds are used to treat host mammals such as mice, rats, rabbits, dogs, horses, monkeys, chimpanzees or primates such as humans with diseases associated with pathological interstitial metalloprotease activity.
Similar use is also expected in the treatment of disease states that may be affected by the activity of metalloproteases such as TNF-α convertases. Examples of such disease states include acute reactions of shock and sepsis, coagulation, bleeding and cardiovascular disease, fever and inflammation, anorexia and cachexia.
In the treatment of disease states associated with pathological interstitial metalloprotease activity, the present MMP inhibitor compounds may be used in the form of amine salts derived from inorganic or organic acids, if appropriate. Exemplary acid salts include, but are not limited to: acetates, adipates, alginates, citrate, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, camphorsulfonates, di Gluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrogen chloride, hydrogen bromide, hydrogen iodide, 2 Hydroxyethanesulfonate, lactate, malate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pival Latex, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate .
In addition, basic nitrogen-containing groups include halogenated lower alkyls (C ₁ -C ₆ ) such as chloride, brominated and iodide, methyl, ethyl, propyl and butyl to increase water solubility; Dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates; Halogenated long chains (C ₈ -C ₂₀ ) such as chloride, brominated and iodide, decyl, lauryl, myristyl and dodecyl; Quaternized with halogenated aralkyl and other agents such as benzyl bromide and phenethyl. This gives a water soluble or fat soluble or dispersible product as desired. Salts are formed by combining a basic compound with the desired acid.
Other compounds useful in the present invention that are acids may also form salts. Examples include salts with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium or salts with organic bases or basic quaternary ammonium salts.
In some cases, salts can be used as a role to assist in the isolation, purification or analysis of the compounds of the present invention.
When the MMP inhibitory effective amount is administered to a host mammal in a single or divided amount, the total daily dose is, for example, about 0.001 to about 100 mg / kg body weight per day, preferably about 0.001 to about 30 mg / kg body weight per day. And, more typically, from about 0.01 to about 10 mg. The dosage unit composition may comprise an equivalent amount or a divided amount thereof to fill a daily dose. Appropriate doses may be administered in several subdoses per day. Multiple doses per day may also increase the total daily dose, and such dosage should be determined by the prescriber.
Dosage methods for treating a disease state with a compound and / or composition of the present invention include, but are not limited to, pharmacological considerations such as type, age, weight, sex, diet and medical condition, severity of disease, route of administration, activity, efficacy The pharmacokinetic and toxicological profiles of the specific compounds to be selected, the drug delivery system used, and whether the compounds are administered as part of the drug combination, are chosen according to a variety of factors. Therefore, the administration method actually used may vary widely, and thus may deviate from the preferred administration method described above.
Compounds useful in the present invention may be formulated as pharmaceutical compositions. Such compositions are then administered orally, parenterally, by inhalation spray, rectally or topically in the form of a dosage unit formulation comprising a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and vehicle as desired. Can be. Topical administration may also include the use of transdermal methods of administration, such as transdermal patches or iontophoretic devices. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, sternal, or infusion techniques. Formulations of the drug are described, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania; 1975 and Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.
Injectables, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in a nontoxic parenterally acceptable diluent or solvent, such as, for example, a solution in 1,3-butanediol. Possible vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Moreover, sterile, nonvolatile oils may be suitably used as a solvent or suspending medium. For this purpose, any mixed nonvolatile oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables. Surfactants including dimethyl acetamide, ionic and nonionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents are also useful as described above.
Suitable suppositories for rectal administration are drug-free excipients, such as cocoa butter, synthetic mono-, di-, or triglycerides that are solid at normal temperatures or liquid at rectal temperatures and can melt in the rectum to release the drug. It can be prepared by mixing with the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of the present invention are usually combined with one or more adjuvants suitable for the designated route of administration. Compounds administered orally include lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid, and sodium salts of calcium sulfate, gelatin, acacia rubber , Sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then can be tableted or encapsulated for convenient administration. Such capsules or tablets may include controlled release formulations as may be provided by dispersing the active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets and pills, the formulation may also further comprise a buffer such as sodium citrate, carbonate or magnesium bicarbonate or calcium. Tablets and pills may further be prepared as enteric coatings.
Therapeutic formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from aseptic powders or granules containing one or more carriers or diluents mentioned for use in the formulation for oral administration. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art.
Liquid formulations for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, including inert diluents commonly used in the art, such as water. Such compositions may also include adjuvant such as wetting agents, emulsifiers and suspending agents, and sweetening agents, seasonings, and fragrances.
To prepare a single formulation, the amount of active ingredient that can be combined with the carrier material will vary depending upon the mammalian host being treated and the particular mode of administration.
Preparation of Useful Compounds
Schemes 1-4 and 5-6c below describe the preparation of compounds in which general and specific chemical methods and conversions are useful in the present invention, ie compounds of Formula 1-4 (with particular emphasis on compounds of Formulas 2 and 4) and analogous inhibitors Illustrates that they may be useful.
Compounds of the present invention can be prepared according to the following synthetic schemes.

Schemes 1-4 illustrate general methods and examples of chemical conversions useful for the preparation of compounds of the present invention. Scheme 1 begins with the conversion of a protected carboxylic acid to a protected alpha-beta unsaturated carboxylic acid, where R ² and R ¹ are as defined above. Preferred reagents are bis-halogen ring methane such as methylene iodide. Bases can be in several categories, as discussed below. Preferred bases are organic strong bases such as metalamides, lithiumalkyl or metal hydrides, hindered bases and / or non-nucleophilic bases. Preferred solvents are aprotic solvents or amphoteric aprotic solvents as discussed below. Most preferred are amphoteric aprotic solvents such as DMF.
P represents a carboxylic acid protecting group such as an ester or an acid. In addition, P may represent an -OH group according to conditions easily understood by those skilled in the art.
The double bond compounds produced by this method can be oxidized to epoxides. Oxidation can be carried out, for example, with peracid or hydrogen peroxide, or other similar oxidants as discussed below. The desired epoxide can also be obtained by methods well known in the art, either by halohydrin formation with HOCl or halogenation with halogens such as chlorine or bromine, followed by base treatment with, for example, metal hydroxides. In addition, a Darzen type reaction (forming glycidic acid derivatives) may also be used in which an alpha-halocarbonyl compound, such as an alpha-chloro carboxylic acid ester, is treated with an aldehyde or a ketone in the presence of a base. Form an epoxide directly. Preferred bases are nonnucleophilic or intermediate nucleophilic bases such as metalalcoholates, metalamides, magnesium reagents, lithium reagents or metal hydrides as discussed below.
Scheme 1 also illustrates the ring opening of an exemplary epoxide intermediate of the present invention using a nucleophilic thiol or thiolate reagent. Thiolate nucleophiles can be formed by methods well known in the art, such as treating the thiol with a base in situ or using preformed thiolates. The use of preformed thiolates can maintain the protecting group. These methods will be discussed further below as part of the description of the Michael reaction. Preferred bases are potassium hydroxide if the hydrolysis of the protecting group is desired, for example an alcoholate such as sodium methoxylate if the methyl ester protecting group should be kept in use, and alkyllithium or lithium amide if the holding of the protecting group is desired.
The product of nucleophilic ring opening (epoxide ring opening) can be oxidized to sulfone in one step using two equivalents of oxidant. Starting materials for this reaction may be protecting groups such as esters or amides or carboxylic acids or sulfides where P is OH. Reagents for this method include peroxymonosulfate (OXONE). ), Hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, perlactic acid, tert-butyl peroxide, tert-butyl hydroperoxide, tert-butyl hydrochloric acid, sodium hypochlorite, hypochlorous acid, sodium metaperate, Iodic acid and the like. Pure or mixed protic, aprotic, amphoteric aprotic solvents such as methanol / water can be selected.
The oxidation is carried out at a temperature of about -68 ° C to about 50 ° C and can usually be selected in the range of -10 ° C to about 40 ° C. This oxidation can be carried out in two steps through the synthesis of sulfoxides which require only about 1 equivalent of one of the preferred oxidants at about 0 ° C. The solvents listed above can be used for such selective oxidation to sulfoxides, for example methanol or methanol / water with temperatures of about −10 ° C. to 30 ° C. is preferred. In the case of more active oxidants, although not required, it is preferred to carry out the reaction in an inert gas atmosphere with or without degassed solvent. The sulfoxide is then oxidized to sulfone using two equivalents of oxidant in a separate step that can be carried out in the synthesis step chosen by those skilled in the art. In addition, in the synthesis of this product compound, those skilled in the art can determine whether to maintain or remove the protecting group by selecting reagents, solvents and pH conditions. For example, protic solvents or mixed solvents, such as water or water / solvent mixtures under basic conditions, may produce acids directly, while some peroxy acids in aprotic or amphoteric aprotic solvents may remove protective groups. It can oxidize sulfur without doing so. Preferred oxidizing agents for the reaction carried out under conditions in which the methyl ester, which is the preferred protecting group, are hydrolyzed are peroxymonosulfates.
Scheme 1 also illustrates the formation of hydroxamate for preparing the hydroxamic acid product of the present invention. Preferred methods in this case are the direct reaction of the activated esters with hydrosylamine (aqueous) and diimide coupling. The second preferred method is for example exchange with methyl ester. This type of reaction is well known in the art, in particular in the field of peptide synthesis and will be discussed further below.
Scheme 2 is a protected alpha-beta unsaturated carboxyl with a thiol such as R ¹ SH to form the product of the present invention, ie sulfideamide or sulfide ester, where the amide or ester serves as a carboxylic acid protecting group. Illustrate the Michael reaction of acid. This reaction can be carried out using a catalytic amount of several bases, or by using one or more equivalents of base, or by adding a preformed thiolate reagent such as a preformed thiol salt of the base.
Non-limiting examples include sodium salts, potassium salts, lithium salts, calcium salts or magnesium salts of thiophenols, substituted thiophenols or heteroarylthiols as defined above. Bases that can be used include, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide or magnesium hydroxide, oxides such as oxides of sodium, potassium, lithium, calcium or magnesium, sodium, potassium, lithium, calcium or magnesium Metal carbonates such as carbonates, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, I °, II ° or III ° organic amines, such as alkylamines, arylalkylamines, alkylarylalkylamines, heterocyclic amines or heteroarylamines, ammonium hydroxide Or quaternary ammonium hydroxides. Non-limiting examples of the amine include triethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine, diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine, N, N '-Dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine and the like. Non-limiting examples of ammonium hydroxides generally prepared from amines and water include ammonium hydroxide, triethylammonium hydroxide, trimethylammonium hydroxide, methyldiisopropylammonium hydroxide, tribenzylammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholine hydroxide, and hydroxides. N-methyl morpholine, N, N'- dimethyl piperazine, N-ethyllipidine hydroxide, etc. are mentioned. Non-limiting examples of quaternary ammonium hydroxides include tetraethylammonium hydroxide, tetramethylammonium hydroxide, dimethyldiisopropylammonium hydroxide, benzylmethyldiisopropylammonium hydroxide, methyldiazabicyclononylammonium hydroxide, methyltribenzylammonium hydroxide, N , N-dimethylmorpholine®, N, N, N ', N'-tetramethylpiperazene®, and N-ethyl-N'-hexylpeperidine® hydroxide and the like. Metal hydrides such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, tert-butoxylated potassium, ethoxylated, magnesium ethoxide, sodium amide, potassium diisopropylamide, metal amide or metal alcoholate May also be a suitable reagent. Organometallic deprotonating agents, such as alkyllithium or aryllithium reagents such as methyllithium, phenyllithium or butyllithium, Grignard reagents such as methylmagnesium bromide or methylmagnesium chloride, and organiccardium reagents such as dimethylkadium, may also cause salt formation or Or as a base to catalyze the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for facilitating phase transfer coupling or as phase transfer reagents.
The reaction medium may consist of a single solvent, or a mixed solvent of the same or different classes, or serve as a reagent in a single or mixed solvent system.
Non-limiting examples of protic solvents include water, methanol (MeOH), modified or pure 95% or anhydrous ethanol, isopropanol and the like. Typical aprotic solvents include acetone, tetrahydrofuran (THF), dioxane, diethyl ether, tert-butyl methyl ether (TBME), aromatics such as xylene, toluene or benzene, ethyl acetate, methyl acetate, butyl acetate, Trichloroethane, methylene chloride, ethylene dichloride (EDC), hexane, heptane, isooctane, cyclohexane, etc. are mentioned. Amphoteric aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, nitromethane, tetramethylurea, N-methylpyrrolidone and the like. Non-limiting examples of reagents that can be used as a solvent or as part of a mixed solvent system include hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine , Monoprotic or multiprotic organic or inorganic acids or bases, such as piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for the production of esters or amines, or thiols for the production of the products of the invention. Can be.
Room temperature or lower or slightly warmed temperature (-10 ° C. to 60 ° C.) is the preferred reaction temperature. If desired, the reaction temperature may be from about −78 ° C. to the reflux point of the reaction solvent or solvents.
The beta-SR ¹ derivatives prepared as discussed above can then proceed as is or be oxidized to the corresponding sulfones by the methods discussed above. Any of these products can then be reacted with aldehydes or ketones under condensation conditions, wherein R ⁶ and R ⁷ are independently hydrogen or one or more carbon atoms, ie directly to carbon atoms which are alpha relative to the carbonyl group in the formula. It may be a group represented by R ² having a carbon atom exemplified as being attached. This produces an unsaturated sulfide or sulfone containing the carboxylic acid or protected carboxylic acid illustrated in Scheme 2.
This alpha-beta unsaturated sulfide can be oxidized to sulfone after condensation as shown in the scheme. The oxidation of unsaturated sulfides or sulfones containing carboxylic acids or protected carboxylic acids with epoxide containing analogs is also illustrated. Oxidation of the sulfide can produce epoxide rings and sulfones in one step.
Scheme 2 also illustrates the hydroxylation of the double bond. This method is well known in the art and examples of reagents for this conversion include iodine with osmium tetraoxide, permanganate containing hydroxide if desired, and lead acetate. Presence of reagents such as N-methylmorpholine-N-oxide (NMM-N-oxide) for in situ recycling (reoxidation) to tetraoxide after halohydrin formation followed by substitution of halogen with base or conversion to epoxide Ring is opened by hydroxide or catalytic osmium tetraoxide.
These schemes illustrate the conversion of sulfides or sulfones to hydroxamic acid derivatives in which P is hydrogen or a protected intermediate such as an O-arylalkylether, acyl or O-cycloalkoxyalkylether group. In the case of compounds having P = H, the hydroxylsamic acid compound of the present invention can be directly provided by treatment with at least one equivalent of hydroxylamine hydrochloride at room temperature or above in a solvent or solvents as listed above. There may also be exchange methods such as exchange between hydroxylamine and methyl esters which can be further catalyzed by adding additional acids. Alternatively, hydroxylamine may be formed in situ using a base such as a salt of an alcohol used as the solvent, for example sodium methoxide in methanol, and exchanged with an ester or an amide.
This exchange may also be carried out using protected hydroxylamines such as tetrahydropyranylhydroxyamine (THPONH ₂ ), benzylhydroxylamine (BnONH ₂ ), in which case P is tetrahydropyranyl (THP). Or benzyl (Bn) is the product. If desired, for example, removal of the protecting group after further conversion or storage in another part of the molecule can be carried out by acid hydrolysis of the THP group or metal catalysts such as palladium, platinum, platinum oxide, palladium on carbon or nickel and benzyl by hydrogen. It can be accomplished by standard methods well known in the art, such as reductive removal of groups.
Alternatively, carboxylic acids of the present invention can be converted to activated carbonyl compounds using reagents well known in the art, including peptide and protein synthesis and amino acid coupling or conjugate techniques. Examples of such reagents are thionyl chloride, oxalyl chloride, phosphorus oxychloride, HOBT, isopropylchloroformate and the like, with or without intermediate condensation agents (carbonyl activators) such as diimide. These useful activated carbonyl intermediates (chlorides, mixed anhydrides, etc.) are then hydroxamic or hydroxamic acid such that P is H, benzyl or THF by condensation with hydroxylamine or O-protected hydroxylamine derivatives. Can be converted to derivatives.
Carboxylic acids of the invention can be prepared and used directly or in protected form as described above. Protected groups for carboxylic acids are well known in the art, and examples include esters, amides, ortho-esters, and groups commonly known as ethers such as tetrahydropyranylester or tetrahydropyranylether. . Alkyl esters such as methyl esters, ethyl esters or tert-butyl esters and aralkyl esters such as benzyl esters, benzhydryl esters and trityl esters are well known in the art as well as their preparation and removal. Primary, secondary or tertiary amines are also well known in the art as well as their preparation and removal. Many amides and esters are commercially available. Preferred protecting groups are methyl esters, and the preferred method of converting the esters to acids is via base hydrolysis, and in certain reactions where this conversion is carried out in situ in a single vessel, the use of basic reagents or basic conditions is preferred. .
Scheme 3 illustrates another general method of synthesizing sulfone-containing carbonyl compounds of the present invention, namely using the SN ₂ class of reactions. Bimolecular nucleophilic substitution (SN ₂ ) reactions are illustrated here, which ring-open an epoxide ring or substitute an activated hydroxyl group derivative of a diol, or convert alcohol to a nucleophilic salt (hydroxyanionic salt) by base. Let's do it. In the latter example, the preparation of the compounds of the invention wherein R ² is methoxyalkyl is carried out by base treatment, preferably using a non-nucleophilic base such as sodium hydride, calcium hydride, potassium hydride or alkyllithium or an amide reagent. By conversion of a hydroxyl group to its alkoxide anion, which may be done. Preferred base is sodium hydride. Preferred nucleophiles, ie nucleophilic compounds, are methyl halides or organic sulfonate methyl esters. Most preferred nucleophile is methyl iodide. Although the solvents, solvent mixtures or solvent / reagent mixtures described are satisfactory, aprotic or amphoteric aprotic solvents such as acetone, acetonitrile, DMF and the like are preferred examples of the group. Salts of these amines can be prepared by standard methods known in the art, for example by treating amines with HCl to form hydrochlorides.
Other SN ₂ used in the preparation of the compounds of the invention include the conversion of the alcohols of the diols shown in the scheme to electrophiles such as halides or organic sulfonate esters. Examples of halides are chlorides, bromide or iodide and the preparation thereof is well known in the art. Examples of organic sulfonate esters are tosylate, benzenesulfonate, camphorsulfonate, mesylate and triflate, the preparation of which is well known in the art. Preferred halides are bromide and preferred sulfonates are trifluoromethanesulfonates (triplates). Examples of methods for preparing halides include treatment of double bonds with hypohalite or ring opening of epoxide rings with hydrohalic acid such as HBr, HCl or HI. Examples of methods for preparing the sulfonate esters include treating the alcohol with a base such as a tertiary amine or a hindered or non-nucleophilic base as discussed above to form an alkoxide anion followed by a triacid anhydride or methanesulfonyl chloride. There is a method of adding sulfonic anhydride or chloride. Substitution of the halide or sulfonate leaving group with ammonia, alkylamine, dialkylamine, morpholine, pyrrolidine or thiomorpholine (SN ₂ ) may provide a compound of the invention. Preferred solvents for these reactions are listed above and include amphoteric aprotic solvents such as DMF.
The choice of atmosphere for the reaction of this scheme as well as other schemes usually depends on many variables known to those skilled in the art. The option may be an inert atmosphere such as nitrogen, argon, helium or the like or normal or dry air. If the conditions of this method are unclear, it is preferable to use an inert atmosphere. One of these variables, particularly one of ordinary skill in the art, is to control the oxidation of thiols or salts of thiols to their corresponding disulfide or mixed disulfides by air or another means. While the use of a humid atmosphere with organometallic compounds requiring synthesis is undesirable for economic or safety reasons, the use of air is common for aqueous hydrolysis or exchange reactions, in which case oxidation, for example, Will not happen.
If desired, protecting groups are used to prepare the compounds of the present invention and these protecting groups have been discussed above. However, selection of protecting groups for use with specific functional groups, as well as determining whether to use protecting groups, is based on the specific purpose and is made by those skilled in the art. For example, the factors in selecting methyl esters and tert-butyl esters for the protection of certain carboxylic acid functional groups depend on the preferred method of preparation and the preferred method of removal. For example, methyl esters are known to be easily hydrolyzed by bases or exchanged by amines or hydroxylamines, whereas tert-butyl esters are relatively resistant to removal or exchange by bases but are easily resistant by acids. Removed. Examples of such protecting groups include acyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groups, and trisubstituted silyl groups. Examples of such protecting groups include acetyl, THP, benzyl, Z (benzyloxycarbonyl), tert-butyldimethylsilyl (TBDMS) groups, and the like. Protecting groups are described, for example, in Green, T., "Protecting Groups in Organic Chemistry", and other papers and other books.
Isomers of optically active compounds as well as isomers of mixed or non-optically active compounds are strictly included as part of the present invention. Examples of isomers are the RS isomers, enantiomers, diastereomers, racemates, cis isomers, trans isomers, E isomers, Z isomers, syn-isomers, anti isomers, tautomers and the like. Aryl, heterocyclo or heteroaryl tautomers, heteroatom isomers and ortho, meta or para substituted isomers are also included as isomers. Solvents or solvent addition compounds, such as hydrates or alcoholates, are all strictly included as compounds of the present invention and for example included in formulations or pharmaceutical compositions for delivery.
Examples 1 and 5

Examples 2-4, 6 and 7

Examples 2-4, 6 and 7

Examples 2-4, 6 and 7

Examples 2-4, 6 and 7

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following specific preferred embodiments are to be construed as illustrative only and do not in any way limit the remaining disclosure.
Example 1: Preparation of N, 2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl) sulfonyl] propanamide
Part A: Powdered potassium hydroxide (114.24 g, 2.04 mol) was added over 10 minutes to methanol (1 L) in a flask equipped with an overhead stirrer. The solution was cooled to 0 ° C. on an ice bath and methyl 2-methylglycidate (99.2 g, 0.85 mol) in methanol (40 mL) was added over 15 minutes. Upon warming to ambient temperature a precipitate formed. After 30 minutes the mixture was cooled to 5 ° C. and 4- (phenoxy) benzenethiol (151.73 g, 0.75 mol) was added dropwise over 10 minutes. The mixture was warmed to ambient temperature. After 24 hours the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with 3M HCl and saturated NaCl. Concentration in vacuo gave the sulfide as a solid (256.36 g, quantitative yield).
Part B: The crude sulfide (256.3 g, 0.75 mol (theoretical value)) of Part A was divided into three equal parts. One third (0.25 mol) was dissolved in THF (1710 mL) and H ₂ O (190 mL). Oxone in this solution (474 g, 0.77 mol) was added and the mixture was stirred for 1.25 h. Excess Oxone Was removed by filtration and the filtrate was concentrated in vacuo. This process was repeated twice and the products were combined, dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . After concentration in vacuo to a volume of 30% the solution was poured into hexane. The obtained solid was collected by vacuum filtration. Recrystallization from ethyl acetate / hexanes gave the sulfone as a white solid (207 g, 83%).
Part C: 1- (3-dimethylaminopropyl) in a solution of sulfone (153.35 g, 455.90 mmol) and N-hydroxybenzotriazole.H ₂ O (73.86 g, 547.08 mmol) in Part B in DMF (1.5 L) ) -3-ethylcarbodiimide hydrochloride (96.14 g, 501.49 mmol) was added. After stirring for 1 h at ambient temperature the solution was cooled to 8 ° C. and Na ₂ OH _(aq) (50%, 81 mL, 1.37 mol) was added slowly. After 30 minutes at ambient temperature the DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . Recrystallization from hot acetone and hexanes gave the title compound as a white solid (90 g, 56%). HRMS calcd for C ₁₆ H ₁₇ NO ₆ S: 352.0855, found: 352.0834.
Example 1A: (S) -N, 2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl) sulfonyl] propanamide
Chiralpak was a solution of N, 2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl) sulfonyl] propanamide (20 g) in ethanol (1500 mL). AD filled Prochrom 12 mL was sequentially injected into the column (ID 50 mm, bed length 36 mm). The mobile phase used was 30% isopropyl alcohol / 70% heptane. Fractions were automatically collected and collected. The first elution peak was taken and the appropriate fractions combined to give the title compound (8.351 g). HPLC purity: 100%.
Example 1B: Preparation of (R) -N, 2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl) sulfonyl] propanamide
A solution of N, 2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl) sulfonyl] propanamide (20 g) in ethanol (1500 mL) was transferred to a Chiralpak AD packed Prochrom column (ID 50 mm, layer). Length 36mm) was sequentially injected 12mL. The mobile phase used was 30% isopropyl alcohol / 70% heptane. Fractions were automatically collected and collected. The second eluting peak was taken and the appropriate fractions combined to give the title compound (8.176 g). HPLC purity: 92%.
Example 2: Preparation of N, 2-dihydroxy-2- (hydroxymethyl) -3-[(4-phenoxyphenyl) sulfonyl] propanamide
Part A: To a solution of methyl 2- (bromomethyl) acrylate (9.90g, 55.3mmol) and 4- (phenoxy) benzenethiol (11.7g, 57.9mmol) in acetonitrile (70mL), K ₂ CO ₃ ( 7.50 g, 54.3 mmol) was added. After stirring for 1 h at ambient temperature the solution was concentrated to half volume in vacuo and partitioned between ethyl acetate and H ₂ O. The organic layer was dried over MgSO ₄ . Concentration in vacuo gave a yellow liquid. A solution of this crude liquid in methanol (100 mL) was converted to Oxone in methanol (150 mL) and H ₂ O (25 mL). (100 g) was added to the mixture. After 1 hour the solution was concentrated and partitioned between ethyl acetate and H ₂ O. The organic layer was washed with H ₂ O and dried over MgSO ₄ . Concentration in vacuo gave a dark oily product which was recrystallized from hot ethyl ether to give a sulfone as a white solid (13.3 g, 73%).
Part B: To a solution of 4-methylmorpholine N-oxide (10 g, 85 mmol) in 8: 1 acetone / water (50 mL) was added osmium tetraoxide (2.5% in t-butanol, 25 mL, 2.0 mmol) and then 8: Part A acrylate (13.3 g, 40.1 mmol) in 1 acetone / water (80 mL) was added. After stirring for 20 h at ambient temperature Na ₂ SO ₃ (5 g) was added and stirring was continued for 1 h. Concentrated in vacuo and partitioned between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl. Elution through a silica pad (ethyl acetate) followed by concentration afforded the diol as a white solid (15 g, quantitative yield). HRMS calcd for C ₁₇ H ₁₈ O ₇ S: 367.0852. Found: 367.0868.
Part C: Na ₂ OH _(aq) (50%, 9.0 mL, 138 mmol) was added to a solution of part B diol (2.5 g, 6.8 mmol) in THF (20 mL) and methanol (20 mL). After stirring for 72 h at ambient temperature additional Na ₂ OH _(aq) (10 mL) was added and stirring continued for 72 h. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl. The suspension obtained was concentrated in vacuo to a minimum volume and filtered to give the title compound as a white solid (1.7 g, 68%). HRMS calcd for C ₁₆ H ₁₇ NO ₇ S: 368.0804, found: 368.0759.
Example 3: Preparation of N, α-dihydroxy-α-[[(4-phenoxyphenyl) sulfonyl] methyl] -4-morpholine propanamide, monohydrochloride
Part A: To a solution of methyl 2- (bromomethyl) acrylate (9.90g, 55.3mmol) and 4- (phenoxy) benzenethiol (11.7g, 57.9mmol) in acetonitrile (70mL), K ₂ CO ₃ ( 7.50 g, 54.3 mmol) was added. After stirring for 1 h at ambient temperature the solution was concentrated to half volume in vacuo and partitioned between ethyl acetate and H ₂ O. The organic layer was dried over MgSO ₄ . Concentration in vacuo gave a yellow liquid. A solution of this crude liquid in methanol (100 mL) was converted to Oxone in methanol (150 mL) and H ₂ O (25 mL). (100 g) was added to the mixture. After 1 hour the solution was concentrated and partitioned between ethyl acetate and H ₂ O. The organic layer was washed with H ₂ O and dried over MgSO ₄ . Concentration in vacuo gave a dark oily product which was recrystallized from hot ethyl ether to give a sulfone as a white solid (13.3 g, 73%).
Part B: To a solution of 4-methylmorpholine N-oxide (10 g, 85 mmol) in 8: 1 acetone / water (50 mL) was added osmium tetraoxide (2.5% in t-butanol, 25 mL, 2.0 mmol) and then 8: Part A sulfone (13.3 g, 40.1 mmol) in 1 acetone / water (80 mL) was added. After stirring for 20 h at ambient temperature Na ₂ SO ₃ (5 g) was added and stirring was continued for 1 h. The organic phase was concentrated in vacuo after partitioning between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl. Elution through a silica pad (ethyl acetate) followed by concentration afforded the diol as a white solid (15 g, quantitative yield).
Part C: Pyridine (1.35 mL, 16.7 mmol) was added to a solution of part B diol (5.48 g, 15.0 mmol) in dichloromethane (70 mL) cooled to −78 ° C. followed by trifluoromethanesulfonic anhydride (2.71 mL, 16.1 mmol) was added slowly. After stirring at −78 ° C. for 30 minutes, the solution was returned to ambient temperature and stirred for 3 hours. The solution was concentrated in vacuo and partitioned between ethyl acetate and 1M citric acid. The organic layer was washed with saturated NaCl, dried over MgSO ₄ and concentrated in vacuo. The crude material was chromatographed on silica gel to give a 63:35 mixture of epoxide and triflate which was used in the next step without further purification.
Part D: Morpholine (3.9 mL, 45.0 mmol) was added to a solution of the Part C epoxide / triplate (15.0 mmol) mixture in methanol (30 mL) cooled to 0 ° C. The solution was warmed and stirred at ambient temperature for 1.5 hours. The solvent was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with H ₂ O and saturated NaCl. Concentration in vacuo gave a yellow oily foam which was dissolved in acetonitrile and concentrated HCl (1 mL) was added. Concentration in vacuo and trituration with ethyl ether gave HCl salt of the morpholine methyl ester compound as a white solid (4.2 g, 60%). HPLC purity:> 98%.
Part E: Na ₂ OH _(aq) (50%, 5 mL, 67.6 mmol) was added to a solution of the methyl ester of Part D (4.1 g, 8.74 mmol) in THF (45 mL) and methanol (45 mL) and the mixture was allowed to 72 h. Stirred. The solution was concentrated to an original volume of 25% and partitioned between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl, dried over MgSO ₄ and concentrated in vacuo. The obtained oily substance was triturated with ethyl acetate / ethyl ether to obtain a white solid. HCl (concentrated, 1 mL) was added to a solution of free base in acetonitrile (40 mL) to form an HCl salt. Concentration in vacuo and trituration with THF and methanol gave the title compound as a white solid (2.2 g, 53%).
Example 4: 3-[[4- (3,4-dimethylphenoxy) phenyl] sulfonyl] -N, 2-dihydroxy-2- (hydroxymethyl) propanamide
Part A: K ₂ CO ₃ (33.17 g, 0.24 mmol) in a solution of 4-fluoroacetophenone (27.63 g, 0.20 mol) and 3,4-dimethylphenol (24.43 g, 0.20 mol) in dimethylacetamide (200 mL) ) Was added and the mixture was heated at reflux for 8 h. After concentration of the solvent the residue was dissolved in ethyl acetate (400 mL) and washed with H ₂ O (200 mL), 1N HCl (200 mL) and saturated NaCl (200 mL) and dried over Na ₂ SO ₄ . Recrystallization from hot ethyl acetate / hexanes gave acetophenone as a solid (28.5 g, 59%). HPLC purity: 99%.
Part B: Oxone in a solution of acetophenone (26.04 g, 108.4 mmol) in Part A in methanol (590 mL) and H ₂ O (65 mL) (133 g, 216.7 mmol) was added. Excess Oxone after heating the mixture at reflux for 5.5 hours and cooling to ambient temperature Was removed by filtration and washed with methanol. After concentration of the solvent, the residue was dissolved in ethyl acetate (400 mL), washed with H ₂ O (300 mL) and dried over Na ₂ SO ₄ . Purification by chromatography (10% ethyl acetate / hexanes to 20% ethyl acetate / hexanes) gave phenol as a solid (13.98 g, 60%). HPLC purity:> 99%. MS (CI) MH ⁺ calcd for C ₁₄ H ₁₄ 0 ₂ : 215, found: 215.
Part C: Phenol (13.7 g, 64.0 mmol) in Part B was added to a solution of KOH (8 g, 143 mmol) in H ₂ O (85 mL) cooled to 0 ° C., followed by dimethylthiocarbamoyl chloride in THF (75 mL). 10.6 g, 85.8 mmol) was added dropwise. The solution was stirred at 0 ° C. for 4.5 h and then extracted with toluene (2 × 125 mL). The combined organic layers were dried over MgSO ₄ . Purification by chromatography (95: 5 hexanes / ethyl acetate and 1% triethylamine) afforded thiocarbamate as a white solid (10.9 g, 56%). HPLC purity:> 99%.
Part D: Thiocarbamate (10.9 g, 53.6 mmol) of Part C was heated to 290 ° C. for 15 minutes. The compound was cooled to ambient temperature and dissolved in an 8: 1 mixture of ethylene glycol / H ₂ O. KOH (9.0 g, 161 mmol) was added to this solution, and the mixture was stirred for 1.5 hours. The mixture was poured onto ice (125 g) and concentrated HCl (6 mL) was added. The mixture was extracted with chloroform (1 × 100 mL) and dichloromethane (2 × 60 mL) and the combined organic layers were dried over MgSO ₄ . Purification by chromatography (hexane) afforded thiophenol as a colorless liquid (4.0 g, 32%).
Part E: K ₂ CO ₃ (2.6 g, 18.8 mmol) in a solution of thiophenol (2.2 g, 9.48 mmol) and 2- (bromomethyl) acrylic acid (1.56 g, 9.45 mmol) of Part D in acetonitrile (40 mL). ) Was added. After stirring for 1 hour the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1N HCl. The organic layer was dried over MgSO ₄ and concentrated in vacuo. The crude solid was dissolved in methanol (100 mL) and H ₂ O (8 mL) and Oxone (16 g, 28.4 mmol) was added. After 90 minutes, the reaction mixture was filtered Was taken and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the sulfone as a white solid (2.85 g, 86%).
Part F: Osmium tetraoxide (t) in a solution of sulfone (2.83 g, 8.1 mmol) and 4-methylmorpholine N-oxide (1.9 g, 16.2 mmol) in Part E in 8: 1 acetone / H ₂ O (45 mL) 2.5% in butanol, 5 mL, 0.4 mmol) was added and the solution was stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and acidified with 1N HCl. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with H ₂ O and saturated NaCl and dried over MgSO ₄ . Concentration in vacuo and trituration with ethyl ether gave diol as a solid, not a white (2.5 g, 81%).
Part G: 1- (3-dimethylaminopropyl) in a solution of diol (2.4 g, 6.3 mmol) and N-hydroxybenzotriazole.H ₂ O (1.1 g, 8.2 mmol) of Part F in DMF (25 mL). 3-ethylcarbodiimide hydrochloride (1.3 g, 6.9 mmol) was added. After stirring for 1 h at ambient temperature Na ₂ OH _(aq) (50%, 1.25 mL, 21.7 mmol) was added. After 40 minutes the solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. The organic layer was dried over MgSO ₄ . Trituration with a combination of ethylether, isopropanol, methanol and THF gave the title compound as a white solid (750 g, 30%). HRMS calcd for C ₁₈ H ₂₁ NO ₇ S: 396.1117, found 396.1125.
Example 5: 3-[[4- (3,4-dimethylphenoxy) phenyl] sulfonyl] -N, 2-dihydroxy-2-methylpropanamide
Part A: K ₂ CO ₃ (33.17 g, 0.24 mol) in a solution of 4-fluoroacetophenone (27.63 g, 0.20 mol) and 3,4-dimethylphenol (24.43 g, 0.20 mol) in dimethylacetamide (200 mL) ) Was added and the mixture was heated at reflux for 8 h. After concentration of the solvent the residue was dissolved in ethyl acetate (400 mL) and H ₂ O (200 mL), washed with 1N HCl (200 mL) and saturated NaCl (200 mL) and dried over Na ₂ SO ₄ . Recrystallization from hot ethyl acetate / hexanes gave acetophenone as a solid (28.5 g, 59%). HPLC purity: 99%.
Part B: Oxone in a solution of acetophenone (26.04 g, 108.4 mmol) in Part A in methanol (590 mL) and H ₂ O (65 mL) (133 g, 216.7 mmol) was added. Excess Oxone after heating the mixture at reflux for 5.5 hours and cooling to ambient temperature Was removed by filtration and washed with methanol. After concentration of the solvent, the residue was dissolved in ethyl acetate (400 mL), washed with H ₂ O (300 mL) and dried over Na ₂ SO ₄ . Purification by chromatography (10% ethyl acetate / hexanes to 20% ethyl acetate / hexanes) gave phenol as a solid (13.98 g, 60%). HPLC purity:> 99%. MS (CI) MH ⁺ calcd for C ₁₄ H ₁₄ 0 ₂ : 215, found: 215.
Part C: Phenol (13.7 g, 64.0 mmol) in Part B was added to a solution of KOH (8 g, 143 mmol) in H ₂ O (85 mL) cooled to 0 ° C., followed by dimethylthiocarbamoyl chloride in THF (75 mL). 10.6 g, 85.8 mmol) was added dropwise. The solution was stirred at 0 ° C. for 4.5 h and then extracted with toluene (2 × 125 mL). The combined organic layers were dried over MgSO ₄ . Purification by chromatography (95: 5 hexanes / ethyl acetate and 1% triethylamine) afforded thiocarbamate as a white solid (10.9 g, 56%). HPLC purity:> 99%.
Part D: Thiocarbamate (10.9 g, 53.6 mmol) of Part C was heated to 290 ° C. for 15 minutes. The compound was cooled to ambient temperature and dissolved in an 8: 1 mixture of ethylene glycol / H ₂ O. KOH (9.0 g, 161 mmol) was added to this solution, and the mixture was stirred for 1.5 hours. The mixture was poured onto ice (125 g) and concentrated HCl (6 mL) was added. The mixture was extracted with chloromum (1 × 100 mL) and dichloromethane (2 × 60 mL) and the combined organic layers were dried over MgSO ₄ . Purification by chromatography (hexane) afforded thiol as a colorless liquid (4.0 g, 32%).
Part E: Methyl 2-methylglycidate (0.9 mL, 8.5 mmol) was added to a solution of KOH (1.14 g, 20.4 mmol) in methanol (10 mL) cooled to 0 ° C. The solution was warmed and stirred at ambient temperature for 30 minutes. The solution was again cooled to 0 ° C. and thiol (1.78 g, 7.73 mmol) of Part D was added thereto. This solution was stirred at ambient temperature for 24 hours. After concentration removed the solvent, the residue was dissolved in ethyl acetate and acidified with 1N HCl. The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Concentration in vacuo gave the sulfide as a solid (3.2 g, quantitative yield). HPLC purity: 99%.
Part F: Oxone in a solution of sulfide (2.6 g, 7.8 mmol) of Part E in THF (59 mL) and H ₂ O (6 mL). (14.4 g, 23.5 mmol) was added and the mixture was stirred for 1 hour. Excess Oxone Was collected by filtration and washed with THF. The filtrate was concentrated and the residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Concentration in vacuo gave the sulfone as a solid (2.83 g, quantitative yield). HPLC purity: 99%. MS (CI) MH ⁺ calcd for C ₁₈ H ₂₀ 0 ₆ S: 365, found: 365.
Part G: 1- (3-dimethylaminopropyl) in a solution of acid (2.74 g, 7.52 mmol) and N-hydroxybenzotriazole.H ₂ O (1.22 g, 9.02 mmol) in Part F in DMF (25 mL) 3-Ethylcarbodiimide hydrochloride (1.59 g, 8.27 mmol) was added. After stirring for 1 h at ambient temperature Na ₂ OH _(aq) (50%, 1.3 mL, 22.56 mmol) was added. After 15 minutes the solvent was removed in vacuo and the residue was dissolved in ethyl acetate, washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . Recrystallization from hot acetone / hexanes gave the title compound as a white powder (1.35 g, 47%). HPLC purity: 99%. MS (CI) MH ⁺ calcd for C ₁₈ H ₂₁ NO ₆ S: 380, found: 380.
Example 6: N, 2-dihydroxy-2- (methoxymethyl) -3-[(4-phenoxyphenyl) sulfonyl] propanamide
Part A: To a solution of methyl 2- (bromomethyl) acrylate (9.90g, 55.3mmol) and 4- (phenoxy) benzenethiol (11.7g, 57.9mmol) in acetonitrile (70mL), K ₂ CO ₃ ( 7.50 g, 54.3 mmol) was added. After stirring for 1 h at ambient temperature the solution was concentrated to half volume in vacuo and partitioned between ethyl acetate and H ₂ O. The organic layer was dried over MgSO ₄ . Concentration in vacuo gave a yellow liquid. A solution of this crude liquid in methanol (100 mL) was added to Oxone in a mixture of methanol (150 mL) and H ₂ O (25 mL). (100 g) was added. After 1 hour the solution was concentrated and partitioned between ethyl acetate and H ₂ O. The organic layer was washed with H ₂ O and dried over MgSO ₄ . Concentration in vacuo gave a dark oily product which was recrystallized from hot ethyl ether to give a sulfone as a white solid (13.3 g, 73%).
Part B: To a solution of 4-methylmorpholine N-oxide (10 g, 85 mmol) in 8: 1 acetone / water (50 mL) was added osmium tetraoxide (2.5% in t-butanol, 25 mL, 2.0 mmol) and then 8: Part A acrylate (13.3 g, 40.1 mmol) in 1 acetone / water (80 mL) was added. After stirring for 20 h at ambient temperature Na ₂ SO ₃ (5 g) was added and stirring was continued for 1 h. Concentrated in vacuo and partitioned between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl. Elution through a silica pad (ethyl acetate) followed by concentration afforded the diol as a white solid (15 g, quantitative yield).
Part C: NaH (66 mg, 4.7 mmol) was added to a solution of the methyl ester of Part B (535 g, 1.46 mmol) in DMF (20 mL) cooled to 0 ° C. After stirring for 5 minutes, iodomethane (505 mg, 8.14 mmol) was added. After stirring for 70 minutes the solution was purified by flash chromatography (50/50 ethyl acetate / hexanes) to give methyl ester as a foam (262 mg, 47%).
Part D: Na ₂ OH _(aq) (50%, 1 mL, 13.6 mmol) was added to a solution of the methyl ester of Part C (260 mg, 0.68 mmol) in THF (1.5 mL) and methanol (1.5 mL) and the solution Stir at 20 h. 1.5 mL of Na ₂ OH _(aq) was further added and the solution stirred for 96 h. The solution was partitioned between ethyl acetate and H ₂ O and the organic layer was dried over MgSO ₄ and concentrated in vacuo to afford the title compound as a foam (20 mg, 8%).
Example 7: α-[[[4- (3,4-dimethylphenoxy) phenyl] sulfonyl] methyl] -N-2-dihydroxy-4-morpholinepropanamide
Part A: K ₂ CO ₃ (33.17 g, 0.24 mol) in a solution of 4-fluoroacetophenone (27.63 g, 0.20 mol) and 3,4-dimethylphenol (24.43 g, 0.20 mol) in dimethylacetamide (200 mL) ) Was added and the mixture was heated at reflux for 8 h. After concentration of the solvent the residue was dissolved in ethyl acetate (400 mL) and H ₂ O (200 mL), washed with 1N HCl (200 mL) and saturated NaCl (200 mL) and dried over Na ₂ SO ₄ . Recrystallization from hot ethyl acetate / hexanes gave acetophenone as a solid (28.5 g, 59%). HPLC purity: 99%.
Part B: Oxone in a solution of acetophenone (26.04 g, 108.4 mmol) in Part A in methanol (590 mL) and H ₂ O (65 mL) (133 g, 216.7 mmol) was added. Excess Oxone after heating the mixture at reflux for 5.5 hours and cooling to ambient temperature Was removed by filtration and washed with methanol. After concentration of the solvent, the residue was dissolved in ethyl acetate (400 mL), washed with H ₂ O (300 mL) and dried over Na ₂ SO ₄ . Purification by chromatography (10% ethyl acetate / hexanes to 20% ethyl acetate / hexanes) gave phenol as a solid (13.98 g, 60%). HPLC purity:> 99%. MS (CI) MH ⁺ calcd for C ₁₄ H ₁₄ 0 ₂ : 215, found: 215.
Part C: Phenol (13.7 g, 64.0 mmol) in Part B was added to a solution of KOH (8 g, 143 mmol) in H ₂ O (85 mL) cooled to 0 ° C., followed by dimethylthiocarbamoyl chloride in THF (75 mL). 10.6 g, 85.8 mmol) was added dropwise. The solution was stirred at 0 ° C. for 4.5 h and then extracted with toluene (2 × 125 mL). The combined organic layers were dried over MgSO ₄ . Purification by chromatography (95: 5 hexanes / ethyl acetate and 1% triethylamine) afforded thiocarbamate as a white solid (10.9 g, 56%). HPLC purity:> 99%.
Part D: Thiocarbamate (10.9 g, 53.6 mmol) of Part C was heated to 290 ° C. for 15 minutes. The compound was cooled to ambient temperature and dissolved in an 8: 1 mixture of ethylene glycol / H ₂ O. KOH (9.0 g, 161 mmol) was added to this solution, and the mixture was stirred for 1.5 hours. The mixture was poured onto ice (125 g) and concentrated HCl (6 mL) was added. The mixture was extracted with chloroform (1 × 100 mL) and dichloromethane (2 × 60 mL) and the combined organic layers were dried over MgSO ₄ . Purification by chromatography (hexane) afforded thiophenol as a colorless liquid (4.0 g, 32%).
Part E: K ₂ CO ₃ (2.6 g, 18.8 mmol) in a solution of thiophenol (2.2 g, 9.48 mmol) and 2- (bromomethyl) acrylic acid (1.56 g, 9.45 mmol) of Part D in acetonitrile (40 mL). ) Was added. After stirring for 1 hour the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 1N HCl. The organic layer was dried over MgSO ₄ and concentrated in vacuo. The crude solid was dissolved in methanol (100 mL) and H ₂ O (8 mL) and Oxone (16 g, 28.4 mmol) was added. After 90 minutes, the reaction mixture was filtered Was taken and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the sulfone as a white solid (2.85 g, 92%).
Part F: Thionyl chloride (19 mL, 259.8 mmol) was added dropwise to a solution of sulfone (45.0 g, 129.9 mmol) in part E in methanol (600 mL). This solution was heated at reflux for 3 hours. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated NaHCO ₃ . The aqueous solution was extracted once with ethyl acetate and the combined organic layers were washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the methyl ester as a tan oil (45.8 g, 98%). This compound was used in the next step without further purification. HPLC purity: 92%.
Part G: Osmium tetraoxide (2.5% in t-butanol 2.5%, 15.65 mL, 1.25 mmol) in a solution of 4-methylmorpholine N-oxide (29.3 g, 249.71 mmol) in 8: 1 acetone / H ₂ O (100 mL) Was added, followed by dropwise addition of the methyl ester of Part F (45.0 g, 125 mmol) in 8: 1 acetone / H ₂ O. The solution was stirred at ambient temperature for 1 hour. Na ₂ CO ₃ (16 g) was added to this mixture and stirring was continued for 30 minutes. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate / H ₂ O. The aqueous layer was extracted once with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO ₄ . Purification by chromatography (ethyl acetate / hexane) afforded the diol as a white solid (41.6 g, 85%).
Part H: Pyridine (0.69 mL, 8.52 mmol) was added to a solution of Part G diol (3.0 g, 7.61 mmol) in dichloromethane (38 mL) cooled to −71 ° C. followed by triflic anhydride (1.4 mL, 7.99 mmol). Was added slowly. This solution was stirred at −71 ° C. for 25 minutes. Additional pyridine (69 mL, 8.52 mmol) and trifluoromethanesulfonic anhydride (1.4 mL, 7.99 mmol) were added and the solution was stirred for 1 hour. The solution was partitioned between ethyl acetate and citric acid (5%). The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Concentration in vacuo gave the triflate as an oil (4.27 g, quantitative yield).
Part I: Morpholine (2.1 mL, 24.33 mmol) was added to a solution of the triflate (4.27 g, 8.11 mmol) of Part H in THF (15 mL) cooled to 0 ° C. The solution was stirred at ambient temperature for 1.5 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate, washed with saturated NaHCO ₃ and saturated NaCl and dried over Na ₂ SO ₄ . After concentration the residue was dissolved in acetonitrile and acidified with concentrated HCl. Trituration with ethyl ether gave an ethyl morpholine compound as a white solid (2.95 g, 73%).
Part J: To a solution of part I ethylmorpholine (2.95 g, 5.89 mmol) in 1: 1 THF / methanol (14 mL) was added Na ₂ OH _(aq) (50%, 7 mL, 118 mmol). After stirring at ambient temperature for 20 hours, further Na ₂ OH _(aq) (7 mL) was added and the solution was stirred for another 24 hours. After concentration in vacuo the residue was dissolved in ethyl acetate, washed with saturated NaHCO ₃ , H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . The solution was acidified with concentrated HCl and triturated with ethyl ether to give a crude solid. Recrystallized from hot THF and ethyl ether to give α-[[[4- (3,4-dimethylphenoxy) phenyl] sulfonyl] methyl] -N-2-dihydroxy-4-morpholinepropanamide as a white solid. Obtained (1.5 g, 51%). HPLC purity: 98%. MS (CI) MH ⁺ calcd for C ₂₂ H ₂₈ N ₂ O ₇ .HCl: 465. Found: 465.
Example 8: N, 2-dihydroxy-3-[(4-methoxyphenyl) sulfonyl] propanamide
Part A: To a solution of β-chlorolactic acid (2.0 g, 16.1 mmol) in DMF (45 mL) was added 4-methoxybenzenethiol (2.0 mL, 16.1 mmol) and K ₂ CO ₃ (4.4 g, 31.8 mmol) and the solution Was stirred at ambient temperature for 1 hour. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was dried over MgSO ₄ and concentrated in vacuo. Oxone to a solution of this crude sulfide in methanol (100 mL) and H ₂ O (5 mL) (30 g, 48.3 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. The mixture was filtered and the filtrate was acidified to pH = 7 with aqueous K ₂ CO ₃ . This solution was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with saturated NaCl, dried over MgSO ₄ and concentrated in vacuo. Chromatography (ethyl acetate / hexane) gave the sulfone methyl ester as a clear colorless oil (2.3 g, 52%).
Part B: To a solution of Part A sulfone (2.3 g, 8.4 mmol) in methanol (25 mL) and THF (25 mL) was added 50% aqueous hydroxylamine (5.7 mL, 84 mmol) and the solution was stirred for 1 h. The solution was diluted with ethyl acetate and concentrated in vacuo to afford N, 2-dihydroxy-3-[(4-methoxyphenyl) sulfonyl] propanamide as a white powder (1.75 g, 76%). HPLC purity:> 99%. HRMS calcd for C ₁₀ H ₁₃ NO ₆ S: 276.0542, found 276.0546.
Example 9: N, 2-dihydroxy-3-[(4-phenoxyphenyl) sulfonyl] propanamide
Part A: To a solution of β-chlorolactic acid (10.0 g, 80.3 mmol) in DMF (85 mL) add 4-fluorothiophenol (10.3 mg, 80.3 mmol) and K ₂ CO ₃ (22 g, 16 mmol) and surround the solution Stir at temperature for 1 hour. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and 1N HCl. The organic layer containing sulfide was dried over MgSO ₄ and concentrated in vacuo. Oxone in a solution of crude sulfide in methanol (250 mL) and H ₂ O (100 mL) (149 g, 240 mmol) was added and the mixture was stirred at ambient temperature for 6 hours. The mixture was filtered and the filtrate was triturated with ethyl ether to give the sulfone as a white solid (19 g, 91%).
Part B: Phenol (633 mg, 6.45 mmol) and K ₂ CO ₃ (1.8 g, 12.9 mmol) were added to a solution of sulfone (1.0 g, 4.3 mmol) in Part A in DMF (45 mL) and the solution was stirred at 60 ° C. for 18 hours. Heated during. After the solution was concentrated in vacuo, the residue was dissolved in methanol and HCl gas was bubbled into the solution to form methyl ester. Concentration in vacuo gave the methyl ester as a white solid (630 mg, 43%).
Part C: To a solution of the methyl ester of Part B (630 mg, 1.9 mmol) in methanol (4 mL) and THF (4 mL) was added 50% aqueous hydroxylamine (1.4 mL, 19 mmol) and the solution was stirred for 18 h. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous KHSO ₄ . The organic layer was washed with saturated NaCl and dried over MgSO ₄ . Chromatography (ethyl acetate / methanol) gave N, 2-dihydroxy-3-[(4-phenoxyphenyl) sulfonyl] propanamide as a white solid (250 mg, 40%). HPLC purity:> 97%. HRMS calcd for C ₁₅ H ₁₅ NO ₆ S: 338.0698. Found: 338.0678.
Example 10: (R) -N, 2-dihydroxy-3-[(4-phenoxyphenyl) sulfonyl] propanamide
Part A: To a solution of D-serine (25.0 g, 237.9 mmol) in 6N HCl (300 mL) cooled to 0 ° C. was added sodium nitrite (19.0 g, 275 mmol) and the solution was stirred for 3.5 h. The solution was extracted with ethyl ether and the combined chloro compound containing organic layers were dried over Na ₂ SO ₄ . Concentration in vacuo gave the chloro compound as a yellow oil (15.2 g, 51%).
Part B: To a solution of the Part A chloro compound (15.2 g, 122.1 mmol) in ethanol (75 mL) cooled to 0 ° C. was added KOH (13.7 g, 244.13 mmol). The solution was heated at ambient temperature for 18 hours. The reaction was filtered and the filtrate was concentrated in vacuo to give the epoxide as a pale yellow solid (11.9 g, 77%).
Part C: To a solution of 4- (phenoxy) benzenethiol (4.0 g, 19.8 mmol) in methanol (35 mL) cooled to 0 ° C. was added epoxide (2.5 g, 19.8 mmol) of Part B, followed by sodium methoxide ( Preformed with 500 mg sodium in 50 mL methanol). The solution was stirred at 40 ° C for 24 h. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the crude sulfide as a tan solid (5.7 g).
Part D: To a solution of Part C sulfide (5.7 g, 19.7 mmol) in methanol (100 mL) was added thionyl chloride (2.9 mL, 39.3 mmol) and heated at reflux for 1 h. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated NaHCO ₃ . The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated NaCl and dried over MgSO ₄ . Chromatography (ethyl acetate / hexane) afforded methyl ester as a colorless oil (3.8 g, 63%).
Part E: Oxone in a solution of sulfide (3.76 g, 12.3 mmol) in Part D in methanol (90 mL) and H ₂ O (10 mL) (26.6 g, 43.2 mmol) was added and the solution was stirred at ambient temperature for 18 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the sulfone as a white solid (3.9 g, 93%).
Part F: To a solution of Part E sulfone (3.9 g, 11.6 mmol) in methanol (20 mL) and THF (20 mL) was added 50% aqueous hydroxylamine (14 mL). The solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and recrystallized (acetone / H ₂ O) to give (R) -N, 2-dihydroxy-3-[(4-phenoxyphenyl) sulfonyl] propanamide as a white solid (2.6 g) , 67%). HPLC purity: 99%. HRMS calcd for C ₁₅ H ₁₅ NO ₆ S: 338.0698, found: 338.0673.
Example 11: (S) -N, 2-dihydroxy-3-[(4-phenoxyphenyl) sulfonyl] propanamide
Part A: To a solution of L-serine (25.0 g, 237.9 mmol) in 6N HCl (300 mL) cooled to 0 ° C. was added sodium nitrite (19.0 g, 275 mmol) and the solution was stirred for 3.5 h. The solution was extracted with ethyl ester and the combined organic layers were dried over Na ₂ SO ₄ . Concentration in vacuo gave the chloro compound as a yellow oil (19.7 g, 67%).
Part B: To a solution of the Part A chloro compound (19.7 g, 160.6 mmol) in ethanol (50 mL) cooled to 0 ° C. was added KOH (14 g, 249.5 mmol). The solution was heated at ambient temperature for 18 hours. The reaction was filtered and the filtrate was concentrated in vacuo and triturated with ethyl ether to give epoxide as a pale yellow solid (14.1 g, 70%).
Part C: To a solution of 4- (phenoxy) benzenethiol (4.0 g, 19.8 mmol) in methanol (35 mL) cooled to 0 ° C. was added epoxide (3.1 g, 24.7 mmol) of part B, followed by sodium methoxide ( Preformed with 600 mg sodium in 50 mL methanol). The solution was stirred at 40 ° C for 24 h. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the crude sulfide as a tan solid (7.3 g, 86%).
Part D: To a solution of Part C sulfide (5.7 g, 19.7 mmol) in methanol (100 mL) was added thionyl chloride (2.9 mL, 39.3 mmol) and heated at reflux for 1 h. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated NaHCO ₃ . The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated NaCl and dried over MgSO ₄ . Chromatography (ethyl acetate / hexane) gave methyl ester as a colorless oil (4.1 g, 84%).
Part E: Oxone in a solution of the methyl ester of Part D (4.1 g, 13.5 mmol) in methanol (100 mL) and H ₂ O (20 mL) (29.0 g, 47.2 mmol) was added and the solution was stirred at ambient temperature for 72 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the sulfone as a white solid (4.4 g, 98%).
Part F: To a solution of Part E sulfone (3.9 g, 11.6 mmol) in methanol (20 mL) and THF (20 mL) was added 50% aqueous hydroxylamine (14 mL). The solution was stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and recrystallized (acetone / H ₂ O) to give (S) -N, 2-dihydroxy-3-[(4-phenoxyphenyl) sulfonyl] propanamide as a white solid (3.0 g , 77%). HPLC purity: 97.6%. HRMS calcd for C ₁₅ H ₁₅ NO ₆ S: 338.0698. Found: 338.0748.
Example 12 N, 2-dihydroxy-3-[[(4-phenylthio) phenyl] sulfonyl] propanamide
Part A: Add 4-fluorothiophenol (10.3 g, 80.3 mmol) and K ₂ CO ₃ (22 g, 16 mmol) to a solution of β-chlorolactic acid (10.0 g, 80.3 mmol) in DMF (85 mL) and surround the solution. Stir at temperature for 1 hour. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was dried over MgSO ₄ and concentrated in vacuo. Oxone to a solution of this crude sulfide in methanol (250 mL) and H ₂ O (100 mL) (149 g, 240 mmol) was added and the mixture was stirred at ambient temperature for 6 hours. The mixture was filtered and the filtrate was concentrated and triturated with ethyl ether to give the sulfone as a white solid (19 g, 91%).
Part B: To a solution of Part A sulfone (7.4 g, 34.3 mmol) in DMF (70 mL) was added thiophenol (6.6 mL, 68.6 mmol) and K ₂ CO ₃ (11.8 g, 85.5 mmol) and the solution at 60 ° C. Heated for 18 hours. The reaction was concentrated and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was dried over MgSO ₄ and concentrated in vacuo. This crude acid was dissolved in methanol (250 mL) and treated with thionyl chloride (3.0 mL, 41.2 mmol). The solution was stirred at ambient temperature for 72 hours. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo and trituration with ethyl ether gave sulfonmethyl ester as a white solid (5.9 g, 49%).
Part C: 50% aqueous hydroxylamine (3.5 mL, 60 mmol) was added to a solution of Part B sulfone methyl ester (2.1 g, 6.0 mmol) in methanol (20 mL) and THF (20 mL) and the solution was allowed to stand at ambient temperature for 18 hours. Was stirred. The obtained precipitate was filtered to give N, 2-dihydroxy-3-[[(4-phenylthio) phenyl] sulfonyl] propanamide as a white solid (1.4 g, 66%). HPLC purity:> 98%. HRMS calcd for C ₁₅ H ₁₅ NO ₅ S: 354.0470. Found: 354.0465.
Example 13: N, 2-dihydroxy-2- (hydroxymethyl) -3-[[4- (phenylthio) phenyl] sulfonyl] propanamide
Part A: To a solution of 2- (bromomethyl) acrylic acid (12.9 g, 78.0 mmol) in acetonitrile (400 mL) was added K ₂ CO ₃ (21.6 g, 156 mmol). The solution was stirred at ambient temperature for 1 hour and then concentrated in vacuo. The residue was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the sulfide as a yellow solid (16.2 g, 98%).
Part B: Oxone in a solution of sulfide (16.2 g, 76.4 mmol) in Part A in methanol (250 mL) and H ₂ O (50 mL) (153 g, 250 mmol) was added and the solution was stirred at ambient temperature for 20 hours. Excess Oxone Was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the sulfone as a white solid (18.3 g, 96%).
Part C: To a solution of Part B sulfone (18.3 g, 71.0 mmol) in methanol (250 mL) was added thionyl chloride (11.0 mL, 150 mmol) and the solution was heated at reflux for 3 h. The solution was then cooled and stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated NaHCO ₃ . The aqueous solution was extracted once with ethyl acetate, the combined organic layers washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the methyl ester as a tan oil (16.0 g, 80%).
Part D: Osmium tetraoxide (2.5% by weight in 2-methyl-2-propanol) in a solution of 4-methylmorpholine N-oxide (14.5 g, 123.9 mmol) in acetone / H ₂ O (8: 1, 150 mL) Was added followed by the methyl ester of Part C (16.0 g, 61.9 mmol) in acetone / H ₂ O. The solution was stirred at ambient temperature for 18 hours. Na ₂ SO ₃ (8 g) was added to the reaction and the mixture was stirred for 30 minutes and then concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave the diol as a white solid (16.3 g, 90%).
Part E: K ₂ CO ₃ (950 mg, 6.84 mmol) was added to a solution of thiophenol (700 mg, 6.84 mmol) in DMF (10 mL) and the solution was stirred for 30 minutes. Diol (1.0 g, 3.42 mmol) of Part D was added to the solution, and the solution was heated to 70 ° C. for 2 hours and then stirred at ambient temperature for 18 hours. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was washed with H ₂ O and saturated NaCl and dried over MgSO ₄ . Concentration in vacuo gave a mixture of ester and acid. This crude product was dissolved in acetic acid (15 mL) and concentrated HCl (15 mL) and heated at 70 ° C. for 3 hours. The solution was concentrated in vacuo. Reverse phase chromatography (acetonitrile / H ₂ O) gave the acid as a white solid (740 mg, 57%).
Part F: N-hydroxybenzotriazole (330 mg, 2.41 mmol), 4-methylmorpholine (0.70 mL, 6.03 mmol), 50% in a solution of part E acid (740 mg, 2.01 mmol) in DMF (10 mL) Aqueous hydroxylamine (2.4 mL, 40.2 mmol) and EDC (420 mg, 2.21 mmol) were added. After stirring for 1 hour and left for 72 hours, the solution was concentrated in vacuo. Reversed phase chromatography (acetonitrile / H ₂ O) followed by recrystallization (acetone / ethanol) to give N, 2-dihydroxy-2- (hydroxymethyl) -3-[[4- (phenylthio) phenyl] sulfonyl] Propanamide was obtained as white crystals (300 mg, 33%). HPLC purity: 98.7%. HRMS calcd for C ₁₆ H ₁₇ NO ₆ S ₂ : 384.0576. Found: 384.0578.
Example 14 N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] pentylbenzamide
Part A: Triethylamine (14.6 mL, 105 mmol) was added to a solution of 4-nitrothiophenol (80%, 15.518 g, 92.9 mmol) in methanol (200 mL) followed by chloroacetone (8.4 mL, 105 mmol). The solution was stirred at ambient temperature for 1 hour. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with 5% KHSO ₄ , saturated NaHCO ₃ and saturated NaCl and dried over Na ₂ SO ₄ . Chromatography (ethyl acetate / hexane) afforded sulfide as an oil (16.6 g, 85%).
Part B: To a solution of sulfide (16.6 g, 78.4 mmol) in Part A in dichloromethane (150 mL) cooled to 4 ° C. was added trimethylsilyl cyanide (8.56 g, 86.3 mmol) and zinc iodide (1.8 g). The solution was stirred at 4 ° C. for 1 hour and at ambient temperature for 18 hours. The solution was partitioned between ethyl acetate and H ₂ O, washed with saturated NaCl and dried over Na ₂ SO ₄ . Concentration in vacuo gave the protected cyanohydrin as a yellow oil (23.7 g).
Part C: 12N HCl was added to a solution of cyanohydrin (23.7 g) in Part B in acetic acid (100 mL) and the solution was heated at reflux for 17 h. After concentration in vacuo, the residue was triturated with ethyl ether to give the acid as a white solid (15.2 g, 75%, 2 steps).
Part D: Oxone in a solution of the acid of Part C (15.2 g, 59 mmol) in methanol (270 mL) and H ₂ O (30 mL) (112.4 g, 183 mmol) was added and the solution was stirred at ambient temperature for 18 hours. The solution was filtered to remove insoluble salts and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Concentration in vacuo gave the sulfone as a solid (12.6 g, 74%).
Part E: Thionyl chloride (6.35 mL, 87.1 mmol) was added dropwise to a solution of part D sulfone (12.6 g, 43.6 mmol) in methanol (200 mL) cooled to 0 ° C. This solution was heated at reflux for 1 h. The solution was cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and saturated NaCO ₃ and dried over Na ₂ SO ₄ . Concentration in vacuo gave the methyl ester as a beige solid (12.7 g, 96%).
Part F: 10% Pd / C was added to a solution of the methyl ester of Part E (12.6 g, 41.5 mmol) in THF (250 mL) under H ₂ . The solution was stirred at ambient temperature for 18 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the aniline compound as a non-white solid (11.1 g, 98%).
Part G: Pyridine (0.044 mL, 0.55 mmol) was added to a suspension of the Part F aniline compound (100 mg, 0.37 mmol) in dichloromethane (8 mL) followed by 4-pentylbenzoyl chloride (0.093 mL, 0.44 mmol). The mixture was heated to 60 ° C. for 1 h. Polyamine resin (0.368 g, 1.1 mmol, 2.98 meq / g charge) was added to this solution and heating of the solution was continued at 60 ° C. for 1 hour. The mixture was filtered and concentrated in vacuo to give the amide as a white solid (167 mg, quantitative yield).
Part H: To a solution of Part G amide (163 mg, 0.36 mmol) in THF (4 mL) and methanol (4 mL) was added 50% aqueous hydroxylamine (0.60 mL, 10.2 mmol). The solution was stirred at ambient temperature for 96 hours and at 40 ° C. for 24 hours. The solution was concentrated and redissolved in THF (1.5 mL) and 50% aqueous hydroxylamine (1.5 mL). The solution was stirred for 24 hours and then concentrated. The residue was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . Reverse phase chromatography (acetonitrile / H ₂ O) with hydroxyxamate, N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] Pentylbenzamide was obtained as a pink solid (103 mg, 63%). MS (CI) MH ⁺ calcd for C ₂₂ H ₂₈ N ₂ 0 ₆ S: 449. Found: 449.
Example 15 N, 2-dihydroxy-2-methyl-3-[[4-[[(phenylamino) carbonyl] amino] phenyl] sulfonyl] propanamide
Part A: To a solution of Example 14, Part F aniline (500 mg, 1.83 mmol) in dichloromethane (10 mL) was added phenylisocyanate (436 mg, 3.66 mmol) and the solution was stirred at ambient temperature for 20 hours. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . Concentration in vacuo gave ureamethylester as an oil (392 mg, 55%).
Part B: To a solution of ureamethylester (392 mg, 1.0 mmol) of part A was added 50% aqueous hydroxylamine (3.0 mL) and the solution was stirred for 96 h. The solution was diluted with ethyl acetate and washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . Reversed phase chromatography (acetonitrile / H ₂ O) gives N, 2-dihydroxy-2-methyl-3-[[4-[[(phenylamino) carbonyl] amino] phenyl] sulfonyl] propanamide pink Obtained as a solid (77 mg, 20%). MS (CI) MH ⁺ calcd for C ₁₇ H ₁₉ N ₃ 0 ₆ S: 394. Found: 394.
Example 16: N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide
Part A: Pyridine (0.22 mL, 2.7 mmol) was added to a solution of Example 14, aniline (500 mg, 1.83 mmol) in 1,2-dichloromethane (20 mL) followed by benzoyl chloride (0.25 mL, 2.2 mmol). Was added. The solution was stirred at ambient temperature for 1 hour, then polyamine resin (3.0 meq / g charge, 1.5 g, 4.5 mmol) was added and stirring was continued for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give the amidemethyl ester as a non-white solid (688 mg, 99%).
Part B: To a solution of amidemethyl ester of Part A (674 mg, 1.79 mmol) in THF (15 mL) was added 50% aqueous hydroxylamine (15 mL) and stirred for 72 h. The solution was concentrated and the residue was extracted with ethyl acetate, washed with saturated NaCl and dried over Na ₂ SO ₄ . Trituration with ethyl acetate and ethyl ether gave N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide as a white solid ( 328 mg, 48%). MS (CI) MH ⁺ calcd for C ₁₇ H ₁₈ N ₂ 0 ₆ S: 379, found: 379.
Example 17 N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -3-methylbutanamide
Part A: Pyridine (0.22 mL, 2.7 mmol) was added to a solution of Example 14, Part A, aniline (500 mg, 1.83 mmol) in 1,2-dichloromethane (20 mL), followed by isovaleryl chloride (0.27 mL, 2.2 mmol) was added. The solution was stirred at ambient temperature for 1.5 hours, then polyamine resin (3.0 meq / g charge, 1.5 g, 4.5 mmol) was added and stirring was continued for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give methylesteramide as a yellow solid (746 mg, quantitative yield).
Part B: To a solution of methyl esteramide (736 mg, 1.83 mmol) of Part A in THF (10 mL) was added 50% aqueous hydroxylamine (10 mL) and stirred for 96 h. The solution was concentrated and the residue was extracted with ethyl acetate, washed with saturated NaCl and dried over Na ₂ SO ₄ . Reversed phase chromatography (acetonitrile / H ₂ O) gives N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -3-methyl Butanamide was obtained as a pink solid (247 mg, 38%). MS (CI) MH ⁺ calcd for C ₁₅ H ₂₂ N ₂ 0 ₆ S: 359. Found: 359.
Example 18 4-chloro-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide
Part A: Pyridine (0.133 mL, 1.65 mmol) was added to a solution of Example 14, Part A, aniline (300 mg, 1.10 mmol) in 1,2-dichloromethane (10 mL), followed by 4-chlorobenzoyl chloride (0.17 mL, 1.3 mmol) was added. The solution was stirred at ambient temperature for 1 hour. The obtained precipitate was triturated with ethyl ether and collected to give an amide methyl ester as a white solid (368 mg, 81%).
Part B: To a solution of amidemethyl ester (368 mg, 0.89 mmol) of Part A in THF (2 mL) and methanol (4 mL) was added 50% aqueous hydroxylamine (3 mL) and stirred for 96 h. The solution was concentrated and the residue was extracted with ethyl acetate, washed with saturated NaCl and dried over Na ₂ SO ₄ . Trituration with ethyl acetate gave 4-chloro-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide as a white solid. (126 mg, 34%). MS (CI) MH ⁺ calcd for C ₁₇ H ₁₇ N ₂ 0 ₆ SCl: 430. Found: 430.
Example 19: N, 2-dihydroxy-2-methyl-3-[[4-[[[(2-methylphenyl) amino] carbonyl] amino] phenyl] sulfonyl] propanamide
Part A: o-tolyl isocyanate (0.354 mL, 2.74 mmol) was added to a solution of Example 14, Part A, aniline (500 mg, 1.83 mmol) in 1,2-dichloromethane (15 mL). The solution was heated to 60 ° C. for 15 hours and then polyamine resin (3.0 meq / g charge, 1.00 g, 3.00 mmol) was added and heating continued for 7 hours. The mixture was filtered and the filtrate was concentrated. Chromatography (ethyl acetate / hexane) gave ureamethyl ester as a pink solid (496 mg, 67%).
Part B: To a solution of ureamethyl ester (496 mg, 1.22 mmol) of Part A in THF (12 mL) was added 50% potassium trimethylsilane octanoate (188 mg, 1.46 mmol) and stirred at ambient temperature for 20 hours. The solution was cooled to 0 ° C., diluted with H ₂ O and acidified with 1N HCl (1.5 mL). THF was removed. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Concentration in vacuo gave the acid as a yellow solid (480 mg, quantitative yield).
Part C: N-hydroxybenzotriazole (181 mg, 1.34 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodii in a solution of the Part B acid (480 mg, 1.22 mmol) in DMF (12 mL) Mid hydrochloride (257 mg, 1.34 mmol) was added. After stirring for 1 hour at ambient temperature 50% aqueous hydroxylamine (0.216 mL, 3.66 mmol) and 4-methylmorpholine (0.54 mL, 4.9 mmol) were added. After 30 minutes the DMF was removed and the residue was partitioned between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Reversed phase chromatography gave N, 2-dihydroxy-2-methyl-3-[[4-[[[(2-methylphenyl) amino] carbonyl] amino] phenyl] sulfonyl] propanamide as a pink solid ( 39 mg, 8%). MS (CI) MH ⁺ calcd for Ci ₈ H ₂₁ N ₃ 0 ₆ S: 408, found: 408.
Example 20 N, 2-dihydroxy-2-methyl-3-[[4-[[[(3-methylphenyl) amino] carbonyl] amino] phenyl] sulfonyl] propanamide
Part A: To a solution of Example 14, Part A, aniline (500 mg, 1.83 mmol) in 1,2-dichloromethane (15 mL), m-tolyl isocyanate (0.353 mL, 2.74 mmol) was added. The solution was heated to 60 ° C. for 15 hours and then polyamine resin (3.0 meq / g charge, 1.00 g, 3.00 mmol) was added and heating continued for 7 hours. The mixture was filtered and the filtrate was concentrated. Chromatography (ethyl acetate / hexane) gave ureamethyl ester as a pale yellow solid (346 mg, 47%).
Part B: Potassium trimethylsilanate (131 mg, 1.02 mmol) was added to a solution of urea methyl ester (346 mg, 0.851 mmol) in Part A in THF (10 mL) and stirred at ambient temperature for 18 hours. The solution was cooled to 0 ° C., diluted with H ₂ O and acidified with 1N HCl. THF was removed. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Concentration in vacuo gave the acid as a pink solid (330 mg, 99%).
Part C: N-hydroxybenzotriazole (125 mg, 0.925 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodii in a solution of the acid of Part B (330 mg, 0.841 mmol) in DMF (8 mL) Mid hydrochloride (177 mg, 0.925 mmol) was added. After stirring for 1 hour at ambient temperature 50% aqueous hydroxylamine (0.149 mL, 2.52 mmol) and 4-methylmorpholine (0.37 mL, 3.7 mmol) were added. After 30 minutes the DMF was removed and the residue was partitioned between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Reversed phase chromatography gave N, 2-dihydroxy-2-methyl-3-[[4-[[[(3-methylphenyl) amino] carbonyl] amino] phenyl] sulfonyl] propanamide as a white solid ( 265 mg, 77%). MS (CI) MH ⁺ calcd for Ci ₈ H ₂₁ N ₃ 0 ₆ S: 408, found: 408.
Example 21 N, 2-dihydroxy-2-methyl-3-[[4-[[[(4-methylphenyl) amino] carbonyl] amino] phenyl] sulfonyl] propanamide
Part A: To a solution of Example 14, Part A, aniline (500 mg, 1.83 mmol) in THF (15 mL), p-tolyl isocyanate (0.461 mL, 3.66 mmol) was added. The solution was stirred at ambient temperature for 72 hours. The solution was then diluted with dichloromethane (50 mL) and polyamine resin (3.0 meq / g charge, 2.50 g, 7.50 mmol) was added and the mixture was stirred for 4 hours. The mixture was filtered and the filtrate was concentrated. Chromatography (ethyl acetate / hexane) gave ureamethyl ester as a white solid (554 mg, 74%).
Part B: To a solution of urea methyl ester (554 mg, 1.36 mmol) in part A in THF (13 mL) was added potassium trimethylsilanoate (210 mg, 1.64 mmol) and stirred at ambient temperature for 18 hours. The solution was cooled to 0 ° C., diluted with H ₂ O and acidified with 1N HCl. THF was removed. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with saturated NaCl and dried over Na ₂ SO. Concentration in vacuo gave the acid as a non-white solid (530 mg, 99%).
Part C: N-hydroxybenzotriazole (189 mg, 1.40 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodii in a solution of the acid of Part B (500 mg, 1.27 mmol) in DMF (13 mL) Mid hydrochloride (268 mg, 1.40 mmol) was added. After stirring for 1 hour at ambient temperature 50% aqueous hydroxylamine (0.282 mL, 3.81 mmol) and 4-methylmorpholine (0.56 mL, 5.1 mmol) were added. After 30 minutes the DMF was removed and the residue was partitioned between ethyl acetate and H ₂ O. The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Reversed phase chromatography gives N, 2-dihydroxy-2-methyl-3-[[4-[[[(4-methylphenyl) amino] carbonyl] amino] phenyl] sulfonyl] propanamide as a non-white solid. (202 mg, 39%). MS (CI) MH ⁺ calcd for Ci ₈ H ₂₁ N ₃ 0 ₆ S: 408, found: 408.
Example 22 6-Chloro-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -3-pyridinecarboxamide
Part A: Pyridine (0.22 mL, 2.7 mmol) was added to a solution of Example 14, aniline (500 mg, 1.83 mmol) in 1,2-dichloromethane (10 mL) followed by 6-chloronicotinyl chloride (383 mg, 2.2 mmol) was added. The solution was stirred at ambient temperature for 1 hour, then polyamine resin (3.0 meq / g charge, 1.5 g, 4.5 mmol) was added and stirring was continued for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give amidemethylester as a non-white solid (750 mg, 99%).
Part B: To a solution of the amide methyl ester (750 mg, 1.82 mmol) of Part A in THF (10 mL) was added 50% aqueous hydroxylamine (3 mL) and stirred for 96 h. The solution was concentrated and the residue was extracted with ethyl acetate, washed with saturated NaCl and dried over Na ₂ SO ₄ . Reversed-phase chromatography (acetonitrile / H ₂ O) gave 6-chloro-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] 3-Pyridinecarboxamide was obtained as a white solid (29 mg, 4%). MS (CI) MH ⁺ calcd for C ₁₆ H ₁₆ N ₃ 0 ₆ SCl: 412. Found: 412.
Example 23 N- [4-[[2-hydroxy-3- (hydroxyamino) -3-oxopropyl] sulfonyl] phenyl] benzamide
Part A: To a solution of β-chlorolactic acid (10.0 g, 80.3 mmol) in DMF (200 mL) was added K ₂ CO ₃ (33.3 g, 240.96 mmol) and 4-aminothiophenol (11.60 g, 92.66 mmol). The solution was stirred at ambient temperature for 20 hours. The solution was concentrated in vacuo and the residue was dissolved in H ₂ O and acidified to pH = 2.5 with 6N HCl. The precipitate obtained was collected by vacuum filtration and dried to give acid sulfide as a non-white solid (12.4 g, 72%).
Part B: Thionyl chloride (12.2 mL, 167.13 mmol) was added to a solution of the acid sulfide (11.88 g, 55.71 mmol) of Part A in methanol (200 mL) cooled to 0 ° C. The solution was heated at reflux for 2 h and then concentrated in vacuo. The residue was dissolved in saturated NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over Na ₂ SO ₄ . Concentration in vacuo gave the methyl ester as a tan solid (11.47 g, 91%).
Part C: Pyridine (5.34 mL, 66.00 mmol) and benzoyl chloride (5.62 mL, 48.4 mmol) were added to a suspension of the methyl ester of Part B (10.00 g, 44.0 mmol) in dichloromethane (100 mL). The solution was stirred at ambient temperature for 20 hours. The solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and H ₂ O and the organic layer was washed with H ₂ O and saturated NaCl. Concentration in vacuo gave the amide sulfide as a solid rather than a white (14.56 g, quantitative yield).
Part D: Oxone in a solution of amide sulfide (3.00 g, 9.05 mmol) of Part C in THF (100 mL) and H ₂ O (10 mL) (10.0 g, 16.3 mmol) was added. The solution was stirred at 0 ° C for 2 h. The mixture was filtered and the filtrate was concentrated to one third volume. The solution was diluted with ethyl acetate and washed with H ₂ O and saturated NaCl and dried over Na ₂ SO ₄ . Purification by chromatography (ethyl acetate / hexane) afforded sulfonemethyl ester as a non-white solid (2.68 g, 81%).
Part E: 50% aqueous hydroxylamine (6 mL) was added to a solution of part D's sulfonemethyl ester (500 mg, 1.38 mmol) in THF (6 mL). The solution was stirred at ambient temperature for 8 hours. Trituration with THF gave N- [4-[[2-hydroxy-3- (hydroxyamino) -3-oxopropyl] sulfonyl] phenyl] benzamide as a non-white solid (393 mg, 78%). MS (CI) MH ⁺ calcd for C ₁₆ H ₁₆ N ₂ 0 ₆ S: 365, found: 365.
Example 24: 4- (heptyloxy) -N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide
Part A: Triethylamine (1.09 mL, 7.8 mmol) and 4-heptyloxybenzoyl chloride (502 mg, 1.95 mmol) were added to a solution of Example 14, the aniline compound (532 mg, 1.95 mmol) of Part F in THF (15 mL). Was added and the solution was refluxed for 1.5 h. Chromatography (ethyl acetate / hexane) afforded amidemethyl ester (605 mg, 63%).
Part B: To a solution of amidemethyl ester (500 mg, 1.02 mmol) of Part A in THF (10 mL) and methanol (10 mL) was added 50% aqueous hydroxylamine (12 mL) and the solution was stirred at ambient temperature for 11 days. The solvent was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Crystallize (hexane) to give 4- (heptyloxy) -N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide Obtained as a solid (215 mg, 43%). HRMS (MH ⁺ ) calcd for C ₂₄ H ₃₂ N ₂ O ₇ S: 493.2008, found 493.2027.
Example 25 4-butoxy-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide
Part A: In a solution of Example 14, Part A aniline compound (560 mg, 2.05 mmol) in THF (15 mL), triethylamine (1.14 mL, 8.2 mmol) and 4-butoxybenzoyl chloride (654 mg, 3.075 mmol) were added. And the solution was refluxed for 5 hours. The solution was concentrated in vacuo and triturated with ethyl ether to give the amide methyl ester as a white solid (407 mg, 43%).
Part B: To a solution of the amide methyl ester of Part A (400 mg, 0.89 mmol) in THF (10 mL) was added 50% aqueous hydroxylamine (10 mL) and the solution was stirred at ambient temperature for 72 hours. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and the organic layer was dried over Na ₂ SO ₄ . Concentration in vacuo afforded 4-butoxy-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide as a white solid. (335 mg, 84%). HRMS (MH ⁺ ) calcd for C ₂₁ H ₂₆ N ₂ 0 ₇ S: 451.1539. Found: 451.1540.
Example 26 N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -4-propylbenzamide
Part A: To a solution of Example 14, Part A aniline compound (530 mg, 1.94 mmol) in THF (10 mL) was added triethylamine (1.08 mL, 7.76 mmol) followed by 4-propylbenzoyl chloride (532 mg, 2.91 mmol). Was added and the solution was heated at reflux for 3 h. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Recrystallization (ethyl acetate / hexane) afforded amide methyl ester as white crystals (570 mg, 70%).
Part B: To a solution of amidemethyl ester (560 mg, 1.3 mmol) of Part A in THF (10 mL) was added 50% hydroxylamine (10 mL) and the solution was stirred for 7 days. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. The organic layer was dried over Na ₂ SO ₄ . Concentration in vacuo gave N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -4-propylbenzamide as a white solid ( 438 mg, 80%). HRMS (MH ⁺ ) calcd for C ₂₀ H ₂₄ N ₂ 0 ₆ S: 421.1433, found: 421.1396.
Example 27 N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -3-methoxybenzamide
Part A: Triethylamine (1.0 mL, 7.19 mmol) was added to a solution of Example 14, Part A aniline compound (563 mg, 2.06 mmol) in THF (10 mL), followed by m-anisoyl chloride (0.434 mg, 3.09 mmol). ) Was added and the solution was heated at reflux for 3 h. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Recrystallization (ethyl acetate / hexane) afforded amide methyl ester as white crystals (539 mg, 64%).
Part B: To a solution of amidemethyl ester (530 mg, 1.3 mmol) of Part A in THF (10 mL) was added 50% hydroxylamine (10 mL) and the solution was stirred for 7 days. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. Reversed phase chromatography (acetonitrile / H ₂ O) gives N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -3-me Oxybenzamide was obtained as a white solid (190 mg, 36%). HRMS (MH ⁺ ) calcd for Ci ₈ H ₂₀ N ₂ 0 ₇ S: 409.1069, found 409.1093.
Example 28: 4-butyl-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide
Part A: To a solution of Example 14, Part A aniline compound (573 mg, 2.10 mmol) in THF (10 mL) was added triethylamine (1.3 mL, 9.3 mmol) followed by 4-butylbenzoyl chloride (619 mg, 3.15 mmol). Was added and the solution was heated at reflux for 4.5 h. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Recrystallization (ethyl acetate / hexane) afforded amide methyl ester as a white solid (682 mg, 75%).
Part B: To a solution of amidemethyl ester (682 mg, 1.6 mmol) of Part A in THF (10 mL) was added 50% hydroxylamine (10 mL) and the solution was stirred for 10 days. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. Concentration in vacuo afforded 4-butyl-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide as a white solid ( 522 mg, 75%). HRMS (MH ⁺ ) calcd for C ₂₁ H ₂₆ N ₂ 0 ₆ S: 435.1590, found: 435.1577.
Example 29: 3-fluoro-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide
Part A: To a solution of Example 14, Part A aniline compound (566 mg, 2.07 mmol) in THF (10 mL) was added triethylamine (1.0 mL, 7.2 mmol) followed by 3-fluorobenzoyl chloride (490 mg, 3.1 mmol). ) Was added and the solution was heated at reflux for 4.5 h. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Chromatography (ethyl acetate / hexane) gave amide methyl ester as an oil (460 mg, 56%).
Part B: To a solution of amidemethyl ester (400 mg, 1.0 mmol) of Part A in THF (20 mL) and methanol (5 mL) was added 50% hydroxylamine (20 mL) and the solution was stirred for 20 h. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. Concentration in vacuo afforded 3-fluoro-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide as a white solid. (363 mg, 91%). HRMS (MH ⁺ ) calcd for Ci ₇ H ₁₇ N ₂ 0 ₆ SF: 397.0870, found 397.0864.
Example 30 N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -3-methylbenzamide
Part A: To a solution of Example 14, Part A aniline compound (537 mg, 1.97 mmol) in THF (10 mL) was added triethylamine (1.0 mL, 7.2 mmol) followed by m-toluoyl chloride (0.39 mL, 2.9 mmol). ) Was added and the solution was heated at reflux for 5 hours. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Chromatography (ethyl acetate / hexane) afforded amidemethyl ester as a white solid (550 mg, 71%).
Part B: To a solution of amidemethyl ester (500 mg, 1.3 mmol) of Part A in THF (10 mL) and methanol (5 mL) was added 50% hydroxylamine (20 mL) and the solution was stirred for 25 h. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. Concentration in vacuo gave N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -3-methylbenzamide as a white solid ( 352 mg, 70%). HRMS (MH ⁺ ) calcd for Ci ₈ H ₂₀ N ₂ 0 ₆ S: 393.1120, found: 393.1127.
Example 31: 3-chloro-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide
Part A: Triethylamine (1.0 mL, 7.2 mmol) was added to a solution of Example 14, Part A aniline compound (525 mg, 1.92 mmol) in THF (10 mL), followed by 3-chlorobenzoyl chloride (0.322 mL, 2.88 mmol). ) Was added and the solution was heated at reflux for 5 hours. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Crystallization (ethyl acetate / hexane) afforded amidemethyl ester as a white solid (230 mg, 29%).
Part B: To a solution of amidemethyl ester (230 mg, 0.56 mmol) of Part A in THF (5 mL) and methanol (5 mL) was added 50% hydroxylamine (10 mL) and the solution was stirred for 48 h. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. Concentration in vacuo afforded 3-chloro-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide as a white solid ( 160 mg, 70%). HRMS (MH ⁺ ) calcd for Ci ₇ H ₁₇ N ₂ 0 ₆ S: 430.0840, found 430.0864.
Example 32: 3,4-difluoro-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide
Part A: To a solution of Example 14, Part A aniline compound (531 mg, 1.94 mmol) in THF (10 mL) was added triethylamine (1.0 mL, 7.2 mmol) followed by 3,4-difluorobenzoyl chloride (0.367). mL, 2.92 mmol) was added and the solution was heated at reflux for 18 h. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Chromatography (ethyl acetate / hexane) afforded amidemethyl ester as a white solid (360 mg, 45%).
Part B: To a solution of amidemethyl ester (359 mg, 0.87 mmol) of Part A in THF (10 mL) and methanol (5 mL) was added 50% hydroxylamine (15 mL) and the solution was stirred for 20 h. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. Concentrated in vacuo by reverse phase chromatography (acetonitrile / H ₂ O) to give 3,4-difluoro-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3- Oxopropyl] sulfonyl] phenyl] benzamide was obtained as a white solid (165 mg, 46%). HRMS (MH ⁺ ) calcd for Ci ₇ H ₁₆ N ₂ 0 ₆ SF ₂ : 415.0775. Found: 415.0778.
Example 33: N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -3-nitrobenzamide
Part A: To a solution of Example 14, Part A aniline compound (750 mg, 2.75 mmol) in THF (30 mL) was added triethylamine (1.32 mL, 9.6 mmol) followed by 3-nitrobenzyl chloride (765 mg, 4.12 mmol). Was added and the solution was heated at reflux for 6 h. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Chromatography (ethyl acetate / hexane) gave amidemethyl ester as a white solid (109 mg, 9%).
Part B: To a solution of amidemethyl ester (100 mg, 0.24 mmol) of Part A in methanol (20 mL) was added 50% hydroxylamine (20 mL) and the solution was stirred for 20 h. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. Concentration in vacuo gave N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] -3-nitrobenzamide as a white solid ( 43 mg, 43%). HRMS (MH ⁺ ) calcd for Ci ₇ H ₁₇ N ₃ 0 ₈ S: 424.0815, found 424.0827.
Example 34: 3-[(4-hydroxybutyl) amino] -N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl ] Benzamide
Part A: Triethylamine (3.0 mL, 21.6 mmol) was added to a solution of Example 14, Part A aniline compound (789 mg, 2.9 mmol) in THF (20 mL), followed by 3-nitrobenzoyl chloride (2.0 g, 10.8 mmol). ) Was added and the solution was heated at reflux for 3.5 h. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Chromatography (ethyl acetate / hexane / methanol) gave nitroamide methyl ester as a white solid (313 mg, 25%).
Part B: To a solution of 4% Pd / C (130 mg) in methanol under N ₂ atmosphere was added the nitroamide methyl ester compound (508 mg, 1.2 mmol) of Part A in THF (20 mL). The atmosphere was purged five times with 50 psi of H ₂ . Then celite the solution The catalyst was removed by filtration through. The filtrate was purified by chromatography (ethyl acetate / methanol) to give THF adduct aminemethyl ester (240 mg, 43%).
Part C: 50% hydroxylamine (20 mL) was added to a solution of the THF adduct amidemethyl ester (230 mg, 0.49 mmol) of Part B in methanol (20 mL) and the solution was stirred for 20 h. The solution was concentrated in vacuo and the residue was partitioned between ethyl acetate and H ₂ O. Concentrated in vacuo, 3-[(4-hydroxybutyl) amino] -N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl ] Benzamide was obtained as a white solid (105 mg, 46%). HRMS (MH ⁺ ) calcd for C ₂₁ H ₂₇ N ₃ 0 ₇ S: 466.1648. Found: 466.1643.
Example 35: 3-amino-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide
Part A: Triethylamine (3.0 mL, 21.6 mmol) was added to a solution of Example 14, Part A aniline compound (789 mg, 2.9 mmol) in THF (20 mL), followed by 3-nitrobenzoyl chloride (2.0 g, 10.8 mmol). ) Was added and the solution was heated at reflux for 3.5 h. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with H ₂ O and dried over Na ₂ SO ₄ . Chromatography (ethyl acetate / hexane / methanol) gave nitroamide methyl ester as a white solid (313 mg, 25%).
Part B: To a solution of 4% Pd / C (200 mg) in methanol under N ₂ atmosphere was added an ester compound of Part A (600 mg, 1.4 mmol) in methanol (80 mL). The atmosphere was purged five times with 50 psi of H ₂ . The solution was stirred overnight. Then celite the solution The catalyst was removed by filtration through. The filtrate was purified by chromatography (ethyl acetate / methanol) to give aniline methyl ester (543 mg, 99%).
Part C: 50% hydroxylamine (5 mL) was added to a solution of Part B aniline methyl ester (540 mg, 1.38 mmol) in methanol (5 mL) and the solution was stirred for 24 h. The solution was concentrated in vacuo. Trituration (ethyl acetate / ethyl ether) to yield 3-amino-N- [4-[[2-hydroxy-3- (hydroxyamino) -2-methyl-3-oxopropyl] sulfonyl] phenyl] benzamide Obtained as a white solid (434 mg, 80%). HRMS (MH ⁺ ) calcd for Ci ₇ H ₁₉ N ₃ 0 ₆ S: 394.1073, found: 394.1070.
Example 36 In vitro Metalloprotease Inhibition
The compounds prepared by the methods described in Examples 1-9 were tested for activity in vitro. Knight et al., FEBS Lett. 296 (3): 263 (1992). Briefly, 4-aminophenylmercuric acetate (APMA) or trypsin activated MMP was incubated with various concentrations of inhibitor compound for 5 minutes at room temperature.
In more detail, recombinant human MMP-13 and MMP-1 enzymes were prepared in the assignee's laboratory. MMP-13 was expressed in baculovirus as a proenzyme, first purified on heparin agarose column, and then purified on chelated zinc chloride column. To use the proenzyme for testing, it was activated with APMA. MMP-1 expressed in transfected HT-1080 cells was described by Dr. Washington, University of St. Louis, Missouri. Provided by Howard Welgus. This enzyme was also activated using APMA and then purified on a hydroxamic acid column.
Enzyme substrates are polypeptides containing methoxycoumarin having the following sequence:
MCA-ProLeuGlyLeuDpaAlaArgNH ₂ , where MCA is methoxycoumarin and Dpa is 3- (2,4-dinitrophenyl) -L-2,3-diaminopropionyl alanine. This substrate is commercially available from Baychem as M-1895 product.
The buffer used for the test included 100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl ₂ and 0.05% polyethylene glycol (23) lauryl ether at pH 7.5. The test was performed at room temperature and dimethyl sulfoxide (DMSO) was used to dissolve the inhibitor compound at a final temperature of 1%.
Inhibitor compounds tested in DMSO / buffer solutions were microfluor White Plate (Dynatech) was used to compare the same amount of DMSO / buffer without any inhibitor as control. The inhibitor or control solution was kept on the plate for 10 minutes and the substrate was added to a final temperature of 4 μM.
In the absence of inhibitor activity, luminescent peptides are cleaved at gly-leu peptide bonds, separating the highly luminescent peptides from 2,4-dinitrophenyl terminators, thereby increasing the fluorescence intensity (emission at excitation / 415 nm) at 328 nm. Caused. Inhibition was measured as a decrease in fluorescence intensity due to the function of inhibitor concentration using a Perkin Elmer L550 plate reader. IC ₅₀ values are calculated from these values. The results are recorded as IC ₅₀ for three meaningful forms and shown in the inhibition table (Table 51) below.
IC ₅₀ value (nM) ExampleMMP-13MMP-1MMP-2MMP-3MMP-8MMP-9 One1.111000.5302.54.8 1A (S)0.7510050.39 1.7 1B (R)21.5＞ 10,00011.0 328 21.24701.0444.17 3360001.0166420 40.490000.448.54.512.4 51.3＞ 10,0002.426.82.53.4 630800014.8 72.1＞ 10,0002.051.84.013.0 8200＞ 10,000 90.230000.4 16.0 101.040000.4 18.0 115.070007 66.0 123.7＞ 10,0002.0 175 135.0＞ 10,0002.3 70.0 140.5＞ 10,000<0.1 153200＞ 10,00087 16110＞ 10,0000.8 1160 17900＞ 10,000400 1813＞ 10,0000.5 1910,000＞ 10,0002600 206600＞ 10,000300 213600＞ 10,00034 22280＞ 10,0006.7 23220＞ 10,0002.8 1330 24<0.1＞ 10,000<0.1 251.2＞ 10,0000.2 261.2＞ 10,0000.1 27666＞ 10,00010.0 280.8＞ 10,000<0.1 2980＞ 10,0001.8 30316＞ 10,00020 31600＞ 10,00037.2 3280＞ 10,0001.6 331600＞ 10,00050 341600＞ 10,00032.7 35290＞ 10,0006.7
Example 37: Intravascular Angiogenesis Test
Studies on angiogenesis rely on reliable and reproducible models for stimulation and inhibition of neovascular responses. Corneal micropocket testing provides a model of such angiogenesis in the cornea of mice (Kenyon, BM, et al., Investigative Ophthalmology & Visual Science, July 1996, Vol. 37, No. Reference).
In this test, Hydron of constant size including bFGF and sucralate Pellets were prepared and surgically implanted into the stromal mouse cornea adjacent to the lateral corneal limbus. Pellets were 10 μg recombinant bFGF, 10 mg sucralate and 12% Hydron in ethanol A suspension of 20 μL sterile saline containing 10 μL was made and formed. The slurry was then placed on a sheet of 10 × 10 mm sterile nylon mesh. After drying, the nylon fibers of the mesh were separated and the pellets were removed.
The corneal pockets were made by anesthetizing 7 week old C57Bl / 6 female mice and then protruding the eye with a jeweler forceps. Using an anatomical microscope, a central, intrastromal, straight corneal cutout of about 0.6 mm in length was performed with a # 15 surgical knife parallel to the engraftment of the lateral rectus muscles. Using a modified cataract knife, the lamellar micropockets were incised toward the lateral corneal limbus. The pocket was stiff within 1.0 mm of lateral corneal limbus. A single pellet was placed on the corneal surface at the base of the pocket using a jeweler forceps. The pellet was then advanced to the lateral end of the pocket. Then, antibiotic ointment was applied to the eyes.
Mice were dosed daily until the end of the test. Administration to experimental animals was based on the bioavailability and overall efficacy of the compounds. In one example the dose was 50 mg / kg bid, po. The neovascularization of the corneal strom began on day 3 and could continue under the influence of the test compound until day 5. On day 5, angiogenesis inhibition was recorded by observing the neovascularization progression with a slit lamp microscope.
Mice were anesthetized and the eye under test was once again protruded. The maximum vessel length of neovascularization, which extends from the limbal angular plexus to pellets, was measured. In addition, the adjacent surrounding area of neovascularization was measured by the time of the clock such that 30 ° of the arc is equal to one hour of the clock. The area of angiogenesis was calculated as follows.
The mice tested were then compared to control mice and the difference in neovascularization area was recorded. While the vehicle control compound showed 0% inhibition, the compound typically exhibited about 25 to about 75% inhibition. The results of this test for several inhibitors are shown in Table 52 below.
ExamplePercentage of control One51.9 1A (S)62.7 1B (R)49.3 253.4 377.4 465.2 557.8 961.1 1641.6
From the foregoing, numerous variations and modifications may be made without departing from the true spirit and scope of the novel inventive concept. It should be understood that no limitation to the particular embodiments presented should be intended or implied. This disclosure is intended to fall within the scope of the claims, including all such modifications by the appended claims.

权利要求:
Claims (38)
[1" claim-type="Currently amended] The compound according to the formula (1).
(Formula 1)

Where
R ² is hydrido, C ₁ -C ₄ hydrocarbyl, hydroxy-C ₁ -C ₄ hydrocarbyl, C ₁ -C ₄ hydrocarbyloxy, halo-C ₁ -C ₄ hydrocarbyl, C _1- C ₄ hydrocarbyloxymethyl, aminomethyl, (NC ₁ -C ₃ hydrocarbyl) aminomethyl, (N, N-di-C ₁ -C ₃ hydrocarbyl) aminomethyl, (N-morpholi No) methyl, (N-pyrrolidino) methyl, or (N-thiomorpholino) methyl;
R ¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical directly bonded to the SO ₂ -group shown in the formula, which is approximately longer than the length of the hexyl group and shorter than the length of the acyl group Is a substituent having a length, and R ¹ is a 3 or 4 SO ₂ -bonded 1-position of an axial or 5-membered ring radical connected through the 4-position with the SO ₂ -bonded 1-position of the 6-membered ring radical Define a three-dimensional volume when rotated about the connecting axis through the center of the bond, and the widest width transverse to the axis of rotation is from about one furanyl ring to about two phenyl rings.
[2" claim-type="Currently amended] According to claim 1, wherein said 5 or 6 membered cycloalkyl hydrocarbyl, heterocycloalkyl, aryl or heteroaryl radical is a compound being substituted with a substituent R ³ has a chain length of 3 to about 14 carbon atoms of R ^1.
[3" claim-type="Currently amended] According to claim 2, wherein the R ³ substituent is a phenyl group, phenoxy group, thiophenoxy group, alinino group, phenylazo group, ureidophenyl, benzamido, nicotinamido, isnicotinamido, picolineamido group, Heterocyclo, heterocyclohydrocarbyl, arylheterocyclohydrocarbyl, arylhydrocarbyl, heteroarylhydrocarbyl, heteroarylheterocyclohydrocarbyl, arylhydrocarbyloxyhydrocarbyl, aryloxyhydrocarbyl, Hydrocarbonylhydrocarbyl, arylhydrocarbonylhydrocarbyl, arylcarbonylhydrocarbyl, arylazoaryl, arylhydrazinoaryl, hydrocarbylthiohydrocarbyl, hydrocarbylthioaryl, arylthiohydrocarbyl , Heteroarylthiohydrocarbyl, hydrocarbylthioarylhydrocarbyl, arylhydrocarbylthiohydrocarbyl, arylhydrocarbylthioaryl, aryl Draw hydrocarbyl amino, heteroaryl, hydrocarbyl amino, and the compounds being selected from the group consisting of heteroaryl thio groups.
[4" claim-type="Currently amended] The method of claim 3, wherein the R ³ substituent is halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxy Carbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy , Hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, hetero Arylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocycle, heteroaryl, hydroxide Hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyl oil, arylcarbonyl, arylhydrocarbyl oil, hydrocarbonyloxy, arylhydrocarbonyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyl Oxy, hydrocarbylthio, hydrocarbyloxy hydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydro Carbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclo Hydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydro Revilcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino , Heterocyclohydrocarbylsulfonylamino and one or more substituents selected from the group consisting of N-mono-substituted or N, N-disubstituted aminohydrocarbyl groups, and the substituent (s) on nitrogen are hydrocarbyl , Aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl and hydrocarbonyl, or two substituents attached to nitrogen and nitrogen To 8 membered heterocyclic or heteroaryl ring group.
[5" claim-type="Currently amended] The compound according to the formula (1).
(Formula 1)

Where
R ² is also Hi give, C ₁ -C ₄ hydrocarbyl, hydroxy -C _1- C ₄ hydrocarbyl, C ₁ -C ₄ hydrocarbyl oxy, halo -C ₁ -C ₄ hydrocarbyl, C _1- C ₄ hydrocarbyloxymethyl, aminomethyl, (NC ₁ -C ₃ hydrocarbyl) aminomethyl, (N, N-di-C ₁ -C ₃ hydrocarbyl) aminomethyl, (N-morpholi No) methyl, (N-pyrrolidino) methyl, or (N-thiomorpholino) methyl:
R ¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical directly bonded to the SO ₂ -group represented by the formula, and in the six-membered ring at its own 4-position and 5-membered When in the ring at its own 3 or 4 position, one other monocyclic cyclohydrocarbyl, heterocyclo, aryl or heteroaryl group, C ₃ -C ₁₄ hydrocarbyl group, C ₂ -C ₁₄ hydrocarbyloxy group , A phenoxy group, a thiophenoxy group, a 4-thiopyridyl group, a phenylazo group, a ureidophenyl group, a nicotinamido group, an isonicotinamido group, a picolinamido group, an anilino group and a benzamido group ^It is a substituent substituted by ³ itself.
[6" claim-type="Currently amended] 6. The substituent of claim 5, wherein the R ¹ substituent is PhR ³ , wherein Ph is phenyl substituted with R ³ at position 4, and R ³ is phenyl, phenoxy, thiophenoxy, phenylazo, benzamido, anyl A lino, nicotinamido, isoninicotinamido, picolineamido or ureidophenyl group.
[7" claim-type="Currently amended] 6. The substituent according to claim 5, wherein the R ¹ substituent is PhR ³ , wherein Ph is phenyl substituted with R ³ at position 4, wherein R ³ is halogen in the meta- or para-position or both positions, C ₁ -C ₉ hydrocarbyloxy group, C ₁ -C ₁₀ hydrocarbyl group, di-C ₁ -C ₉ hydrocarbylamino group, carboxyl C ₁ -C ₈ hydrocarbyl group, C ₁ -C ₄ hydrocarbyloxycarbonyl C Optionally substituted with a moiety selected from the group consisting of ₁ -C ₄ hydrocarbyl group, C ₁ -C ₄ hydrocarbyloxycarbonyl C ₁ -C ₄ hydrocarbyl group and carboxamido C ₁ -C ₈ hydrocarbyl group Or phenyl, phenoxy, anilino or thiophenoxy groups substituted in two methyl groups or methylenedioxy groups in the meta- and para-positions.
[8" claim-type="Currently amended] The method of claim 1, wherein the R ¹ substituent is PhR ³ , where Ph is phenyl substituted with R ³ at the 4 position, and the R ³ substituent is benzamido, nicotinamido, isnicotinamido, picolinamido Or a ureidophenyl group, wherein the R ³ substituent is halogen, nitro, C ₁ -C ₈ hydrocarbyl, C ₁ -C ₇ hydrocarbyloxy, amino in its meta- or para-position or both positions And optionally substituted with a moiety selected from the group consisting of amino-C ₂ -C ₄ -hydroxyalkyl groups.
[9" claim-type="Currently amended] The compound of claim 1, wherein the R ¹ substituent is longer than the length of the octyl group and shorter than the length of the stearyl group.
[10" claim-type="Currently amended] The compound according to the formula (2).
(Formula 2)

Where
R ² is also Hi give, C ₁ -C ₄ hydrocarbyl, hydroxy -C _1- C ₄ hydrocarbyl, C ₁ -C ₄ hydrocarbyl oxy, halo -C ₁ -C ₄ hydrocarbyl, C _1- C ₄ hydrocarbyloxymethyl, aminomethyl, (NC ₁ -C ₃ hydrocarbyl) aminomethyl, (N, N-di-C ₁ -C ₃ hydrocarbyl) aminomethyl, (N-morpholi No) methyl, (N-pyrrolidino) methyl, or (N-thiomorpholino) methyl:
Ph is phenyl substituted with R ³ at the 4-position, R ³ is phenyl, phenoxy, thiophenoxy, anilino, phenylazo, benzamido, nicotinamido, isnicotinamido, picolinamido Or a ureidophenyl group, wherein the PhR ³ group has a length longer than the length of the octyl group and shorter than the length of the stearyl group, and is connected through the SO ₂ -bonded 1-position and 4-position of the phenyl ring Ph. The three-dimensional volume is defined when rotated about an axis, and the widest width transverse to the axis of rotation is from about one furanyl ring to about two phenyl rings.
[11" claim-type="Currently amended] 11. A compound according to claim 10, wherein R ³ is halogen in its meta- or para-position or both positions, a C ₁ -C ₉ hydrocarbyloxy group, a C ₁ -C ₁₀ hydrocarbyl group, a di-C _1- C ₉ hydrocarbylamino group, carboxyl C ₁ -C ₈ hydrocarbyl group, C ₁ -C ₄ hydrocarbyloxycarbonyl C ₁ -C ₄ hydrocarbyl group, C ₁ -C ₄ hydrocarbyloxycarbonyl C Optionally substituted by itself with a moiety selected from the group consisting of _1- C ₈ hydrocarbyl groups and carboxamido C ₁ -C ₈ hydrocarbyl groups, or two methyl groups in the meta- and para-positions or methylenedioxy And phenyl, phenoxy, anilino or thiophenoxy groups substituted with groups.
[12" claim-type="Currently amended] 12. The compound of claim 11, wherein R ³ is an unsubstituted phenoxy or thiophenoxy group.
[13" claim-type="Currently amended] 11. The method of claim 10, wherein the R ³ substituent is benzamido, nicotinamido, isicotinamido, picolinamido or ureidophenyl group, wherein the R ³ substituent is halogen in its meta or para-position, Compound optionally substituted with a moiety selected from the group consisting of nitro, C ₁ -C ₈ hydrocarbyl, C ₁ -C ₇ hydrocarbyloxy, amino and amino-C ₂ -C ₄ -hydroxyalkyl groups .
[14" claim-type="Currently amended] 11. The compound of claim 10, wherein the R ² substituent is a methyl, hydroxymethyl, methoxymethyl or (N-morpholino) methyl group.
[15" claim-type="Currently amended] The compound according to claim 10, wherein the compound is an enantiomer having a stereoconfiguration as shown in the following formula (4).
(Formula 4)

[16" claim-type="Currently amended] A compound characterized by the following formula.

[17" claim-type="Currently amended] A compound characterized by the following formula.

[18" claim-type="Currently amended] A compound characterized by the following formula.

[19" claim-type="Currently amended] A compound characterized by the following formula.

[20" claim-type="Currently amended] A compound characterized by the following formula.

[21" claim-type="Currently amended] A compound characterized by the following formula.

[22" claim-type="Currently amended] A compound characterized by the following formula.

[23" claim-type="Currently amended] A compound characterized by the following formula.

[24" claim-type="Currently amended] A compound characterized by the following formula.

[25" claim-type="Currently amended] A compound characterized by the following formula.

[26" claim-type="Currently amended] A method for the treatment of a host mammal with a disease associated with pathological interstitial metalloprotease activity, the structure consisting of administering to a mammalian host having the disease in an amount effective to inhibit MMP enzymes. How to feature.

Where
R ² is hydrido, C ₁ -C ₄ hydrocarbyl, hydroxy-C ₁ -C ₄ hydrocarbyl, C ₁ -C ₄ hydrocarbyloxy, halo-C ₁ -C ₄ hydrocarbyl, C _1- C ₄ hydrocarbyloxymethyl, aminomethyl, (NC ₁ -C ₃ hydrocarbyl) aminomethyl, (N, N-di-C ₁ -C ₃ hydrocarbyl) aminomethyl, (N-morpholi No) methyl, (N-pyrrolidino) methyl, or (N-thiomorpholino) methyl;
R ¹ is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical directly bonded to the SO ₂ -group shown in the formula, which is approximately longer than the length of the hexyl group and shorter than the length of the acyl group Is a substituent having a length, and R ¹ is a 3 or 4 SO ₂ -bonded 1-position of an axial or 5-membered ring radical connected through the 4-position with the SO ₂ -bonded 1-position of the 6-membered ring radical Define a three-dimensional volume when rotated about the connecting axis through the center of the bond, and the widest width transverse to the axis of rotation is from about one furanyl ring to about two phenyl rings.
[27" claim-type="Currently amended] R ¹ is a 5- or 6-membered monocyclic cyclohydrocarbyl, heterocyclo, aryl or heteroaryl substituent, which is at its own 4-position in the 6-membered ring and at its 3- or 4 in the 5-membered ring In-position, one other monocyclic aryl or heteroaryl group, a C ₃ -C ₁₄ hydrocarbyl group, a C ₂ -C ₁₄ hydrocarbyloxy group, a phenoxy group, a thiophenoxy group, an alino group, 4-thio And a substituent substituted by itself with a substituent R ³ selected from the group consisting of a pyridyl group, a phenylazo group, a ureidophenyl group, a nicotinamido group, an isonicotinamido group, a picolinamido group and a benzamido group.
[28" claim-type="Currently amended] 27. The radical of claim 26, wherein the R ¹ radical is PhR ³ , wherein Ph is phenyl substituted at position 4 with R ³ , and R ³ is phenyl, phenoxy, anilino, thiophenoxy, phenylazo, benzami And a nicotinamido, isonicotinamido, picolineamido or ureidophenyl group.
[29" claim-type="Currently amended] The radical of claim 26, wherein the R ¹ radical is PhR ³ , wherein Ph is phenyl substituted with R ³ at position 4, wherein R ³ is halogen in a meta- or para-position or both positions, C ₁ -C ₉ hydrocarbyloxy group, C ₁ -C ₁₀ hydrocarbyl group, di-C ₁ -C ₉ hydrocarbylamino group, carboxyl C ₁ -C ₈ hydrocarbyl group, C ₁ -C ₄ hydrocarbyloxycarbonyl C Optionally substituted with a moiety selected from the group consisting of ₁ -C ₄ hydrocarbyl group, C ₁ -C ₄ hydrocarbyloxycarbonyl C ₁ -C ₄ hydrocarbyl group and carboxamido C ₁ -C ₈ hydrocarbyl group Or phenyl, phenoxy, anilino or thiophenoxy groups substituted at the methyl- and para-positions with two methyl groups or methylenedioxy groups.
[30" claim-type="Currently amended] 27. The radical of claim 26, wherein the R ¹ radical is PhR ³ , wherein Ph is phenyl substituted at position 4 with R ³ , and the R ³ substituent is benzamido, nicotinamido, isnicotinamido, picolinamido Or a ureidophenyl group, wherein the R ³ substituent is halogen, nitro, C ₁ -C ₈ hydrocarbyl, C ₁ -C ₇ hydrocarbyloxy, amino in its meta- or para-position or both positions And optionally a moiety selected from the group consisting of amino-C ₂ -C ₄ -hydroxyalkyl groups.
[31" claim-type="Currently amended] 27. The method of claim 26, wherein the R ¹ radical is longer than the length of the octyl group and shorter than the length of the stearyl group.
[32" claim-type="Currently amended] The method of claim 26, wherein the compound corresponds to the following Chemical Formula 2.
(Formula 2)

Where
R ² is also Hi give, C ₁ -C ₄ hydrocarbyl, hydroxy -C _1- C ₄ hydrocarbyl, C ₁ -C ₄ hydrocarbyl oxy, halo -C ₁ -C ₄ hydrocarbyl, C _1- C ₄ hydrocarbyloxymethyl, aminomethyl, (NC ₁ -C ₃ hydrocarbyl) aminomethyl, (N, N-di-C ₁ -C ₃ hydrocarbyl) aminomethyl, (N-morpholi No) methyl, (N-pyrrolidino) methyl, or (N-thiomorpholino) methyl:
Ph is phenyl substituted with R ³ at the 4-position, R ³ is phenyl, phenoxy, anilino, thiophenoxy, phenylazo, benzamido, nicotinamido, isnicotinamido, picolinamido Or a ureidophenyl group, wherein the PhR ³ group has a length longer than the length of the octyl group and shorter than the length of the stearyl group, and is connected through the SO ₂ -bonded 1-position and 4-position of the phenyl ring Ph. The three-dimensional volume is defined when rotated about an axis, and the widest width transverse to the axis of rotation is from about one furanyl ring to about two phenyl rings.
[33" claim-type="Currently amended] 27. The compound of claim 26, wherein R ³ is in its meta- or para-position or both positions a halogen, a C ₁ -C ₉ hydrocarbyloxy group, a C ₁ -C ₁₀ hydrocarbyl group, a di-C _1- C ₉ hydrocarbylamino group, carboxyl C ₁ -C ₈ hydrocarbyl group, C ₁ -C ₄ hydrocarbyloxycarbonyl C ₁ -C ₄ hydrocarbyl group, C ₁ -C ₄ hydrocarbyloxycarbonyl C Optionally substituted by itself with a moiety selected from the group consisting of _1- C ₈ hydrocarbyl groups and carboxamido C ₁ -C ₈ hydrocarbyl groups, or two methyl groups in the meta- and para-positions or methylenedioxy A phenyl, phenoxy, alinino or thiophenoxy group substituted with a group.
[34" claim-type="Currently amended] 27. The method of claim 26, wherein R ³ is an unsubstituted phenoxy or thiophenoxy group.
[35" claim-type="Currently amended] 27. The substituent of claim 26, wherein the R ³ substituent is a benzamido, nicotinamido, isnicotinamido, picolinamido or ureidophenyl group, and the R ³ substituent is halogen in its meta- or para-position. Optionally substituted with a moiety selected from the group consisting of nitro, C ₁ -C ₈ hydrocarbyl, C ₁ -C ₇ hydrocarbyloxy, amino and amino-C ₂ -C ₄ -hydroxyalkyl groups Way.
[36" claim-type="Currently amended] 27. The method of claim 26, wherein the R ² substituent is a methyl, hydroxymethyl, methoxymethyl or (N-morpholino) methyl group.
[37" claim-type="Currently amended] 27. The method of claim 26, wherein the compound is an enantiomer having the stereoconfiguration shown in Formula 3 or 4.
(Formula 3)

(Formula 4)

[38" claim-type="Currently amended] 27. The method of claim 26, wherein said compound is administered multiple times.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1997-03-04|Priority to US3518297P

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1997-03-04|Priority to US60/035,182

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1998-03-04|Application filed by 죤 에이치. 뷰센, 몬산토컴퍼니

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2000-12-26|Publication of KR20000075955A

优先权:

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申请号 | 申请日 | 专利标题

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US3518297P| true| 1997-03-04|1997-03-04|

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US60/035,182|1997-03-04|