WO2000040564A1 - N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase - Google Patents
N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase Download PDFInfo
- Publication number
- WO2000040564A1 WO2000040564A1 PCT/US1999/028339 US9928339W WO0040564A1 WO 2000040564 A1 WO2000040564 A1 WO 2000040564A1 US 9928339 W US9928339 W US 9928339W WO 0040564 A1 WO0040564 A1 WO 0040564A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- hydrogen
- alkyl
- benzyl
- integer
- Prior art date
Links
- GAWBIXQKUIBKRW-XBXARRHUSA-N C/C=C/c1c(CC=C)cccc1 Chemical compound C/C=C/c1c(CC=C)cccc1 GAWBIXQKUIBKRW-XBXARRHUSA-N 0.000 description 1
- ZUINRFZOGIHWBI-ULNSLHSMSA-N CC(C)C[C@@H](C(O)=O)N(Cc1ccccc1C[C@@H]1CNC([C@H](Cc2ccccc2)SC(c2ccccc2)=O)=O)C1=O Chemical compound CC(C)C[C@@H](C(O)=O)N(Cc1ccccc1C[C@@H]1CNC([C@H](Cc2ccccc2)SC(c2ccccc2)=O)=O)C1=O ZUINRFZOGIHWBI-ULNSLHSMSA-N 0.000 description 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N Cc1c[nH]cn1 Chemical compound Cc1c[nH]cn1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- MMPs matrix metalloproteinases
- the matrix metalloproteinases are a family of zinc containing endopeptidases which are capable of cleaving large biomolecules such as the collagens, proteoglycans and gelatins. Expression is upregulated by pro-inflammatory cytokines and/or growth factors.
- the MMP's are secreted as inactive zymogens which, upon activation, are subject to control by endogenous inhibitors, for example, tissue inhibitor of metalloproteinases (TIMP) and ⁇ -macroglobulin.
- TIMP tissue inhibitor of metalloproteinases
- MMPs Three groups of MMPs have been delineated: the collagenases which have triple helical interstitial collagen as a substrate, the gelatinases which are proteinases of denatured collagen and Type IV collagen, and the stromelysins which were originally characterized as proteoglycanases but have now been identified to have a broader proteolytic spectrum.
- specific collagenases include fibroblast coUagenase (MMP-1), neutrophil coUagenase (MMP-8), and coUagenase 3 (MMP-13).
- MMP-1 fibroblast coUagenase
- MMP-8 neutrophil coUagenase
- MMP-13 coUagenase 3
- gelatinases include 72 kDa gelatinase (gelatinase A; MMP-2) and 92 kDa gelatinase (gelatinase B; MMP-9).
- stromelysins examples include stromelysin 1 (MMP-3), stromelysin 2 (MMP-10) and matrilysin (MMP-7).
- MMPs which do not fit neatly into the above groups include metalloelastase (MMP-12), membrane-type MMP (MT- MMP or MMP- 14) and stromelysin 3 (MMP-1 1). Beckett, R.P. et al, supra.
- MMPs Over-expression and activation of MMPs have been linked with a wide range of diseases such as cancer; rheumatoid arthritis; osteoarthritis; chronic inflammatory disorders, such as emphysema and smoking-induced emphysema; cardiovascular disorders, such as atherosclerosis; corneal ulceration; dental diseases such as gingivitis and periodontal disease; and neurological disorders, such as multiple sclerosis.
- diseases such as cancer; rheumatoid arthritis; osteoarthritis; chronic inflammatory disorders, such as emphysema and smoking-induced emphysema
- cardiovascular disorders such as atherosclerosis
- corneal ulceration corneal ulceration
- dental diseases such as gingivitis and periodontal disease
- neurological disorders such as multiple sclerosis.
- invasive proximal gastric cells express the 72 kDa form of coUagenase Type IV, whereas the noninvasive cells do not. Schwartz, G.K. et
- Rat embryo cells transformed by the Ha-r ⁇ -s and v-myc oncogenes or by YLa-ras alone are metastatic in nude mice and release the 92 kDa gelatinase/collagenase (MMP-9). Bernhard, E.J. et al., Proc. Natl. Acad. Sci. 91, 4293- 4597 (1994).
- the plasma concentration of MMP-9 was significantly increased (P ⁇
- a range of MMPs can hydrolyse the membrane-bound precursor of the pro-inflammatory cytokine tumor necrosis factor ⁇ (TNF- ⁇ ).
- This pharmacological action is a probable contributor to the antiarthritic action of this class of compounds seen in animal models. Beckett, R.P. et al., supra.
- Stromelysin has been observed to degrade the ⁇ i-proteinase inhibitor which regulates the activity of enzymes such as elastase, excesses of which have been linked to chronic inflammatory disorders such as emphysema and chronic bronchitis. Beeley, N.R.A. et al., supra.; Wahl, R.C. et al., Annual Reports in Medicinal Chemistry 25, 177- 184 (1990).
- MMP- 12 is required for the development of smoking-induced emphysema in mice. Science, 277, 2002 (1997). Inhibition of the appropriate MMP may thus potentiate the inhibitory activity of endogenous inhibitors of this type.
- CoUagenase, stromelysin and gelatinase have been implicated in the destruction of the extracellular matrix of the cornea. This is thought to be an important mechanism of morbidity and visual loss in a number of ulcerative ocular diseases, particularly those following infection or chemical damage. Burns, F.R. et al., Invest. Opthalmol. and Visual Sci. 32, 1569-1575 (1989).
- the MMPs present in the eye during ulceration are derived either endogenously from infiltrating leucocytes or fibroblasts, or exogenously from microbes.
- CoUagenase and stromelysin activities have been identified in fibroblasts isolated from inflamed gingiva and the levels of enzyme have been correlated with the severity of the gingivitis observed.
- the present invention provides a method of inhibiting matrix metallo-proteinases (MMPs) in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of the N-carboxymethyl substituted benzolactams of formula (1):
- R and R' are independently selected from the group consisting of hydrogen and C ⁇ -C 6 alkyl or R and R' taken together with the nitrogen atom to which they are attached form a N-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
- R ⁇ is selected from the group consisting of hydrogen, C ⁇ -C 6 alkyl, -(CH 2 ) a -CO 2 R 5 ,
- R 5 is selected from the group consisting of hydrogen, C ⁇ -C 4 alkyl, and benzyl;
- Ari is a radical selected from the group consisting of
- R 6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C ⁇ _C 4 alkyl, hydroxy, and C ⁇ -C alkoxy;
- R 7 is selected from the group consisting of hydrogen, halogen, C]-C alkyl, and C].C 4 alkoxy;
- Ar 2 is a radical selected from the group consisting of
- R 2 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy C].C 4 alkyl, and C ⁇ -C alkoxy;
- R 3 is selected from the group consisting of C C 6 alkyl, -(CH 2 ) m -W, -(CH 2 ) P -Ar 3 , -(CH 2 ) k -CO 2 R 9 , -(CH 2 ) m -NR 8 SO 2 -Y,, and -(CH 2 ) m -Z-Q wherein m is an integer from 2 to 8; p is an integer from 0-10; k is an integer from 1 to 9; W is phthalimido; Ar 3 is selected from the group consisting of
- R 23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C]-C alkyl, and C ⁇ -C 4 alkoxy;
- R 8 - is hydrogen or C ⁇ -C 6 alkyl
- R 9 is hydrogen or C ⁇ -C 6 alkyl
- Yi is selected from the group consisting of hydrogen, -(CH 2 ),-Ar 4 , and -N(R 2 )? wherein j is 0 or 1 ;
- R 24 each time selected is independently hydrogen or C ⁇ -C 6 alkyl or are taken together with the nitrogen to which they are attached to form N- morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; Ar is
- R 25 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C ⁇ -C alkyl, and CpC 4 alkoxy;
- Z is selected from the group consisting of -0-, -NR 8 -, -C(O)NR 8 -, -NR 8 C(O)-, -NR 8 C(0)NH-, -NR 8 C(0)0 -, and -OC(O)NH-;
- R 8 is hydrogen or C ⁇ -C 6 alkyl
- Q is selected from the group consisting of hydrogen, -(CH 2 ) n -Y 2 , and -(CH 2 ) X Y 3 ; wherein n is an integer from 0 to 4; Y is selected from the group consisting of hydrogen, -(CH 2 ) h -Ar 5 and wherein
- AJ" 5 is selected from the group consisting of
- R 26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C ⁇ -C 4 alkyl, and CpC 4 alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6; R27 is hydrogen or C ⁇ -C 6 alkyl; x is an integer from 2 to 4;
- Y 3 is selected from the group consisting of -N(R 28 ) 2 , N-morpholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein
- R 28 each time taken is independently selected from the group consisting of hydrogen and C ⁇ -C 6 alkyl
- R- t is selected from the group consisting of hydrogen, -C(O)R ⁇ 0 , -C(O)-(CH 2 ) q -K and - S-G wherein
- Rio is selected from the group consisting of hydrogen, C ⁇ -C alkyl, phenyl, and benzyl; q is 0, 1, or 2;
- K is selected from the group consisting of
- V is selected from the group consisting of a bond, -CH 2 -, -0-, -S(O),-, - wherein r is 0, 1, or 2;
- R 21 is selected from the group consisting of hydrogen, C ⁇ -C alkyl, and benzyl;
- R 22 is selected from the group consisting of hydrogen, -CF 3 ,
- Ri 1 each time taken is independently selected from the group consisting of hydrogen, C ⁇ -C 4 alkyl, and benzyl;
- G is selected from the group consisting of
- w is an integer from 1 to 3;
- Ri 2 is selected from the group consisting of hydrogen, C ⁇ -C 6 alkyl,
- Ri 3 is selected from the group consisting of hydrogen, hydroxy, amino,
- Ci-C ⁇ alkyl N-methylamino, N,N-dimethylamino, -CO R ⁇ , and - OC(O)R 18 ;
- R ⁇ is hydrogen, -CH 2 O-C(O)C(CH 3 ) , C,-C 4 alkyl, benzyl, or diphenylm ethyl ;
- Ris is hydrogen, C ⁇ -C 6 alkyl or phenyl; Ri 4 is 1 or 2 substituents independently selected from the group consisting of hydrogen, C ⁇ -C 4 alkyl, C ⁇ _C alkoxy, or halogen; V] is selected from the group consisting of -O-, -S-, and -NH-; V 2 is selected from the group consisting of -N- and -CH-;
- V 3 is selected from the group consisting of a bond and -C(O)-;
- V 4 is selected from the group consisting of -O-, -S-, -NR ] 9 -, and - NC(O)R 20 -; wherein R 19 is hydrogen, C ⁇ -C alkyl, or benzyl;
- R 20 is hydrogen, -CF 3 , C ⁇ -C ⁇ 0 alkyl, or benzyl; Ris is selected from the group consisting of hydrogen, C ⁇ -C 6 alkyl and benzyl;
- R] 6 is selected from the group consisting of hydrogen and Cj-C alkyl; and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof.
- Novel N-carboxymethyl substituted benzolactams are encompassed by formula (1). Some of these novel compounds are described by of formula (la), below, which is encompassed by formula (1 ).
- the present invention provides novel N-carboxymethyl substituted benzolactams of formula (la): formula (la) wherein
- Aa is -NRR';
- R and R' are independently selected from the group consisting of hydrogen and C ⁇ -C 6 alkyl or R and R' taken together with the nitrogen atom to which they are attached form a N-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
- Ri is selected from the group consisting of hydrogen, C ⁇ -C 6 alkyl, -(CH 2 ) a -CO 2 R 5 ,
- R 5 is selected from the group consisting of hydrogen, C ⁇ _C alkyl, and benzyl;
- Ari is a radical selected from the group consisting of
- R 6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C ⁇ _C alkyl, hydroxy, and C ⁇ .C 4 alkoxy;
- R 7 is selected from the group consisting of hydrogen, halogen, C ⁇ _C 4 alkyl, and C]-C alkoxy;
- Ar 2 is a radical selected from the group consisting of
- R 2 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy C ⁇ -C 4 alkyl, and C1-C4 alkoxy;
- R 3 is selected from the group consisting of C ⁇ -C 6 alkyl, -(CH ) m -W, -(CH 2 ) P -Ar 3 , -(CH 2 ) k -CO 2 R 9 , -(CH 2 ) m -NR 8 'SO 2 -Y,, and -(CH 2 ) m -Z-Q wherein m is an integer from 2 to 8; p is an integer from 0-10; k is an integer from 1 to 9;
- W is phthalimido
- Ar is selected from the group consisting of
- R 23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, CpC alkyl, and CpC 4 alkoxy;
- R 8 - is hydrogen or C ⁇ -C 6 alkyl
- R 9 is hydrogen or C ⁇ -C 6 alkyl
- Yi is selected from the group consisting of hydrogen, -(CH 2 )_,-Ar , and -N(R 2 ) 2 wherein j is 0 or 1 ;
- R 2 each time selected is independently hydrogen or C ⁇ -C 6 alkyl or are taken together with the nitrogen to which they are attached to form N- morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
- Ar is wherein
- R 25 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C ⁇ -C 4 alkyl, and C ⁇ -C 4 alkoxy;
- Z is selected from the group consisting of -0-, -NR 8 -, -C(O)NR 8 -, -NR 8 C(O)-, -NR 8 C(O)NH-, -NR 8 C(O)O -, and -OC(0)NH-;
- R 8 is hydrogen or C ⁇ -C 6 alkyl
- Q is selected from the group consisting of hydrogen, -(CH 2 ) n -Y 2 , and -(CH 2 ) Y 3 ; wherein n is an integer from 0 to 4;
- Y 2 is selected from the group consisting of hydrogen, -(CH 2 ) h -Ar 5 and -(CH 2 ),-C(O)OR 2 7 wherein
- Ar 5 is selected from the group consisting of
- R 26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C ⁇ -C 4 alkyl, and C C alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6; R 27 is hydrogen or C ⁇ -C 6 alkyl; x is an integer from 2 to 4;
- Y 3 is selected from the group consisting of -N(R 28 ) 2 , N-morpholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein R 2 8 each time taken is independently selected from the group consisting of hydrogen and C ⁇ -C 6 alkyl;
- R 4 is selected from the group consisting of hydrogen, -C(O)R ⁇ o, -C(O)-(CH 2 ) q -K and - S-G wherein
- Rio is selected from the group consisting of hydrogen, C ⁇ -C 4 alkyl, phenyl, and benzyl; q is 0, 1, or 2;
- K is selected from the group consisting of
- V is selected from the group consisting of a bond, -CH 2 -, -0-, -S(0) , -
- NR 2 ,-, and -NC(0)R 22 wherein r is 0, 1 , or 2;
- R 21 is selected from the group consisting of hydrogen, C 1 -C4 alkyl, and benzyl;
- R 22 is selected from the group consisting of hydrogen, -CF 3 , Ci-
- Ri 1 each time taken is independently selected from the group consisting of hydrogen, C 1 -C4 alkyl, and benzyl;
- G is selected from the group consisting of
- w is an integer from 1 to 3;
- R 12 is selected from the group consisting of hydrogen, C ⁇ -C 6 alkyl,
- R 13 is selected from the group consisting of hydrogen, hydroxy, amino, Ci-C ⁇ alkyl, N-methylamino, N,N-dimethylamino, -CO 2 Ri 7 , and - OC(O)R, 8 ;
- R,7 is hydrogen, -CH 2 0-C(O)C(CH 3 ) , C,-C 4 alkyl, benzyl, or diphenylmethyl;
- Ri 8 is hydrogen, C ⁇ -C 6 alkyl or phenyl; R ]4 is 1 or 2 substituents independently selected from the group
- Vi is selected from the group consisting of -0-, -S-, and -NH-;
- V 2 is selected from the group consisting of -N- and -CH-;
- V 3 is selected from the group consisting of a bond and -C(O)-;
- V is selected from the group consisting of -0-, -S-, -NR 19 -, and -
- R 19 is hydrogen, C
- R20 is hydrogen, -CF3, Ci-Cio alkyl, or benzyl
- R 15 is selected from the group consisting of hydrogen, C ⁇ -C 6 alkyl and benzyl
- Ri 6 is selected from the group consisting of hydrogen and C ⁇ -C alkyl; and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof.
- the present invention provides a composition comprising an assayable amount of a compound of formula (1 a) in admixture or otherwise in association with an inert carrier.
- the present invention also provides a pharmaceutical composition comprising an effective matrix metallo-proteinases inhibitory amount of a compound of formula (la) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.
- the compounds of formula (1) exist as stereoisomers. Specifically, it is recognized that they exist as stereoisomers at the point of attachment of the substituents Rj, R , and -SR- , R ] 2 , and -NHR 15 and at the point of attachment of the group -NHC(O)CH(R 3 )(SR ) to the benzolactam.
- the compounds, whether of formula (1), starting materials, or intermediates follow either the (+)- and (-)- designation for optical rotation, the (D)- and (L)- designation of relative stereochemistry, or the Cahn-Ingold-Prelog designation of (R)- and (S)- for the stereochemistry of at specific positions in the compounds represented by formula (1) and intermediates thereof.
- Any reference in this application to one of the compounds of the formula (1) is meant to encompass either specific stereoisomers or a mixture of stereoisomers.
- the specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials which are well known in the art.
- the specific stereoisomers of amino acid starting materials are commercially available or can be prepared by stereospecific synthesis as is well known in the art or analogously known in the art, such as D. A. Evans, et al. J. Am. Chem. Soc, 1 12, 401 1-4030 (1990); S. Ikegami et al. Tetrahedron, 44, 5333-5342 (1988); W.Oppolzer et al. Tet. Lets. 30, 6009-6010 (1989); Synthesis of Optically Active ⁇ - Amino-Acids, R. M.
- stereoisomers of either starting materials or products can be resolved and recovered by techniques known in the art, such as chromatography on chiral stationary phases, enzymatic resolution, or fractional recrystallization of addition salts formed by reagents used for that purpose.
- Useful methods of resolving and recovering specific stereoisomers are known in the art and described in Stereochemistry of Organic Compounds, E. L. Eliel and S. H. Wilen, Wiley (1994) and Enantiomers, Racemates, and Resolutions, J. Jacques, A. Collet, and S. H. Wilen, Wiley (1981).
- halogen refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom
- C ⁇ -C 6 alkyl refers to a branched or straight chained alkyl radical containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, etc.;
- C ⁇ -C 4 alkyl refers to a saturated straight or branched chain alkyl group containing from 1-4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, and t-butyl;
- Ci-Cio alkyl refers to a branched or straight chained alkyl radical containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.;
- d-C 4 alkoxy refers to a straight or branched alkoxy group containing from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, etc.; f) the designation " ⁇ " refers to a bond for which the stereochemistry is not designated;
- NR 8 C(O)0-, and -OC(O)NH- refer to the functionalities represented, respectively, by the following formulae showing the attachment of the group (Q): these designations are referred to hereinafter as amido, amide, urea, N-carbamoyl, and O-carbamoyl, respectively;
- pharmaceutically acceptable acid addition salts is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by formula (1) or any of its intermediates.
- inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate.
- organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids.
- Such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2- phenoxybenzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid.
- Such salts can exist in either a hydrated or substantially anhydrous form.
- the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.
- compositions represented by formula (1) are intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by formula (1) or any of its intermediates.
- Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline.
- Ri is selected from the group consisting of CrC 6 alkyl and -(CH 2 ) d Ar ⁇ are preferred;
- Ri is -(CH2)dAr ⁇ and Ari is phenyl or substituted phenyl are more preferred;
- Examples of compounds encompassed by formula (1) and (la) of the present invention include the following. It is understood that the examples encompass all of the isomers of the compound and mixtures thereof. This list is meant to be representative only and is not intended to limit the scope of the invention in any way: 2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-l ,3,4,5- tetrahydro-benzo[c]azepin-2- yl)-4-methyl-valeric acid, (S)-N- l-(2-methylpropyl)-2-(thio)-ethylamine, disulfide; 2- (4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-l,3,4,5- tetrahydro-benzo[c]azepin-2-yl)- 4-methyl-valeric acid, (R)-l-( 2-methylpropyl)-2-(thio)-ethylamine,
- amino acid refers to naturally occurring amino acids as well as non-naturally occurring amino acids having substituents encompassed by Ri and R 2 as described above.
- the naturally occurring amino acids included are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, histidine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, ornithine, and lysine.
- Non-naturally occurring amino acids within the term "amino acid,” include without limitation, the D-isomers of the naturally occurring amino acids, norleucine, norvaline, alloisoleucine, t-butylglycine, methionine sulfoxide, and methionine sulfone.
- amino acid include without limitation phenylalanines, phenylglycines, homophenylalanines, 3-phenylpropylglycines, 4-phenylbutylglycines; each including those substituted by R 6 and R 6 - as described above; and 1-naphthylalanines and 2- naphthylalanines; including those substituted by R 7 and R 7 - as described above.
- the compounds of formula (1) can be prepared by utilizing techniques and procedures well known and appreciated by one of ordinary skill in the art. To illustrate, general synthetic schemes for preparing starting material, intermediates, and the compounds of formula (1) are set forth below. In the reaction schemes below, the reagents and starting materials are readily available to one of ordinary skill in the art and all substituents are as previously defined unless otherwise indicated.
- step 1 a compound of formula (3) is coupled with a with an appropriate acid derivative of formula (2) to give a compound of formula (4).
- Such coupling reactions are well known in the art.
- An appropriate compound of formula (2) is one in which R 3 - is R 3 as desired in the final product of formula (1) or gives rise after deprotection to R 3 as desired in the final product of formula (1) and Y is a protected thio substituent or Y may be a protected hydroxy substituent or bromo which gives rise upon selective deprotection and displacement or displacement and further deprotection and/or elaboration, if required, to -SR- 4 as desired in the final product of formula (1).
- an appropriate compound of formula (2) may also be one in which R 3 - gives rise to R 3 - which, upon further reaction, gives rise R 3 as desired in the final product of formula (1 ), as described in Reaction Scheme B, and Y is a protected thio substituent.
- an appropriate compound of formula (2) may also be one in which the stereochemistry at the R 3 - and Y bearing carbon is as desired in the final product of formula (1) or gives rise after displacement to the stereochemistry as desired at that carbon in the final product of formula (1).
- protecting groups are within the ability of those skilled in the art and will depend upon compound of formula (2) to be protected, the presence of other protected amino acid residues, other protecting groups, and the nature of the particular R 3 and/or R group(s) ultimately being introduced.
- Compounds of formula (2) in which Y is bromo and protected thio are commercially available or can be prepared utilizing materials, techniques, and procedures well known and appreciated by one of ordinary skill in the art or described herein. See PCT Application WO 96/11209, published 18 April 1996.
- Examples commercially available compounds of formula (2) in which Y is bromo include 2-bromopropionic acid, 2-bromobutyric acid, 2-bromovaleric acid, 2-bromohexanoic acid, 6-(benzoylamino)-2-bromohexanoic acid, 2-bromoheptanoic acid, 2-bromooctanoic acid, 2-bromo-3-methylbutyric acid, 2- bromoisocaproic acid, 2-bromo-3-(5-imidazoyl)proionic acid, (R)-(+)-2-bromopropionic acid, (S)-(-)-2-bromopropionic acid.
- a compound of formula (3) is contacted in a coupling reaction with a compound of formula (2).
- the compound of formula (2) may be converted to an activated intermediate; such as and acid chloride, an anhydride; a mixed anhydride of aliphatic carboxylic acid, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, 2-ethylbutyric acid, trichloroacetic acid, trifluoroacetic acid, and the like; of aromatic carboxylic acids, such as benzoic acid and the like; of an activated ester, such as phenol ester, p-nitrophenol ester, 2,4- dinitrophenol ester, pentafluorophenol ester, pentachlorophenol ester, N- hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1 -hydroxy- lH-benztriazole ester, 0-azabenztriazoyl-N,N,N',N'-
- the reaction is carried out in a suitable solvent, such as dichloromethane, chloroform, tetrahydrofuran, or dimefhylformafide.
- a suitable solvent such as dichloromethane, chloroform, tetrahydrofuran, or dimefhylformafide.
- the reaction generally is carried out at temperaures of from about -20°C to the refluxing temperature of the solvent and generally requires 1 to 48 hours.
- the product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, chromatography, and recrystallization.
- step 2 a compound of formula (4) in which Y is hydroxy or bromo gives rise to a compound of formula (5) in which Y is protected thio.
- a compound of formula (4) in which Y is hydroxy (obtained from protected hydroxy compounds of formula (2)) undergoes a displacement reaction with an appropriate thio introducing reagent by the method of Mitsunobu to give a compound of formula (5) in which Y is a protected thio substituent.
- a compound of formula (4) in which Y is hydroxy reacts with thioacetic acid or thiobenzoic acid, triphenylphosphine, and diethylazodicarboxylate in a suitable aprotic solvent, such as tetrahydrofuran to give a compound of formula (5) in which Y is thioacetyl or thiobenzoyl.
- a suitable aprotic solvent such as tetrahydrofuran
- a solution of p-methoxybenzylmercaptan in a suitable organic solvent such as dimethylformamide is degassed and treated with a suitable base such as sodium hydride. After about 1 to 2 hours, a solution of a compound of formula (4) in which Y is bromo is added.
- the reaction may benefit from the addition of a suitable catalyst, such as tetra-n-butylammonium iodide.
- the reaction mixture is carried out for 1 to 25 hours at temperatures ranging from 0°C to about 100°C.
- the product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, lyophihzation, chromatography, and recrystallization.
- step 3 a compound of formula (5) in which Y is protected thio undergoes selective deprotection to give a compound of formula (6).
- Protected thio substituents include thioesters, such as thioacetyl or thiobenzoyl, thioethers, such as thiobenzyl, thio-4-methoxybenzyl, thiotriphenylmethyl, or thio-t- butyl, or unsymmetrical sulfides, such as dithioethyl or dithio-t-butyl.
- thioesters such as thioacetyl or thiobenzoyl
- thioethers such as thiobenzyl, thio-4-methoxybenzyl, thiotriphenylmethyl, or thio-t- butyl
- unsymmetrical sulfides such as dithioethyl or dithio-t-butyl.
- step 4 a compound of formula (4) in which Y is protected thio is selectively deprotected to give a compound of formula (6), as described above, in Reaction Scheme A, step 3.
- step 5 a compound of formula (6) undergoes a undergoes modification reaction to give a compound of formula (7).
- modification reactions include, thiol esterification and disulfide formation.
- a compound of formula (6) is contacted with about an equimolar amount of an appropriate acid, such as HO-C(O)R ⁇ o or HO-C(O)-(CH 2 ) q -X in the presence of a suitable coupling agent to give a compound of formula (6) in which ⁇ is -C(O)R ⁇ o or -C(O)-(CH 2 ) q -X.
- an appropriate acid such as HO-C(O)R ⁇ o or HO-C(O)-(CH 2 ) q -X
- the reaction is carried out in the presence of a coupling agent such as 2-fluoro-l-methylpyridinium p-toluenesulfate, (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), carbonyldiimidazole, (l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline, or diethylcyanophosphonate in a suitable aprotic solvent such as methylene chloride.
- a suitable aprotic solvent such as methylene chloride.
- the reaction is generally carried out at temperature of between -20°C and the boiling point of the solvent. Generally, the reaction requires 1 to 24 hours.
- the product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, lyophihzation, chromatography, and recrystallization.
- An appropriate compound of formula (8) is one which gives G as desired in the final product of formula (1) or gives rise upon deprotection to G as is desired in the final product of formula (1).
- the compound of formula (8) may have stereochemistry as desired in the final product of formula (1).
- the reaction is carried out in a suitable solvent, such as ethanol, methanol, dichloromethane, or mixtures of ethanol or methanol and dichloromethane.
- the solvent is degassed by passing a stream of nitrogen gas through it for 15 minutes before the reaction is carried out.
- the reaction is carried out using from 1.0 to 4.0 molar equivalents of an appropriate compound of formula (8).
- the reaction is carried out at temperatures of from 0°C to the re fluxing temperature of the solvent, with a temperature of 10°C to 30°C being preferred.
- the reaction generally requires from 1 to 48 hours.
- the product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization.
- step 6 a compound of formula (4) in which Y is hydroxy or bromo is displaced by an appropriate thiol, HSR ⁇ , by the methods described in Reaction Scheme A, step 2, to give a compound of formula (7).
- an appropriate thiol HSR is one which gives ⁇ as desired in the final product of formula (1 ) or gives rise to R as desired in the final product of formula (1 ).
- step 6 a compound of formula (4) in which Y is bromo can be displaced by an appropriate thio ester, Ph 3 S-C(O)-(CH 2 ) q -X by techniques well known and appreciated in the art, as disclosed in U.S. Pat. No. 5,424,425, issued Jun. 13, 1995.
- a compound of formula (5), (6), or (7) is optionally deprotected to give a compound of formula (1).
- Such deprotection reactions are well known appreciated in the art and may include selective deprotections of protecting groups on A', R l 5 R 2 , R 3 , and R , as required to give the desired compound of formula
- step 1 an appropriate compound of formula (5) is deprotected, hydrolyzed, or reduced to give a compound of formula (9).
- step 1 an appropriate compound of formula (5) is one in which A' is A or gives rise to A upon deprotection and modification, if desired, in the final product of formula (1) and R ⁇ , and R 2 are as desired in the final product of formula (1) or give rise upon deprotection to Ri and/or R 2 as desired in the final product of formula (1).
- step 1 an appropriate compound of formula (5) is one in which R 3 - gives rise to a compound of formula (9) in which R 3 - is R 3 as desired in the final product of formula (1) or undergoes further derivitization (step 2) to give a compound of formula (10) in which R 3 is as desired in the final product of formula (1).
- step 1 an appropriate compound of formula (5) is one in which Y is -SR as desired in the final compound of formula (1) or Y gives rise upon deprotection (step 3) and further functionalization (step 4) or deprotection (step 5) to give -SR as desired in the final product of formula (1).
- a compound of formula (5) in which R 3 - is - (CH 2 ) m -W (phthalimido group) is contacted with a molar excess of hydrazine monohydrate to give a compound of formula (9) in which R 3 - is -(CH 2 ) m -NHR 8 in which R 8 is hydrogen.
- the reaction is typically carried out in a protic organic solvent, such as methanol or ethanol.
- the reaction is generally carried out at room temperature for a period of time ranging from 5-24 hours.
- the product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization.
- the reaction is generally carried out at temperatures from about 0°C to about room temperature for a period of time ranging from 1-10 hours.
- the product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization.
- a compound of formula (5) in which R 3 - is -(CH 2 ) m -C(O)OPg 3 and Pg3 is methyl or ethyl is contacted with about 1 to 2 molar equivalents of lithium hydroxide, sodium hydroxide, or potassium hydroxide to give a compound of formula (9) in which R 3 - is -(CH2) m -CO 2 H.
- the reaction is carried out in a suitable solvent, such as methanol, ethanol methanol/water mixtures, ethanol/water mixtures, or tetrahydrofuran/water mixtures and generally requires 1 to 24 hours.
- the reaction is carried out at temperatures of from about 0°C to the refluxing temperature of the solvent.
- the resulting acid is isolated and purified by techniques well known in the art, such as acidification, extraction, evaporation, and precipitation and can be purified by trituration, precipitation, chromatography, and recrystallization.
- a compound of formula (5) in which Ry is -(CH 2 ) m - ⁇ -C ⁇ 2Pg3 in which Pg is methyl or ethyl is contacted with a suitable reducing agent, such as lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, 9-borabicyclo(3.3.1)nonane, preferably lithium borohydride to provide a compound of formula (9) in which R 3 - is -(CH 2 ) n .-i-CH 2 OH.
- a suitable solvent such as dichloromethane, tetrahydrofuran, or toluene, with tetrahydrofuran being preferred.
- the reaction is carried out at a temperature of from about -30°C to about 50°C and generally requires from 2 to 12 hours.
- the product can be isolated by quenching, extraction, evaporation, and precipitation and can be purified by trituration, chromatography, and recrystallization.
- step 2 a compound of formula (9) undergoes a derivitization reaction to give a compound of formula (10) in which R 3 is as desired in the final product of formula (1).
- derivitization reactions include hydrolysis of esters and ester formations as are well known in the art, ether formation, amine alkylation, formation of amides, urea formation, carbamate formation, and formation of sulfonamide.
- a compound of formula (9) in which R 3 - is -(CH 2 ) m - ⁇ -CH 2 ⁇ H is contacted with 1 to 10 molar equivalents of a suitable akylating agent to give a compound of formula (10) in which R 3 is -(CH 2 ) m -Z-Q in which Z is -0-.
- a suitable alkylating agent is one which transfers Q or protected Q as desired in the final product of formula (1), such as benzyl bromide, benzyl chloride, substituted benzyl bromide, substituted benzyl chloride, ethyl bromoacetate, t-butyl bromoaceate, ethyl 3- chloropropionate, ethyl 3-bromopropionate, ethyl 5-bromovalerate, ethyl 4- bromobutyrate, 3-chloropropionamide, 2-bromoethylbenzene, substituted 2- bromoethylbenzene, l-chloro-3-phenylpropane, 1 -bromo-4-phenylbutane, and the like, or nitrogen mustards, including 2-dimethylaminoethyl chloride, 2-diethylaminoethyl chlo ⁇ de, and 3-d ⁇ methylammopropyl chloride
- an ether formation can also be earned out by a procedure similar to the one above using a compound of formula (9) m which R 3 is -(CH2) m ⁇ -CH 2 OH m which the hydroxy group is first converted to a leaving group, such as chloro, bromo, or mesylate and a suitable alcohol which transfers Q or protected Q as desired in the final product of formula (1), such as benzyl alcohol, substituted benzyl alcohol, phenol, substituted phenol, and the like
- a leaving group such as chloro, bromo, and mesylate
- a compound of formula (9) in which R 3 is -(CH 2 ) m -NHR 8 is contacted with 1 to 10 molar equivalents of a suitable akylating agent to give a compound of formula (10) in which R 3 is -(CH 2 ) m -Z-Q in which Z is -NR -
- the reaction may be carried out after protection of the amine function of R 3 in which R 8 is hydrogen by a suitable protecting group, such as benzyl or t-Boc
- a suitable alkylating agent is one as described above for the ether formation and also includes alkylhahdes, such as methyl iodide, methyl bromide, ethyl bromide, propyl bromide, propyl chloride, butyl bromide, butyl chloride, and the like
- the reaction is carried out in a suitable solvent, such as methanol, ethanol, dimethylformamide, or pyri
- a suitable aldehyde is one which transfers Q or protected Q as desired in the final product of formula (1 ), such as benzaldehyde and substituted benzaldehydes.
- the reaction is carried out in a suitable solvent, such as methanol, ethanol, tetrahydrofuran, or mixtures of methanol or ethanol and tetrahydrofuran.
- the reaction may be carried out in the presence of a drying agent, such as sodium sulfate or molecular sieves.
- the reaction is carried out in the presence of from 1.0 to 6.0 molar equivalents of a suitable reducing agent, such as, sodium borohydride or sodium cyanoborohydride with sodium cyanoborohydride being preferred.
- the reaction is generally carried out at temperatures of from 0° C to the refluxing temperature of the solvent. Generally, the reactions require 1 to 72 hours.
- the product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization.
- a compound of formula (9) in which R 3 - is is -(CH 2 ) m -C ⁇ 2 H is contacted with a suitable amine in an amide formation to give a compound of formula (10) in which R 3 is -(CH ) m -Z-Q in which Z is amido.
- amide formation reactions using carboxy activation or suitable coupling agents are well known in the art and described above.
- a suitable amine, HNR 8 Q gives rise to R 8 and Q as desired in the final product of formula (1), such as methylamine, ethylamine, propylamine, butylamine, N-methyl benzylamine, benzyl ⁇ -alanine, 4-(3- aminopropyl)morpholine, and the like.
- a compound of formula (9) in which R 3 - is is -(CH 2 ) m -NHR 8 is contacted with a suitable carboxylic acid in an amide formation to give a compound of formula (10) in which R 3 is -(CH 2 ) m -Z-Q in which Z is amide.
- Suitable carboxylic acids, QC(O)-OH are ones give rise to Q as desired in the final product of formula (1), such as benzoic acid, substituted benzoic acids, phenyl acetic acids, substituted phenylacetic acids, mono-t- butyl malonate, and the like.
- An appropriate isocyanate is one which gives rise to Q as desired in the final product, such as phenyl isocyanate, substituted phenyl isocyanate, napthyl isocyanate, ethyl isocyanatoacetate, and the like.
- the reaction is carried out by adding an equivalent of, or a slight molar excess of, an appropriate isocyanate is added to a solution of a compound of formula (9) in which R 3 - is -(CH 2 ) m -NHR 8 in a suitable solvent, such as diethyl ether, benzene, or toluene.
- a suitable solvent such as diethyl ether, benzene, or toluene.
- the reaction is carried out at temperature of from about 0°C to the refluxing temperature of the solvent and require about 1-24 hours.
- the product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
- chloro formates examples include benzyl chloroformate, naphthyl chloroformate, phenyl chloroformate, and substituted phenyl chloroformates, such as 4-chlorophenyl chloroformate, 4-methylphenyl chloroformate, 4-bromophenyl chloroformate, 4- fluorophenyl chloroformate, 4-methoxyphenyl chloroformate and the like.
- the reaction is carried out by adding an equivalent of, or a slight molar excess of, an appropriate chloro formate to a solution of a compound of formula (9) in which R 3 - is -(CH 2 ) n ⁇ - NHRs in a suitable solvent, such as toluene, tetrahydrofuran, dimethylformamide, dichloromethane, pyridine, or chloroform.
- a suitable solvent such as toluene, tetrahydrofuran, dimethylformamide, dichloromethane, pyridine, or chloroform.
- a suitable base such as triethylamine, sodium carbonate, potassium bicarbonate, pyridine or N,N-diisopropylethylamine.
- the reaction is carried out at a temperature of from -70°C to the refluxing temperature of the solvent and generally requires from 30 minutes to 24 hours.
- the product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization.
- -(CH 2 ) m -i-CH 2 OH is contacted with an appropriate isocyanate, as defined above for urea formation, to give a compound of formula (10) in which R 3 is -(CH 2 ) m -Z-Q in which Z is O-carbamoyl.
- the reaction is carried out in a suitable solvent, such as diethyl ether, tetrahydrofuran, dimethylformamide, or acetonitrile.
- the reaction may be facilitated by the use of catalytic amount of a suitable base, such as sodium hydride, potassium hydride, or potassium t-butoxide.
- the reaction is generally carried out at temperatures of from -20°C to room temperature and require from about 1-24 hours.
- the product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization.
- a compound of formula (9) in which R 3 - is -(CH 2 ) m -NHR 8 is contacted with an appropriate sulfonamide forming reagent.
- An appropriate sulfonamide forming reagent such as a sulfonyl chloride, Y]S(O) 2 Cl, or sulfonyl anhydride, Y ⁇ (O) 2 S-O-S(O) 2 Yi, is one which gives rise to Y, as desired in the final product.
- sulfonamide forming reagents examples include, benzenesulfonyl chloride, dansyl chloride, N-morpholinylsulfonyl chloride, N-piperidinylsulfonyl chloride, 2,4,5-trichlorobenzenesulfonyl chloride, 2,5-dichlorobenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride, 4- bromobenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4- chlorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 4-t- butylbenzenesulfonyl chloride, p-toluenesulfonyl chloride, 2,3,4- trichlorobenzenesulfonyl
- the reaction is carried out in a suitable solvent, such as tetrahydrofuran, dichloromethane, pyridine, or chloroform and in the presence of an excess of a suitable base, such as triethylamine, sodium carbonate, pyridine, or N,N-diisopropylethylamine.
- a suitable solvent such as tetrahydrofuran, dichloromethane, pyridine, or chloroform
- a suitable base such as triethylamine, sodium carbonate, pyridine, or N,N-diisopropylethylamine.
- the reaction is carried out at a temperature of from -50°C to the refluxing temperature of the solvent.
- the reaction generally requires from 30 minutes to 24 hours.
- the product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization.
- step 3 a compound of formula (10) in which R 3 is as desired in the final product of formula (1) undergoes a selective thiol deprotection to give a compound of formula (11).
- a selective thiol deprotections using suitable protecting groups are well known and appreciated in the art as discussed in Reaction Scheme A, step 4, above.
- step 4 a compound of formula (11) undergoes a modification reaction as described in Reaction Scheme A, step 5, above, to give a compound of formula (7).
- an appropriate ⁇ -amino carboxylic acid of formula (20) is deaminobrominated to give a compound of formula (2) in which Y is bromo.
- An appropriate ⁇ -amino carboxylic acid of formula (20), and protected forms thereof, is one which is one in which R 3 is as described above in Reaction Scheme A, step 8, above.
- ⁇ -amino carboxylic acid of formula (20) may also be one in which the stereochemistry at the R 3 bearing carbon gives rise after displacement to the stereochemistry as desired at that carbon in the final product of formula (1).
- Such appropriate ⁇ -amino carboxylic acid of formula (20) are commercially available or may be readily prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art.
- the product can be isolated and purified by techniques well known in the art, such as acidification, extraction, evaporation, chromatography, and recrystallization to give the compound of formula (1 l)in which Y is bromo.
- the product can be isolated and purified by techniques well known and appreciated in the art, such as acidification, basification, filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
- an appropriate carboxylic acid of formula (21) is brominated to give compound of formula (2) in which Y is bromo.
- An appropriate carboxylic acid of formula (21), and protected forms thereof, is one which is one in which R 3 - is as defined in Reaction Scheme A, step 8, above.
- carboxylic acid of formula (21) may also be one in which the stereochemistry at the R 3 - bearing carbon gives rise after displacement to the stereochemistry as desired at that carbon in the final product of formula (1).
- a mixture of a carboxylic acid of formula (21) and dry red phosphorous are treated dropwise with bromine at temperature ranging from about -20° to about 10°C.
- the reaction mixture is then warmed to room temperature and then heated to about 80°C for about 2-5 hours.
- the reaction mixture is then cooled to room temperature, poured into water containing sodium bisulfite, and neutralized using solid sodium carbonate.
- the aqueous layer is extracted and acidified with a suitable acid, such as concentrated hydrochloric acid.
- the precipitate is collected by filtration and dried to give the compound of formula (2) in which Y is bromo.
- the product can be isolated and purified by techniques well known and appreciated in the art, such as acidification, basification, filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
- an appropriate ⁇ -amino carboxylic acid of formula (22) is converted to an compound of formula (21) in which R 3 - is W-(CH ) m -.
- An appropriate ⁇ -amino carboxylic acid of formula (2) is one in which m is as desired in the final product of formula (1) and are readily available in the art.
- the reaction is carried out in a suitable polar solvent, such as water, ethanol, diethyl ether, tetrahydrofuran, or a water/ethanol solvent mixture using a suitable base, such as sodium carbonate and N-carbethoxyphthalimide.
- the reaction mixture is typically stirred at about ambient temperature for 1-5 hours.
- step 1 an appropriate ⁇ , ⁇ -diamino acid of formula (23) undergoes a selective N- ⁇ -protection to give an N- ⁇ -protected- ⁇ -diamino acid of formula (24).
- An appropriate ⁇ , ⁇ -diamino acid of formula (23) is one in which m is as desired in the final product of fomiula (1).
- a selective N- ⁇ -protection of a suitable ⁇ , ⁇ -diamino acid is accomplished by masking the ⁇ -amino group by formation of a benzyhdene imine.
- the benzyhdene imine is formed by dissolving L- lysine monohydrochloride in lithium hydroxide and cooling the solution to a temperature ranging from about 0° to 10°C. Freshly distilled benzaldehyde is then added and the solution is shaken. N- ⁇ -benzylidene-L-lysine is recovered by filtration and evaporation.
- N- ⁇ -benzylidene-L-lysine undergoes protection, such as the introduction of a Cbz or t-Boc group, followed by hydrolytic cleavage of the imine in situ to give N- ⁇ -benzyloxy-carbonyl-L-lysine.
- N- ⁇ -benzylidene-L-lysine is added to a mixture of sodium hydroxide and ethanol, cooled to a temperature of from about -5° to about -25°C. Then, precooled solutions of benzyloxycarbonyl chloride in a solvent, such as ethanol, is added to the reaction mixture.
- the temperature is maintained in a range of from about -10° to about -25°C during the course of addition, and may allowed to rise afterwards.
- the reaction mixture is then acidified using a suitable acid, such as precooled hydrochloric acid, and N- ⁇ -benzyloxycarbonyl-L-lysine, which corresponds to formula (24) where m is 4, is recovered by filtration evaporate and recrystallization.
- step 2 N- ⁇ -benzyloxycarbonyl-L-lysine or other compounds of formula (24) is converted to ⁇ -phthalimido- ⁇ -benzyloxycarbonyl-L- lysine or other ⁇ -phthalimido- ⁇ -aminoprotected carboxylic acid of formula (25) by the method described in Reaction Scheme D.1 , above.
- step 3 the ⁇ -phthalimido- ⁇ -aminoprotected carboxylic acid of formula (25) is deprotected to give compound of formula (20) in which R 3 - is W-
- ⁇ -phthalimido- ⁇ -benzyloxycarbonyl-L-lysine is contacted with hydrogen in the presence of a hydrogenation catalyst, such as 10% palladium/carbon.
- the reactants are typically contacted in a suitable solvent mixture such as ethanol, methanol, water, ethanol/water mixtures, or methanol/water mixtures.
- a suitable solvent mixture such as ethanol, methanol, water, ethanol/water mixtures, or methanol/water mixtures.
- the reactants are typically shaken under a hydrogen atmosphere of 35-45 psi at room temperature for a period of time ranging from 5-24 hours.
- the product is typically recovered by filtration and evaporation of the solvent.
- step 1 a bromoacetate of formula (26) is contacted with an appropriate thiol to give a protected acetic acid ester of formula (27).
- Pg 5 is a protecting group, such as methyl, ethyl, t-butyl, and benzyl.
- An appropriate thiol is one which gives rise to a protected thio group, Y, in the product of formula (11). The use of 4-mefhoxybenzylmercaptan is preferred.
- a bromoacetate of formula (26) is contacted with an appropriate thiol in a suitable organic solvent, such as dimethylformamide.
- a suitable organic solvent such as dimethylformamide.
- the solvent is degassed.
- the reaction is carried out using a suitable base, such as sodium hydroxide, triethylamine, or N,N-diisopropylethylamine.
- the reaction is carried out at temperatures of from about -50° to about ambient temperature and requires about 1 to 72 hours.
- the protected acetic acid ester of formula (27) can be isolated and purified by methods well known and appreciated in the art, such as extraction, evaporation, chromatography, and distillation, and recrystallization.
- step 2 the protected acetic acid ester of formula (27) is alkylated with an appropriate akylating agent to give a compound of formula (28).
- an appropriate alkyl ating agent is one which transfers R 3 - which is R 3 as desired in the final product of formula (1) or gives rise after deprotection to R 3 as desired in the final product of formula (1) or gives rise to R 3 - as defined in Reaction Scheme B, step 1.
- Appropriate alkylating agents include alkylhalides, such as methyl iodide, methyl bromide, ethyl bromide, propyl bromide, propyl chloride, butyl bromide, butyl chloride, and the like; benzyl bromide, benzyl chloride, substituted benzyl bromide, substituted benzyl chloride, ethyl bromoacetate, t-butyl bromoaceate, ethyl 3-chloropropionate, ethyl 3-bromopropionate, ethyl 5-bromovalerate, ethyl 4- bromobutyrate, 3-chloropropionamide, 2-bromoethylbenzene, substituted 2- bromoethylbenzene, l-chloro-3-phenylpropane, 1 -bromo-4-phenylbutane, and the like, N-(2-bromo
- a protected acetic acid ester of formula (27) is alkylated with an appropriate alkylating agent.
- the reaction is carried out in a suitable solvent, such as diethyl ether, tetrahydrofuran, dimethylformamide, and toluene using a suitable base, such as sodium hydride, potassium hydride, potassium t-butoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or lithium diisopropylamide.
- the reaction is generally carried out at temperatures of about -70°C to about room temperature and require from about 1- 24 hours.
- the product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization.
- step 3 the compound of formula (28) the carboxy protecting group Pg 5 is selectively removed to give a compound of formula (3b) in which Y is protected thio.
- Y is protected thio.
- step 1 an appropriate compound of structure (30) is functionalized to give the corresponding compound of structure (31).
- an appropriate compound of formula (30) is treated initially with lithium chloride and a suitable non-nucleophilic base, such as collidine m a suitable solvent such as dimethylformamide This is followed by treatment with a suitable mesylating agent, such as mesyl chloride
- a suitable non-nucleophilic base such as collidine
- a suitable solvent such as dimethylformamide
- mesylating agent such as mesyl chloride
- the reaction is typically carried out at a temperature range of from -30°C to room temperature, preferably 0°C and for a penod of time ranging from 2-10 hours
- the product is recovered from the reaction mixture by extractive methods as are known in the art and may be purified by chromatography
- step 2 the methanesulfonate functionality of the compound of formula (31) is eliminated and the chloro substituted with lodo to a compound of formula (32)
- a compound of formula (31 ) is treated with a suitable non- nucleophihc base, such as potassium tert-butoxide in a suitable aprotic organic solvent, such as diethyl ether
- a suitable aprotic organic solvent such as diethyl ether
- the reaction is typically carried out at a temperature range of from -30°C to room temperature, preferably 0°C and for a penod of time ranging from 15 mmutes to hours to give the corresponding 1- chloromethyl-2-v ⁇ nyl-benzene derivative which is recovered from the reaction mixture by extractive methods as are known in the art
- the 1 -chloromethyl-2-vmyl- benzene derivative is then treated with a suitable lodmating agent, such as sodium iodide, in a suitable solvent, such as acetone
- the reaction is carried out at a temperature range of from room temperature to reflux temperature of the solvent and for a period of time ranging from 15 minutes to hours
- the product is
- step 3 a compound of formula (32) is subjected to an addition, elimination reaction with 2-(b ⁇ s-methylsulfonyl-methyleneammo)- 1 - (10,10-d ⁇ methyl-3,3-d ⁇ oxo-3-th ⁇ a-4-aza-t ⁇ cyclo( 5 2 1 0 1 ,5)dec-4-yl)-ethanone to give the corresponding compound of formula (33)
- the anion of 2-(b ⁇ s-methylsulfonyl-methyleneam ⁇ no)- 1 -( 10,10- d ⁇ methyl-3,3-d ⁇ oxo-3-th ⁇ a-4-aza-t ⁇ cyclo( 5 2 1 0 l,5)dec-4-yl)-ethanone is formed by treating 2-(b ⁇ s-methylsulfonyl-methyleneam ⁇ no)-l-(10,10- d ⁇ methyl-3,3-d ⁇ oxo-3- th ⁇ a-4-aza-t ⁇ cyclo(5 2 1 0 l ,5)dec-4-yl)-ethanone with a suitable non-nucleophihc base, such as n-butylhthium in a suitable aprotic organic solvent, such as tetrahydrofuran.
- a suitable non-nucleophihc base such as n-butylhthium in a suitable aprotic organic solvent, such as tetrahydr
- the reaction is carried out at a temperature range of from -78°C to - 30°C, preferable -78°C and for a period of time ranging from 30 minutes to 2 hours.
- a compound of formula (32) is then added and the reaction is carried out at a temperature range of from -78°C to room temperature for a period of time ranging from 1 -24 hours.
- the product is recovered from the reaction mixture by extractive methods as are known in the art and may be purified by chromatography.
- step 4 a compound of formula (33) is hydrolyzed to give a compound of formula (34).
- a compound of formula (33) is treated with a suitable acid such as aqueous hydrochloric acid in a suitable organic solvent such as tetrahydrofuran.
- a suitable acid such as aqueous hydrochloric acid in a suitable organic solvent such as tetrahydrofuran.
- the reaction is carried out at a temperature range of from -10°C to room temperature and for a period of time ranging from 30 minutes to 20 hours.
- inorganic base such as aqueous lithium hydroxide in a suitable organic solvent, such as tetrahydrofuran.
- the reaction is carried out at a temperature range of from -10°C to room temperature and for a period of time ranging from 30 minutes to 10 hours.
- the corresponding 2-amino- 3-(2-vinyl-phenyl)-propionic acid derivative of formula (34) was isolated by evaporation of solvents.
- step 5 the amino functionality of a compound of formula (34) is protected to give the corresponding compound of formula (35).
- a compound of formula (34) is treated with an appropriate phthalimide protecting agent, such as N-carbethoxyphthalimide in the presence of a suitable non-nucleophilic base, such as aqueous sodium carbonate.
- an appropriate phthalimide protecting agent such as N-carbethoxyphthalimide
- a suitable non-nucleophilic base such as aqueous sodium carbonate.
- the reaction is carried out at a temperature range of from -10°C to room temperature and for a period of time ranging from 1 - 10 hours.
- the product is recovered from the reaction zone by extractive methods as are known in the art and may be purified by chromatography.
- step 6 the carboxylic acid functionality of a compound of formula (35) is esterified to give a compound of formula (36).
- a compound of formula (35) is treated with 2- (trimethylsilyl)ethanol in the presence of a suitable non-nucleophilic base, such as pyridine, in a suitable organic solvent, such as tetrahydrofuran.
- a suitable non-nucleophilic base such as pyridine
- a suitable organic solvent such as tetrahydrofuran.
- the reaction is carried out at a temperature range of from -30°C to room temperature and for a period of time ranging from 30 minutes to 2 hours.
- a coupling agent such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC) is then added and the reaction carried out at a temperature range of from -30°C to room temperature for a period of time ranging from 10 - 48 hours.
- the product is recovered from the reaction zone by extractive methods as are known in the art and may be purified by chromatography.
- step 7 the vinyl functionality of a compound of formula (36) is oxidized to give a compound of formula (37).
- a compound of formula (36) is treated with ozone in a suitable organic solvent such as methylene chloride and methanol.
- a suitable organic solvent such as methylene chloride and methanol.
- the reaction is carried out at a temperature range of from -78°C to -50°C and for a period of time necessary for a blue color to persist.
- the product is recovered from the reaction zone by extractive methods as are known in the art and may be purified by chromatography.
- step 8 a compound of formula (37) is subjected to reductive amination with an appropriate amino acid, tert-butyl ester derivative to give a compound of formula (39).
- an appropriate amino acid, tert-butyl ester derivative is one in which R] is as desired in the final product of formula (1) or gives rise to Ri as is desired in the final product of formula (1).
- an appropriate amino acid, tert-butyl ester derivative is one in which the stereochemistry is as desired in the final product of formula (1).
- amino acid, tert-butyl ester derivatives give rise to compounds of formula (3) in which A' is -O-tert-butyl.
- appropriate amino acid derivatives can have a variety of carboxy substituents give rise to compounds of formula (3) in which A' is other than -O-tert- butyl.
- a compound of formula (37) is treated with an appropriate amino acid, tert-butyl ester derivative in an appropriate polar organic solvent, such as methanol under dehydrating conditions, such as molecular sieves.
- the reaction is carried out at a temperature ranged of from -10°C to reflux temperature of the solvent, preferably room temperature, and for a period of time ranging from 30 minutes to 10 hours.
- a suitable reducing agent such as sodium cyanoborohydride, is then added and the reaction is carried out at a temperature range of from -10° to reflux temperature of the solvent, preferably room temperature, and for a period of time ranging from 30 minutes to 24 hours.
- the product is recovered from the reaction zone by extractive methods as are known in art and may be purified by chromatography.
- those amino acid, tert-butyl ester derivatives wherein Ri has a reactive functionality the reactive functionality may be protected prior to the reductive amination reaction of step 8.
- suitable protecting groups is well known by one of ordinary skill in the art and is described in Protective Groups in Organic Synthesis, Theodora W. Greene, (Wiley 1981).
- step 9 the ester functionality of a compound of formula (39) is hydrolyzed to give a compound of formula (40).
- a compound of formula (39) is treated with an appropriate fluoride reagent, such as tetrabutylammonium fluoride in a suitable organic solvent, such as tetrahydrofuran.
- an appropriate fluoride reagent such as tetrabutylammonium fluoride in a suitable organic solvent, such as tetrahydrofuran.
- the reaction is carried out at a temperature range of from - 10°C to room temperature and for a period of time ranging from 30 minutes to hours.
- the product is recovered from the reaction zone by extractive methods as are known in art and may be purified by chromatography.
- step 10 a compound of formula (39) is subjected to a ring closure amination reaction to give a compound of formula (40).
- a compound of formula (40) is treated with a suitable activating agent, such as isobutylchloro formate, in the presence of a suitable non- nucleophilic base, such as N-methylmorpholine in a suitable organic solvent, such as tetrahydrofuran.
- a suitable activating agent such as isobutylchloro formate
- a suitable non- nucleophilic base such as N-methylmorpholine
- a suitable organic solvent such as tetrahydrofuran.
- the reaction is carried out at a temperature range of from -10°C to reflux temperature of the solvent and for a period of time ranging from 30 minutes to 10 hours.
- the product is recovered from the reaction zone by evaporation and may be purified by chromatography.
- step 11 the protecting group of a compound of formula (40) is removed to give a compound of formula (3) in which A' is -O-tert- butyl as the 4-position (S)-isomer.
- the phthalimide protecting groups of a compound of formula (40) can be removed using hydrazine monohydrate in a suitable protic solvent such as methanol.
- a suitable protic solvent such as methanol.
- the reaction is carried out at a temperature range of from -10°C to room temperature and for a period of time ranging from 2 hours to 4 days.
- the product is recovered from the reaction zone by filtration and evaporation.
- Step h 2-(2-(2-(l,3-Dioxo-l,3,dihydro-isoindol-2-yl)-2-(2- trimethylsilanyl- ethoxycarbonyl)-ethyl)-benzylamino)-4-methyl- valeric acid, tert- butyl ester Dissolve 2-( 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl)-3-(2- formyl-phenyl)- propionic acid, 2-trimethylsilanyl-ethyl ester (250 mg, 0.590 mmol) in methanol (15 mL) and treat with L-leucine tert-butyl ester hydrochloride (0.66 g, 3.0 mmol).
- 6-aminohexanoic acid (6-aminocaproic acid) (8.0 g, 60 mmol) and water (100 mL).
- sodium carbonate (6.84 g, 64 mmol)
- N- carbethoxyphthalimide (14.0 g, 64 mmol).
- extract the reaction mixture with ethyl acetate (100 mL).
- Collect the solid by filtration, rinse with water, and dry to give 6-phthalimidohexanoic acid (12.7 g, 80%. yield).
- the present invention provides a method of inhibiting matrix metalloproteinase
- MMP matrix metalloproteinase inhibiting amount of a compound of formula (1).
- patient refers to warm-blooded animals or mammals, including guinea pigs, dogs, cats, rats, mice, hamsters, rabbits and primates, including humans.
- a patient is in need of treatment to inhibit MMP when it would be beneficial to the patient to reduce the physiological effect of active MMP.
- a patient is in need of treatment to inhibit MMP when a patient is suffering from a disease state characterized by excessive tissue disruption or tissue degradation, such as, but not limited to, a neoplastic disease state or cancer; rheumatoid arthritis; osteoarthritis; cardiovascular disorders, such as atherosclerosis; corneal ulceration; dental diseases, such as gingivitis or periodontal disease; and neurological disorders, such as multiple sclerosis; chronic inflammatory disorders, such as emphysema and especially smoking- induced emphysema.
- a disease state characterized by excessive tissue disruption or tissue degradation
- tissue disruption or tissue degradation such as, but not limited to, a neoplastic disease state or cancer
- rheumatoid arthritis such as atherosclerosis
- corneal ulceration such as atherosclerosis
- dental diseases such as gingivitis or periodontal disease
- neurological disorders such as multiple sclerosis
- chronic inflammatory disorders such as emphysema and especially smoking-
- an "effective matrix metalloproteinase inhibiting amount" of a compound of formula (1) is an amount which is effective, upon single or multiple dose administration to the patient, in providing relief of symptoms associated with MMP and is thus effective in inhibiting MMP-induced tissue disruption and/or MMP-induced tissue degradation.
- "relief of symptoms" of MMP-mediated conditions refers to decrease in severity over that expected in the absence of treatment and does not necessarily indicate a total elimination or cure of the disease. Relief of symptoms is also intended to include prophylaxis.
- an effective matrix metalloproteinase inhibiting dose can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances.
- determining the effective dose a number of factors are considered including, but not limited to: the species of the patient; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of concomitant medication.
- An effective matrix metalloproteinase inhibiting amount of a compound of formula (1) will generally vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 300 milligrams per kilogram of body weight per day (mg/kg/day). A daily dose of from about 1 mg/kg to about 100 mg/kg is preferred.
- Neoplastic disease state refers to an abnormal state or condition characterized by rapidly proliferating cell growth or neoplasm.
- Neoplastic disease states for which treatment with a compound of formula (1) will be particularly useful include: Leukemias, such as, but not limited to, acute lymphoblastic, chronic lymphocytic, acute myeloblastic and chronic myelocytic; Carcinomas and adenocarcinomas, such as, but not limited to, those of the cervix, oesophagus, stomach, small intestines, colon, lungs (both small and large cell), breast and prostate; Sarcomas, such as, but not limited to, oesteroma, osteosarcoma, lipoma, liposarcoma, hemangioma and hemangiosarcoma; Melanomas, including amelanotic and melanotic; and mixed types of neoplasias such as, but not limited to carcinosarcoma, lymphoid tissue type, fo
- Atherosclerosis is a disease state characterized by the development and growth of atherosclerotic lesions or plaque.
- the identification of those patients who are in need of treatment for atherosclerosis is well within the ability and knowledge of one of ordinary skill in the art. For example, individuals who are either suffering from clinically significant atherosclerosis or who are at risk of developing clinically significant atherosclerosis are patients in need of treatment for atherosclerosis.
- a clinician of ordinary skill in the art can readily determine, by the use of clinical tests, physical examination and medical/family history, if an individual is a patient in need of treatment for atherosclerosis.
- chronic inflammatory disease refers to diseases or conditions characterized by persistent inflammation in the absence of an identifiable irritant or microbial pathogen.
- Inflammatory diseases for which treatment with a compound of formula (1) will be particularly useful include: emphysema, chronic bronchitis, asthma, and chronic inflammation, and especially smoking-induced emphysema.
- a compound of formula ( 1 ) can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes.
- the compound can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, topically, intranasally, rectally, inhalation, and the like.
- Oral and inhalation administration is generally preferred.
- One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the disease state to be treated, the stage of the disease, and other relevant circumstances. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990).
- a compound of formula (1) can be administered in the form of pharmaceutical compositions or medicaments which are made by combining a compound of formula (1) with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the chosen route of administration, and standard pharmaceutical practice.
- the pharmaceutical compositions or medicaments are prepared in a manner well known in the pharmaceutical art.
- the carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
- the pharmaceutical composition may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions, gels, ointments, aerosol or the like.
- compositions may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
- a compound of formula (1) may be inco ⁇ orated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of a compound of formula (1), the active mgredient, but may be vaned depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit
- the amount of the active ingredient present in compositions is such that a unit dosage form suitable for administration will be obtained
- the tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants binders such as microcrystalline cellulose, gum tragacanth or gelatin, excipients such as starch or lactose, disintegrating agents such as algimc acid, P ⁇ mogel, corn starch and the like, lubncants such as magnesium stearate or Sterotex, ghdants such as colloidal silicon dioxide, and sweetening agents such as sucrose or saccharin may be added or a flavonng agent such as peppermint, methyl sahcylate or orange flavonng
- the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil
- Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings
- tablets or pills may be coated with sugar, shellac, or other entenc coating agents
- a syrup may contain, in
- the compounds of the present mvention may be inco ⁇ orated into a solution or suspension
- These preparations should contain at least 0 1 % of a compound of the invention, but may be vaned to be between 0 1% and about 50% of the weight thereof
- the amount of the active ingredient present in such compositions is such that a suitable dosage will be obtained
- Preferred compositions and preparations are able to be determined by one skilled in the art
- the solutions or suspensions may also mclude one or more of the following adjuvants stenle diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl paraben, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylene diaminetetraacetic acid, buffers such as acetates, citrates or phosphates and agents for the adjustment of toxicity such as sodium chloride or dextrose.
- the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
- the compounds of the present invention may also be administered by inhalation, such as by aerosol or dry powder. Delivery may be by a liquefied or compressed gas or a suitable pump system which dispenses the compounds of the present invention or a formulation thereof. Formulations for administration by inhalation of compounds of formula (1) may be delivered in single phase, bi-phasic, or tri-phasic systems. A variety of systems are available for the administration by aerosol of the compounds of formula (1). Dry powder formulations are prepared by either pelletizing or milling the compound of formula (1) to a suitable particle size or by admixing the pelletized or milled compound of formula (1) with a suitable carrier material, such as lactose and the like. Delivery by inhalation includes the necessary container, activators, valves, subcontainers, and the like. Preferred aerosol and dry powder formulations for administration by inhalation can be determined by one skilled in the art.
- the selective MMP- 12 inhibitors of the present invention can be evaluated by the procedures that follow.
- ProMMP-1 (EC 3.4.24.7; interstitial coUagenase) was purified from culture medium of human rheumatoid synovial fibroblasts stimulated with macrophage- conditioned medium according to Okada, Y. et al., J. Biol. Chem. 261, 14245-14255 (1986).
- the active MMP-1 was obtained by treatment of proMMP-1 with trypsin (5 ⁇ g/mL) at 37°C for 30 minutes, followed by addition of soybean trypsin inhibitor (50 ⁇ g/mL). Determination of Inhibition Constant (K,) for MMP-1
- the activated MMP-1 is assayed using a fluorogenic substrate, Mca-Pro-Leu- Gly-Leu-Dpa-Ala-Arg-NH 2 , Knight, C.G. et al., FEBS Lett. 296, 263-266 (1992), at
- K values for MMP-1 inhibitors
- a series of intermediate inhibitor solutions were prepared in DMF and 1 or 2 ⁇ L of the diluted inhibitor solution was mixed with 1 ⁇ L of 2 mM substrate solution in DMF in a quartz cuvette containing 2 mL of assay buffer.
- the enzyme (10 ⁇ L of 0.2 ⁇ M MMP-3 dilution in assay buffer) was added at the last to start the reaction.
- the K, for a competitive inhibitor is calculated using: v 0 /V
- Recombinant MMP-2 was purified from the fermentation broth of yeast Pichia pastoris that carries the integrated MMP-2 gene into its chromosome.
- the full- length cDNA for MMP-2 was obtained by reverse transcription of RNA from human melanoma A375M cell line by the reverse transcriptase polymerase chain reaction (RT- PCR) using sequence specific oligonucleotides. The nucleotide sequence was confirmed by Taq cycle sequencing.
- the cDNA was ligated into the Pichia pastoris expression vector pHIL-D2 in such a way that the expression of pro-MMP-2 is under the control of the methanol inducible alcohol oxidase promoter.
- the expression construct was digested with either Sail or Nsil and used to transform the Pichia pastoris strains KM71 and SMD1 168.
- a large-scale culture of a selected clone designated 24S was performed in a high cell density fermentor and the recombinant MMP-2 was purified from the culture supernatant by gelatin-sepharose 4B (Pharmacia).
- the enzyme is sufficiently pure at this stage for routine measurement of inhibition. If desired, however, the enzyme may be further purified by AcA 44 gel filtration (Spectra). Determination of Inhibition Constant (K.) for MMP-2
- the active MMP-2 was obtained by activation of proMMP-2 at 37°C for 1 h with 4-aminophenylmercuric acetate which was then removed by a Sephadex G-50 spin column.
- the enzyme is assayed using a fluorogenic substrate, Mca-Pro-Leu-Gly-Leu- Dpa-Ala-Arg-NH , at 37°C in 2.0 mL of assay buffer containing 50 mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, 0.02% Brij-35, and 50 ⁇ M ⁇ - mercaptoethanol.
- the increase in fluorescence is monitored ( ⁇ ex 328 nm, ⁇ em 393 nm).
- Substrate and inhibitor stock solutions are made in DMF.
- the enzyme is added at the last to start the reaction.
- ProMMP-3 (EC 3.4.24.17; Stromelysin- 1) was purified from culture medium of human rheumatoid synovial fibroblasts stimulated with macrophage-conditioned medium according to Okada, Y. et al., J. Biol. Chem. 261, 14245-14255 (1986).
- the active MMP-3 was obtained by treatment of proMMP-3 with trypsin (5 ⁇ g/mL) at 37°C for 30 minutes, followed by addition of soybean trypsin inhibitor (50 ⁇ g/mL). Aliquots of the activated MMP-3 were stored at -20°C.
- the activated MMP-3 is assayed using a fluorogenic substrate, Mca-Pro-Leu- Gly-Leu-Dpa-Ala-Arg-NH 2 , Knight, C.G. et al., FEBS Lett. 296, 263-266 (1992), at 37°C in an assay buffer containing 50 mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, and 0.02% Brij-35.
- Ki inhibition constant
- the potency of inhibitors of MMP-12 was measured using either quartz cuvettes or microtiter plates.
- the activity of MMP-12 was measured using a fluorogenic substrate, Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2, Knight, C.G. et al., FEBS Lett. 296,263-266 (1992), at 25C in an assay buffer containing 50 mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, and 0.02% Brij-35.
- Ki values were determined using the cuvette method by preparing a series of intermediate inhibitors solutions in 0.1% HC1-DMF and mixing the inhibitor with substrate (final concentration 2 ⁇ M) in a quartz cuvette containing 2 ml of assay buffer. MMP-12 was added to start the reaction at a concentration of 2 nM and progress curves were generated.
- Ki values were determined using the microtiter plate method in a manner similar to that described for the cuvette method with some modifications.
- Four different inhibitor concentrations (50 ⁇ l in assay buffer)of each compound were added to separate wells of a microtiter plate and substrate was added (100 ⁇ l) to get a final concentration of 4 mM.
- MMP-12 was added to a final concentration of 2 nM (50 ⁇ l) to start the reaction. Cleavage of substrate was recorded every 30 seconds for 30 minutes and progress curves were generated. Calculation of Ki values
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002358955A CA2358955A1 (en) | 1998-12-31 | 1999-11-30 | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase |
EP99961877A EP1150957A1 (en) | 1998-12-31 | 1999-11-30 | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase |
AU18369/00A AU1836900A (en) | 1998-12-31 | 1999-11-30 | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US22454998A | 1998-12-31 | 1998-12-31 | |
US09/224,549 | 1998-12-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000040564A1 true WO2000040564A1 (en) | 2000-07-13 |
Family
ID=22841168
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/028339 WO2000040564A1 (en) | 1998-12-31 | 1999-11-30 | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1150957A1 (en) |
AR (1) | AR023366A1 (en) |
AU (1) | AU1836900A (en) |
CA (1) | CA2358955A1 (en) |
WO (1) | WO2000040564A1 (en) |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8952171B2 (en) | 2013-03-15 | 2015-02-10 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9012450B2 (en) | 2011-12-28 | 2015-04-21 | Global Blood Therapeutics, Inc. | Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation |
US9018210B2 (en) | 2011-12-28 | 2015-04-28 | Global Blood Therapeutics, Inc. | Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation |
US9422279B2 (en) | 2013-03-15 | 2016-08-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9447071B2 (en) | 2014-02-07 | 2016-09-20 | Global Blood Therapeutics, Inc. | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
US9458139B2 (en) | 2013-03-15 | 2016-10-04 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9604999B2 (en) | 2013-03-15 | 2017-03-28 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9802900B2 (en) | 2013-03-15 | 2017-10-31 | Global Blood Therapeutics, Inc. | Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin |
US9957250B2 (en) | 2013-03-15 | 2018-05-01 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9981939B2 (en) | 2013-03-15 | 2018-05-29 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10004725B2 (en) | 2015-03-30 | 2018-06-26 | Global Blood Therapeutics, Inc. | Methods of treatment |
US10077249B2 (en) | 2016-05-12 | 2018-09-18 | Global Blood Therapeutics, Inc. | Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde |
US10100043B2 (en) | 2013-03-15 | 2018-10-16 | Global Blood Therapeutics, Inc. | Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation |
US10266551B2 (en) | 2013-03-15 | 2019-04-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10450269B1 (en) | 2013-11-18 | 2019-10-22 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10493035B2 (en) | 2016-10-12 | 2019-12-03 | Global Blood Therapeutics, Inc. | Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
US11014884B2 (en) | 2018-10-01 | 2021-05-25 | Global Blood Therapeutics, Inc. | Modulators of hemoglobin |
US11020382B2 (en) | 2015-12-04 | 2021-06-01 | Global Blood Therapeutics, Inc. | Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
US11053195B2 (en) | 2013-03-15 | 2021-07-06 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US11236109B2 (en) | 2013-03-15 | 2022-02-01 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0599444A1 (en) * | 1992-05-18 | 1994-06-01 | E.R. SQUIBB & SONS, INC. | Dual action inhibitors |
US5424425A (en) * | 1992-02-14 | 1995-06-13 | Merrell Dow Pharmaceuticals Inc. | Aminoacetylmercapto derivatives useful as inhibitors of enkephalinase and ace |
WO1995021854A1 (en) * | 1994-02-14 | 1995-08-17 | Merrell Pharmaceuticals Inc. | Novel mercaptoacetylamido 1,3,4,5-tetrahydro-benzo[c]azepin-3-one disulfide derivatives useful as inhibitors of enkephalinase and ace |
WO1995021839A1 (en) * | 1994-02-14 | 1995-08-17 | Merrell Pharmaceuticals Inc. | Novel mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase and ace |
US5491143A (en) * | 1990-10-18 | 1996-02-13 | Merrell Dow Pharmaceuticals Inc. | Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ACE |
WO1996029313A1 (en) * | 1995-03-21 | 1996-09-26 | The Procter & Gamble Company | Lactam-containing hydroxamic acid derivatives, their preparation and their use as inhibitors of matrix metalloprotease |
-
1999
- 1999-11-30 CA CA002358955A patent/CA2358955A1/en not_active Abandoned
- 1999-11-30 EP EP99961877A patent/EP1150957A1/en not_active Withdrawn
- 1999-11-30 AU AU18369/00A patent/AU1836900A/en not_active Abandoned
- 1999-11-30 WO PCT/US1999/028339 patent/WO2000040564A1/en not_active Application Discontinuation
- 1999-12-30 AR ARP990106863A patent/AR023366A1/en not_active Application Discontinuation
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5491143A (en) * | 1990-10-18 | 1996-02-13 | Merrell Dow Pharmaceuticals Inc. | Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ACE |
US5424425A (en) * | 1992-02-14 | 1995-06-13 | Merrell Dow Pharmaceuticals Inc. | Aminoacetylmercapto derivatives useful as inhibitors of enkephalinase and ace |
EP0599444A1 (en) * | 1992-05-18 | 1994-06-01 | E.R. SQUIBB & SONS, INC. | Dual action inhibitors |
WO1995021854A1 (en) * | 1994-02-14 | 1995-08-17 | Merrell Pharmaceuticals Inc. | Novel mercaptoacetylamido 1,3,4,5-tetrahydro-benzo[c]azepin-3-one disulfide derivatives useful as inhibitors of enkephalinase and ace |
WO1995021839A1 (en) * | 1994-02-14 | 1995-08-17 | Merrell Pharmaceuticals Inc. | Novel mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase and ace |
US5731306A (en) * | 1994-02-14 | 1998-03-24 | Flynn; Gary A. | Mercaptoacetylamido 1,3,4,5-tetrahydro-benzo c!azepin-3-one disulfide derivatives useful as inhibitors of enkephalinase and ace |
WO1996029313A1 (en) * | 1995-03-21 | 1996-09-26 | The Procter & Gamble Company | Lactam-containing hydroxamic acid derivatives, their preparation and their use as inhibitors of matrix metalloprotease |
Non-Patent Citations (1)
Title |
---|
D. TOURWÉ ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 2, no. 10, 1992, pages 1305 - 8, XP000864481 * |
Cited By (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10034879B2 (en) | 2011-12-28 | 2018-07-31 | Global Blood Therapeutics, Inc. | Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation |
US9012450B2 (en) | 2011-12-28 | 2015-04-21 | Global Blood Therapeutics, Inc. | Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation |
US9018210B2 (en) | 2011-12-28 | 2015-04-28 | Global Blood Therapeutics, Inc. | Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation |
US10822326B2 (en) | 2011-12-28 | 2020-11-03 | Global Blood Therapeutics, Inc. | Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation |
US10806733B2 (en) | 2011-12-28 | 2020-10-20 | Global Blood Therapeutics, Inc. | Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation |
US10377741B2 (en) | 2011-12-28 | 2019-08-13 | Global Blood Therapeutics, Inc. | Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation |
US9957250B2 (en) | 2013-03-15 | 2018-05-01 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9422279B2 (en) | 2013-03-15 | 2016-08-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9802900B2 (en) | 2013-03-15 | 2017-10-31 | Global Blood Therapeutics, Inc. | Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin |
US8952171B2 (en) | 2013-03-15 | 2015-02-10 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9981939B2 (en) | 2013-03-15 | 2018-05-29 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US11530191B2 (en) | 2013-03-15 | 2022-12-20 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10017491B2 (en) | 2013-03-15 | 2018-07-10 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9604999B2 (en) | 2013-03-15 | 2017-03-28 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US11236109B2 (en) | 2013-03-15 | 2022-02-01 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10100040B2 (en) | 2013-03-15 | 2018-10-16 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10100043B2 (en) | 2013-03-15 | 2018-10-16 | Global Blood Therapeutics, Inc. | Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation |
US11053195B2 (en) | 2013-03-15 | 2021-07-06 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10266551B2 (en) | 2013-03-15 | 2019-04-23 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10315991B2 (en) | 2013-03-15 | 2019-06-11 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9458139B2 (en) | 2013-03-15 | 2016-10-04 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10435393B2 (en) | 2013-03-15 | 2019-10-08 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10858317B2 (en) | 2013-03-15 | 2020-12-08 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10829470B2 (en) | 2013-03-15 | 2020-11-10 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US9776960B2 (en) | 2013-03-15 | 2017-10-03 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10450269B1 (en) | 2013-11-18 | 2019-10-22 | Global Blood Therapeutics, Inc. | Compounds and uses thereof for the modulation of hemoglobin |
US10722502B2 (en) | 2014-02-07 | 2020-07-28 | Global Blood Therapeutics, Inc. | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
US9447071B2 (en) | 2014-02-07 | 2016-09-20 | Global Blood Therapeutics, Inc. | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
US11452720B2 (en) | 2014-02-07 | 2022-09-27 | Global Blood Therapeutics, Inc. | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
US10137118B2 (en) | 2014-02-07 | 2018-11-27 | Global Blood Therapeutics, Inc. | Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
US10695330B2 (en) | 2015-03-30 | 2020-06-30 | Global Blood Therapeutics, Inc. | Methods of treatment |
US10004725B2 (en) | 2015-03-30 | 2018-06-26 | Global Blood Therapeutics, Inc. | Methods of treatment |
US11944612B2 (en) | 2015-12-04 | 2024-04-02 | Global Blood Therapeutics, Inc. | Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
US11020382B2 (en) | 2015-12-04 | 2021-06-01 | Global Blood Therapeutics, Inc. | Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
US10077249B2 (en) | 2016-05-12 | 2018-09-18 | Global Blood Therapeutics, Inc. | Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde |
US10577345B2 (en) | 2016-05-12 | 2020-03-03 | Global Blood Therapeutics, Inc. | Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde |
US10493035B2 (en) | 2016-10-12 | 2019-12-03 | Global Blood Therapeutics, Inc. | Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde |
US11014884B2 (en) | 2018-10-01 | 2021-05-25 | Global Blood Therapeutics, Inc. | Modulators of hemoglobin |
Also Published As
Publication number | Publication date |
---|---|
AR023366A1 (en) | 2002-09-04 |
AU1836900A (en) | 2000-07-24 |
CA2358955A1 (en) | 2000-07-13 |
EP1150957A1 (en) | 2001-11-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6544980B2 (en) | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase | |
WO2000040564A1 (en) | N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase | |
AU718055B2 (en) | 3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase | |
EP1150975A1 (en) | 1-carboxymethyl-2-oxo-azepan derivatives useful as selective inhibitors of mmp-12 | |
US6262080B1 (en) | 3-(thio-substitutedamido)-lactams useful as inhibitors of matrix metalloproteinase | |
US6486193B2 (en) | 3-substituted pyrrolidines useful as inhibitors of matrix metalloproteinases | |
US6352976B1 (en) | Selective inhibitors of MMP-12 | |
US6770640B1 (en) | 1-Carboxymethyl-2-oxo-azepan derivatives useful as selective inhibitors of MMP-12 | |
EP1150976B1 (en) | 3-(thio-substituted amido)-lactams useful as inhibitors of matrix metalloproteinase | |
US6329550B1 (en) | Amidomalonamides useful as inhibitors of MMP of matrix metalloproteinase | |
EP1140818B1 (en) | Amidomalonamides and their use as inhibitors of matrix metalloproteinase | |
EP1140984B1 (en) | Selective inhibitors of mmp-12 | |
US6455570B1 (en) | Polypyrrolinone based inhibitors of matrix metalloproteases | |
WO2000040553A1 (en) | 3-substituted pyrrolidines useful as inhibitors of matrix metallo-proteinases | |
MXPA01006674A (en) | 3-(thio-substituted amido)-lactams useful as inhibitors of matrix metalloproteinase | |
MXPA01006671A (en) | Amidomalonamides and their use as inhibitors of matrix metalloproteinase | |
MXPA01006719A (en) | Selective inhibitors of mmp-12 | |
MXPA99002577A (en) | 3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
ENP | Entry into the national phase |
Ref country code: AU Ref document number: 2000 18369 Kind code of ref document: A Format of ref document f/p: F |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1999961877 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2358955 Country of ref document: CA Ref country code: CA Ref document number: 2358955 Kind code of ref document: A Format of ref document f/p: F |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 1999961877 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1999961877 Country of ref document: EP |