EP1150957A1 - N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase - Google Patents

N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase

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Publication number
EP1150957A1
EP1150957A1 EP99961877A EP99961877A EP1150957A1 EP 1150957 A1 EP1150957 A1 EP 1150957A1 EP 99961877 A EP99961877 A EP 99961877A EP 99961877 A EP99961877 A EP 99961877A EP 1150957 A1 EP1150957 A1 EP 1150957A1
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Prior art keywords
group
hydrogen
alkyl
benzyl
integer
Prior art date
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EP99961877A
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German (de)
French (fr)
Inventor
Alan Warshawsky
Michael J. Janusz
Gary A. Flynn
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Aventis Pharmaceuticals Inc
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Aventis Pharmaceuticals Inc
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    • 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
  • 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 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;
  • 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).
  • 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

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Abstract

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) wherein A is -OH or -NRR'. Such inhibitors are useful in treating neoplasms, atherosclorosis, and chronic inflammatory diseases. The present invention also provides novel N-carboxymethyl substituted benzolactams of formula (1a) wherein A is -NRR'.

Description

N-CARBOXYMETHYL SUBSTITUTED BENZOLACTAMS AS INHIBITORS OF MATRIX METALLOPROTEINASE
BACKGROUND OF THE INVENTION
The matrix metalloproteinases (MMPs) 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 α -macroglobulin. Chapman, K.T. et al., J. Med. Chem. 36, 4293-4301 (1993); Beckett, R.P. et al., DDT 1, 16-26 (1996). The characterizing feature of diseases involving the enzymes appears to be a stoichiometric imbalance between active enzymes and endogenous inhibitors, leading to excessive tissue disruption, and often degradation. McCachren, S.S., Arthritis Rheum. 34, 1085- 1093 (1991).
The discovery of different families of matrix metalloproteinase, their relationships, and their individual characteristics have been categorized in several reports. Emonard, H. et al., Cell Molec. Biol. 36, 131-153 (1990); Birkedal-Hansen, H., J. Oral Pathol. 17, 445-451 (1988); Matrisian, L.M., Trends Genet. 6, 121-125 (1990); Murphy, G.J.P. et al., FEBS Lett. 289, 4-7 (1991); Matrisian, L.M., Bioessays 14, 455- 463 (1992). 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. Examples of specific collagenases include fibroblast coUagenase (MMP-1), neutrophil coUagenase (MMP-8), and coUagenase 3 (MMP-13). Examples of gelatinases include 72 kDa gelatinase (gelatinase A; MMP-2) and 92 kDa gelatinase (gelatinase B; MMP-9). Examples of stromelysins include stromelysin 1 (MMP-3), stromelysin 2 (MMP-10) and matrilysin (MMP-7). Other 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.
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. For example, in adenocarcinoma, invasive proximal gastric cells express the 72 kDa form of coUagenase Type IV, whereas the noninvasive cells do not. Schwartz, G.K. et al., Cancer 73, 22-27 (1994). Rat embryo cells transformed by the Ha-rα-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 <
0.01) in 122 patients with gastrointestinal tract cancer and breast cancer. Zucker, S. et al., Cancer Res. 53, 140-146 (1993). Moreover, intraperitoneal administration of batimastat, a synthetic MMP inhibitor, gave significant inhibition in the growth and metastatic spread and number of lung colonies which were produced by intravenous injection of the B16-BL6 murine melanoma in C57BL/6N mice. Chirivi, R.G.S. et al., Int. J. Cancer 58, 460-464 (1994). Over-expression of TIMP-2, the endogenous tissue inhibitor of MMP-2, markedly reduced melanoma growth in the skin of immunodeficient mice. Montgomery, A.M. P. et al, Cancer Res. 54, 5467-5473 (1994).
Accelerated breakdown of the extracellular matrix of articular cartilage is a key feature in the pathology of both rheumatoid arthritis and osteoarthritis. Current evidence suggests that the inappropriate synthesis of MMPs is the key event. Beeley, N.R.A. et al., Curr. Qpin. Ther. Patents, 4(1), 7-16 (1994). The advent of reliable diagnostic tools have allowed a number of research groups to recognize that stromelysin is a key enzyme in both arthritis and joint trauma. Beeley, N.R.A. et al., I L; Hasty, K.A. et al., Arthr. Rheum. 33, 388-397 (1990). It has also been shown that stromelysin is important for the conversion of procollagenase to active coUagenase. Murphy, G. et al, Biochem. J. 248, 265-268 (1987).
Furthermore, a range of MMPs can hydrolyse the membrane-bound precursor of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α). Gearing, A.J.H. et al., Nature 370, 555-557 (1994). This cleavage yields mature soluble TNF-α and the inhibitors of MMPs can block production of TNF-α both in vitro and in vivo. Gearing, A.J.H. et al., Id.; Mohler, K.M. et al., Nature 370, 218-220 (1994); McGeehan, G.M. et al., Nature 370, 558-561 (1994). 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 αi-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). In addition, a recent study indicates that 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.
High levels of mRNA corresponding to stromelysin have been observed in atherosclerotic plaques removed from heart transplant patients. Henney, A.M., et al.,
Proc. Natl. Acad. Sci. 88, 8154-8158 (1991). It is submitted that the role of stromelysin in such plaques is to encourage rupture of the connective tissue matrix which encloses the plaque. This rupture is in turn thought to be a key event in the cascade which leads to clot formation of the type seen in coronary thrombosis. MMP inhibition is thus a preventive measure for such thromboses.
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. Beeley, N.R.A. et al., supra.; Overall, CM. et al., J. Periodontal Res. 22, 81-88 (1987).
Excessive levels of gelatinase-B in cerebrospinal fluid has been linked with incidence of multiple sclerosis and other neurological disorders. Beeley, N.R.A. et al., supra.; Miyazaki, K. et al., Nature 362, 839-841 (1993). The enzyme may play a key role in the demyelination of neurones and the breakdown of the blood brain barrier which occurs in such disorders.
SUMMARY OF THE INVENTION 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):
formula ( 1 ) wherein A is selected from the group consisting of -OH and -NRR'; wherein
R and R' are independently selected from the group consisting of hydrogen and Cι-C6 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; Rι is selected from the group consisting of hydrogen, Cι-C6 alkyl, -(CH2)a-CO2R5,
-(CH2)a-C(O)NH2, -(CH2)4NH2, -(CH2)3-NH-C(NH)NH2, -(CH2)2-S(O)b-CH3, -CH2-
OH,
-CH(OH)CH3, -CH2-SH, -(CH2)d-Ar,, and -CH2-Ar2; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0 to 4;
R5 is selected from the group consisting of hydrogen, Cι-C4 alkyl, and benzyl;
Ari is a radical selected from the group consisting of
wherein
R6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι_C4 alkyl, hydroxy, and Cι-C alkoxy; R7 is selected from the group consisting of hydrogen, halogen, C]-C alkyl, and C].C4 alkoxy; Ar2 is a radical selected from the group consisting of
R2 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy C].C4 alkyl, and Cι-C alkoxy;
R3 is selected from the group consisting of C C6 alkyl, -(CH2)m-W, -(CH2)P-Ar3, -(CH2)k-CO2R9, -(CH2)m-NR8 SO2-Y,, and -(CH2)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; Ar3 is selected from the group consisting of
wherein
R23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C]-C alkyl, and Cι-C4 alkoxy;
R8- is hydrogen or Cι-C6 alkyl;
R9 is hydrogen or Cι-C6 alkyl;
Yi is selected from the group consisting of hydrogen, -(CH2),-Ar4, and -N(R2 )? wherein j is 0 or 1 ;
R24 each time selected is independently hydrogen or Cι-C6 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
R25 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C alkyl, and CpC4 alkoxy;
Z is selected from the group consisting of -0-, -NR8-, -C(O)NR8-, -NR8C(O)-, -NR8C(0)NH-, -NR8C(0)0 -, and -OC(O)NH-; wherein
R8 is hydrogen or Cι-C6 alkyl;
Q is selected from the group consisting of hydrogen, -(CH2)n-Y2, and -(CH2)XY3; wherein n is an integer from 0 to 4; Y is selected from the group consisting of hydrogen, -(CH2)h-Ar5 and wherein
AJ"5 is selected from the group consisting of
wherein
R26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and CpC4 alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6; R27 is hydrogen or Cι-C6 alkyl; x is an integer from 2 to 4;
Y3 is selected from the group consisting of -N(R28)2, N-morpholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein
R28 each time taken is independently selected from the group consisting of hydrogen and Cι-C6 alkyl;
R-t is selected from the group consisting of hydrogen, -C(O)Rι0, -C(O)-(CH2)q-K and - S-G wherein
Rio is selected from the group consisting of hydrogen, Cι-C alkyl, phenyl, and benzyl; q is 0, 1, or 2;
K is selected from the group consisting of
N— R„
R, wherein
V is selected from the group consisting of a bond, -CH2-, -0-, -S(O),-, - wherein r is 0, 1, or 2;
R21 is selected from the group consisting of hydrogen, Cι-C alkyl, and benzyl;
R22 is selected from the group consisting of hydrogen, -CF3,
C10 alkyl, phenyl, and benzyl; Ri 1 each time taken is independently selected from the group consisting of hydrogen, Cι-C4 alkyl, and benzyl;
G is selected from the group consisting of
02R16
wherein w is an integer from 1 to 3;
Ri2 is selected from the group consisting of hydrogen, Cι-C6 alkyl,
-CH2CH2S(O)uCH3, and benzyl; wherein u is 0,1, or 2; Ri3 is selected from the group consisting of hydrogen, hydroxy, amino,
Ci-Cό alkyl, N-methylamino, N,N-dimethylamino, -CO Rπ, and - OC(O)R18; wherein
Rπ is hydrogen, -CH2O-C(O)C(CH3) , C,-C4 alkyl, benzyl, or diphenylm ethyl ;
Ris is hydrogen, Cι-C6 alkyl or phenyl; Ri4 is 1 or 2 substituents independently selected from the group consisting of hydrogen, Cι-C4 alkyl, Cι_C alkoxy, or halogen; V] is selected from the group consisting of -O-, -S-, and -NH-; V2 is selected from the group consisting of -N- and -CH-;
V3 is selected from the group consisting of a bond and -C(O)-; V4 is selected from the group consisting of -O-, -S-, -NR] 9-, and - NC(O)R20-; wherein R19 is hydrogen, Cι-C alkyl, or benzyl;
R20 is hydrogen, -CF3, Cι-Cι0 alkyl, or benzyl; Ris is selected from the group consisting of hydrogen, Cι-C6 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'; wherein
R and R' are independently selected from the group consisting of hydrogen and Cι-C6 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, Cι-C6 alkyl, -(CH2)a-CO2R5,
-(CH2)a-C(O)NH2, -(CH2)4NH2, -(CH2)3-NH-C(NH)NH2, -(CH2)2-S(O)b-CH3, -CH2-
OH,
-CH(OH)CH3, -CH2-SH, -(CH2)d-An, and -CH2-Ar2; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0 to 4;
R5 is selected from the group consisting of hydrogen, Cι_C alkyl, and benzyl;
Ari is a radical selected from the group consisting of
wherein
R6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι_C alkyl, hydroxy, and Cι.C4 alkoxy; R7 is selected from the group consisting of hydrogen, halogen, Cι_C4 alkyl, and C]-C alkoxy; Ar2 is a radical selected from the group consisting of
R2 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy Cι-C4 alkyl, and C1-C4 alkoxy;
R3 is selected from the group consisting of Cι-C6 alkyl, -(CH )m-W, -(CH2)P-Ar3, -(CH2)k-CO2R9, -(CH2)m-NR8'SO2-Y,, and -(CH2)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
wherein
R23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, CpC alkyl, and CpC4 alkoxy;
R8- is hydrogen or Cι-C6 alkyl;
R9 is hydrogen or Cι-C6 alkyl;
Yi is selected from the group consisting of hydrogen, -(CH2)_,-Ar , and -N(R2 )2 wherein j is 0 or 1 ;
R2 each time selected is independently hydrogen or Cι-C6 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
R25 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and Cι-C4 alkoxy;
Z is selected from the group consisting of -0-, -NR8-, -C(O)NR8-, -NR8C(O)-, -NR8C(O)NH-, -NR8C(O)O -, and -OC(0)NH-; wherein
R8 is hydrogen or Cι-C6 alkyl;
Q is selected from the group consisting of hydrogen, -(CH2)n-Y2, and -(CH2) Y3; wherein n is an integer from 0 to 4;
Y2 is selected from the group consisting of hydrogen, -(CH2)h-Ar5 and -(CH2),-C(O)OR27 wherein
Ar5 is selected from the group consisting of
wherein
R26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and C C alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6; R27 is hydrogen or Cι-C6 alkyl; x is an integer from 2 to 4;
Y3 is selected from the group consisting of -N(R28)2, N-morpholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein R28 each time taken is independently selected from the group consisting of hydrogen and Cι-C6 alkyl;
R4 is selected from the group consisting of hydrogen, -C(O)Rιo, -C(O)-(CH2)q-K and - S-G wherein
Rio is selected from the group consisting of hydrogen, Cι-C4 alkyl, phenyl, and benzyl; q is 0, 1, or 2;
K is selected from the group consisting of
I' X /*» and -N
\ - - / R.
N— R-
Rιι wherein
V is selected from the group consisting of a bond, -CH2-, -0-, -S(0) , -
NR2,-, and -NC(0)R22; wherein r is 0, 1 , or 2;
R21 is selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl;
R22 is selected from the group consisting of hydrogen, -CF3, Ci-
C10 alkyl, phenyl, and benzyl; Ri 1 each time taken is independently selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl;
G is selected from the group consisting of
C°2 Ri6
wherein w is an integer from 1 to 3;
R12 is selected from the group consisting of hydrogen, Cι-C6 alkyl,
-CH2CH2S(O)uCH3, and benzyl; wherein u is 0,1, or 2; R13 is selected from the group consisting of hydrogen, hydroxy, amino, Ci-Cό alkyl, N-methylamino, N,N-dimethylamino, -CO2Ri7, and - OC(O)R,8;
10 wherein
R,7 is hydrogen, -CH20-C(O)C(CH3) , C,-C4 alkyl, benzyl, or diphenylmethyl;
Ri8 is hydrogen, Cι-C6 alkyl or phenyl; R]4 is 1 or 2 substituents independently selected from the group
15 consisting of hydrogen, Cι_C4 alkyl, C]_C4 alkoxy, or halogen; Vi is selected from the group consisting of -0-, -S-, and -NH-; V2 is selected from the group consisting of -N- and -CH-; V3 is selected from the group consisting of a bond and -C(O)-; V is selected from the group consisting of -0-, -S-, -NR19-, and -
20 NC(O)R20-; wherein
R19 is hydrogen, C|-C alkyl, or benzyl; R20 is hydrogen, -CF3, Ci-Cio alkyl, or benzyl; R15 is selected from the group consisting of hydrogen, Cι-C6 alkyl and benzyl;
Ri6 is selected from the group consisting of hydrogen and Cι-C alkyl; and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof.
In addition, 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.
As is appreciated by one of ordinary skill in the art 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 -NHR15 and at the point of attachment of the group -NHC(O)CH(R3)(SR ) to the benzolactam. Where indicated 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 α- Amino-Acids, R. M. Williams (Pergamon Press, Oxford 1989); M. J. O'Donnell ed.: o Amino-Acid Synthesis, Tetrahedron Symposia in print, No. 33, Tetrahedron 44, No. 17 (1988); U. Schollkopf, PureAppl. Chem. 55, 1799 (1983); U. Hengartner et al. J. QΓ . Chem., 44, 3748-3752 (1979); M. J. O'Donnell et al. Tet. Lets., 2641-2644 (1978); M. J. O'Donnell et al. Tet. Lets. 23, 4255-4258 (1982); M. J. O'Donnell et al. J. Am. Chem. Soc, 110, 8520-8525 (1988).
The specific 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).
As used in this application:
a) the term "halogen" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom;
b) the term "Cι-C6 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) the term "Cι-C4 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;
d) the term "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.;
e) the term "d-C4 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 " ΛΛΛ " refers to a bond for which the stereochemistry is not designated;
g) the designation " ~ " refers to a bond that protrudes forward out of the plane of the page.
h) the designation " " refers to a bond that protrudes backward out of the plane of the page.
i) as used in the examples and preparations, the following terms have the meanings indicated: "g" refers to grams, "mg" refers to milligrams, "μg" refers to micrograms, "mol" refers to moles, "mmol" refers to millimoles, "nmole" refers to nanomoles, "L" refers to liters, "mL" or "ml" refers to milliliters, "μL" refers to microliters, "°C" refers to degrees Celsius, "Rf" refers to retention factor, "mp" refers to melting point, "dec" refers to decomposition, "bp" refers to boiling point, "mm of Hg" refers to pressure in millimeters of mercury, "cm" refers to centimeters, "nm" refers to nanometers, "brine" refers to a saturated aqueous sodium chloride solution, "M" refers to molar, "mM" refers to millimolar, "μM" refers to micromolar, "nM" refers to nanomolar, "HPLC" refers to high performance liquid chromatography, "HRMS" refers to high resolution mass spectrum, "DMF" refers to dimethylformamide, "μCi" refers to microcuries, "i.p." refers to intraperitoneally, "i.v." refers to intravenously, and "DPM" refers to disintegrations per minute;
j) for substituent Z, the designations -C(0)NR8-, -NR8C(O)-, -NR8C(O)NH-, -
NR8C(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;
k) the term "pharmaceutically acceptable salts thereof refers to either an acid addition salt or a basic addition salt.
The expression "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. Illustrative 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. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of 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. In general, 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.
The expression "pharmaceutically acceptable basic addition salts" is 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.
As with any group of structurally related compounds which possess a particular utility, certain groups and configurations of substituents are preferred for the compounds of formula (1 ). Preferred embodiments are given below:
The compounds in which Ri is selected from the group consisting of CrC6 alkyl and -(CH2)dArι are preferred;
The compounds in which Ri is -(CH2)dArι and Ari is phenyl or substituted phenyl are more preferred;
Compounds in which j is selected from the group consisting of hydrogen, -C(O)Rιo and -S-G are preferred;
Compounds in which I ) is hydrogen, are more preferred;
Compounds in which R4 is -C(O)Rιo and R] 0 is C1-C4 alkyl more preferred;
Compounds in which A is -OH are preferred; and
Compounds in which A is -NRR' wherein R is hydrogen and R' is methyl are 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, 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, L-cysteine ethyl ester, 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, N-acetyl- L-cysteine ethyl ester, disulfide; 2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo- 1,3,4,5- tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valeric acid, L-cysteine, disulfide; 2- (4-(2-Thio-3 -phenyl-propionyl-amino)-3 -oxo- 1 ,3,4,5- tetrahydro-benzo [c] azepin-2-yl)- 4-methyl-valeric acid, benzylthio, 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, ethylthio, 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, disulfide, 2-hydroxyethylthio, 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, t-butyl ester, 2-pyridylmethylthio, 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, 2- thioacetic acid morpholine carboxamide, 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, t-butyl ester, benzylthio, 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, t- butyl ester, ethylthio, 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, t-butyl ester, disulfide, 2- hydroxyethylthio, 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, t-butyl ester, 2- pyridylmethylthio, 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, t-butyl ester, 2-thioacetic acid morpholine carboxamide, disulfide.
As used herein the term "amino acid" refers to naturally occurring amino acids as well as non-naturally occurring amino acids having substituents encompassed by Ri and R2 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. Other non-naturally occurring amino acids within the term "amino acid," include without limitation phenylalanines, phenylglycines, homophenylalanines, 3-phenylpropylglycines, 4-phenylbutylglycines; each including those substituted by R6 and R6- as described above; and 1-naphthylalanines and 2- naphthylalanines; including those substituted by R7 and R7- 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.
formula ( 1 ) In Reaction Scheme A, 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 structure (3) in one in which R2 is as desired in the final compound of formula (1), Ri as desired in the final product of formula (1) or gives rise after deprotection to Ri as desired in the final product of formula (1), and A" is A or gives rise to A upon deprotection and modification, if desired, to A as desired in the final compound of formula (1). Appropriate compounds of formula (3) can be prepared by methods described herein and by methods well known and appreciated in the art as described in PCT International Publication Number WO 95/21854, published 17 August 1995 and European Patent Application Publication Number 0 599 444 Al, published 1 June 1994.
An appropriate compound of formula (2) is one in which R3- is R3 as desired in the final product of formula (1) or gives rise after deprotection to R3 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). Alternately, an appropriate compound of formula (2) may also be one in which R3- gives rise to R3 - which, upon further reaction, gives rise R3 as desired in the final product of formula (1 ), as described in Reaction Scheme B, and Y is a protected thio substituent. In addition, an appropriate compound of formula (2) may also be one in which the stereochemistry at the R3- 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).
The use and selection of appropriate protecting groups is 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 R3 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.
For example, 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'-tetramethyluronium hexafluoro-phosphate and the like; activated amide, such as imidazole, dimethylpyrazole, triazole, or tetrazole; or an intermediate formed in the presence of coupling agents, such as dicyclohexylcarbodiimide or l-(3-dimethyaminopropyl)-3- ethylcarbodiimide. The reaction is carried out in 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.
In Reaction Scheme A, 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. For example, 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. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, lyophihzation, chromatography, and recrystallization.
A compound of formula (4) in which Y is bromo undergo a displacement reaction with an appropriate thio introducing reagent to give a compound of formula (5) in which Y is protected thio substituent which gives rise upon deprotection and subsequent elaboration, if desired, the -SR-t as desired in the final compound of formula
For example, 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.
In Reaction Scheme A, 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. The use and selective removal of thio protecting groups is well known and appreciated in the art and described in Protective Groups in Organic Synthesis, Theodora W. Greene (Wiley- Interscience, 2nd Edition, 1991). Alternately, in Reaction Scheme A, 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.
In Reaction Scheme A, step 5, a compound of formula (6) undergoes a undergoes modification reaction to give a compound of formula (7). Such modification reactions include, thiol esterification and disulfide formation.
Compounds of formula (7) in which R is -C(O)R]0 or -C(O)-(CH2)q-X group can be synthesized by thiol esterifications according to techniques well known and appreciated by one of ordinary skill in the art, such as those disclosed in U.S. Pat. Nos. 5,424,425, issued Jun. 13, 1995.
For example, in a thiol esterification a compound of formula (6) is contacted with about an equimolar amount of an appropriate acid, such as HO-C(O)Rιo or HO-C(O)-(CH2)q-X in the presence of a suitable coupling agent to give a compound of formula (6) in which } is -C(O)Rιo or -C(O)-(CH2)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. 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.
Compounds of formula (7) in which R4 is -S-G group can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art, as disclosed in PCT Application No. WO 95/21839, published 17 August 1995 and U.S. Patent Nos. 5,491,143, issued February 13, 1996, and 5,731,306, issued March 24, 1998, and Roques, B.P. et al, J. Med. Chem. 33, 2473-2481 (1992). For example, in a disulfide formation a compound of formula (6) is contacted with an appropriate compound of formula (8).
(8) 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). In addition, 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.
In Reaction Scheme A, 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). In Reaction Scheme A, step 6, 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 ). Also in Reaction Scheme A, step 6, a compound of formula (4) in which Y is bromo can be displaced by an appropriate thio ester, Ph3S-C(O)-(CH2)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.
In Reaction Scheme A, 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', Rl 5 R2, R3, and R , as required to give the desired compound of formula
(1)- Reaction Scheme B
^
In Reaction Scheme B, step 1, an appropriate compound of formula (5) is deprotected, hydrolyzed, or reduced to give a compound of formula (9). In Reaction Scheme B, 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 R2 are as desired in the final product of formula (1) or give rise upon deprotection to Ri and/or R2 as desired in the final product of formula (1). In Reaction Scheme B, step 1, an appropriate compound of formula (5) is one in which R3- gives rise to a compound of formula (9) in which R3- is R3 as desired in the final product of formula (1) or undergoes further derivitization (step 2) to give a compound of formula (10) in which R3 is as desired in the final product of formula (1). In Reaction Scheme B, 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). In Reaction Scheme B, the use of compounds of formula (5) in which Y is a protected thio group, such as thioacetyl, thiobenzoyl, 4- methoxybenzylthio or t-butylthio is preferred.
For example, in a deprotection a compound of formula (5) in which R3- is - (CH2)m-W (phthalimido group) is contacted with a molar excess of hydrazine monohydrate to give a compound of formula (9) in which R3 - is -(CH2)m-NHR8 in which R8 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.
Alternately, for example, in a deprotection of a compound of formula (5) in which R3- is -(QH^m-NRs-t-Boc is contacted with a molar excess of a suitable acid to give a compound of formula (9) in which R3- is -(CH2)m-NHR8. The reaction is typically carried out in a organic solvent, such as methanol, ethanol, ethyl acetate, diethyl ether, or dioxane. Suitable acids for this reaction are well known in the art, including hydrochloric acid, hydrobromic acid, trifluoroacetic acid, and methanesulfonic acid. 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.
For example, in a hydrolysis a compound of formula (5) in which R3- is -(CH2)m-C(O)OPg3 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 R3- is -(CH2)m-CO2H. 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.
For example, in a reduction a compound of formula (5) in which Ry is -(CH2)m-ι-Cθ2Pg3 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 R3 - is -(CH2)n.-i-CH2OH. The reaction is carried out in 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.
In Reaction Scheme B, step 2, a compound of formula (9) undergoes a derivitization reaction to give a compound of formula (10) in which R3 is as desired in the final product of formula (1). Such 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.
For example, in an ether formation a compound of formula (9) in which R3- is -(CH2)m-ι-CH2θH is contacted with 1 to 10 molar equivalents of a suitable akylating agent to give a compound of formula (10) in which R3 is -(CH2)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 chloπde, and 3-dιmethylammopropyl chloride The reaction is carried out in a suitable solvent, such as diethyl ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or acetomtπle and using a suitable base, such as sodium hydride, potassium hydride, potassium t-butoxide, and lithium dnsopropylamide The reaction is generally earned out at temperatures of -70°C and room tempeiature 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
Alternately, as appreciated by those skilled in the art, an ether formation can also be earned out by a procedure similar to the one above using a compound of formula (9) m which R3 is -(CH2)m ι-CH2OH 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 The conversion of hydroxy to leaving groups, such as chloro, bromo, and mesylate are well known and appreciated in the art
For example, in an amine alkylation a compound of formula (9) in which R3 is -(CH2)m-NHR8 is contacted with 1 to 10 molar equivalents of a suitable akylating agent to give a compound of formula (10) in which R3 is -(CH2)m-Z-Q in which Z is -NR - The reaction may be carried out after protection of the amine function of R3 in which R8 is hydrogen by a suitable protecting group, such as benzyl or t-Boc For an amine alkylation 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 pyridme and using a suitable base, such as sodium carbonate, tnethylamme, N,N-dnsopropylethylamine or pyridme The reaction is generally earned out at temperatures of room temperature to the refluxing temperature of the solvent 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 Alternately, for example, in an amine alkylation a compound of formula (9) in which R3 - is -(CH2)m-NH2 is contacted in a reductive alkylation with a suitable aldehyde to give a compound of formula (10) useful as an intermediate for preparing compounds in which R3 is -(CH2)m-Z-Q in which Z is -NR8-. 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. It may be advantageous to maintain the pH in the range of about 4 to 6. 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.
For example, in an amido formation a compound of formula (9) in which R3- is is -(CH2)m-Cθ2H is contacted with a suitable amine in an amide formation to give a compound of formula (10) in which R3 is -(CH )m-Z-Q in which Z is amido. Such amide formation reactions using carboxy activation or suitable coupling agents are well known in the art and described above. A suitable amine, HNR8Q, gives rise to R8 and Q as desired in the final product of formula (1), such as methylamine, ethylamine, propylamine, butylamine, N-methyl benzylamine, benzyl β-alanine, 4-(3- aminopropyl)morpholine, and the like.
For example, in an amide formation a compound of formula (9) in which R3- is is -(CH2)m-NHR8 is contacted with a suitable carboxylic acid in an amide formation to give a compound of formula (10) in which R3 is -(CH2)m-Z-Q in which Z is amide. Such amide formation reactions using carboxy activation or suitable coupling agents are well known in the art and described above. 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.
For example, in a urea formation a compound of formula (9) in which R3- is is -(CH2)m-NHR8 is contacted with an appropriate isocyanate, O=C=N-Q, to give a compound of formula (10) in which R3 is -(CH2)m-Z-Q in which Z is urea. 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 R3 - is -(CH2)m-NHR8 in 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.
For example, in an N-carbamoyl formation a compound of formula (9) in which R is -(CH2)m-NHR8 is contacted with an appropriate chloroformate to give a compound of formula (10) in which R3 is -(CH2)m-Z-Q in which Z is N-carbamoyl. An appropriate chloroformate is one which gives rise to Q as desired in the final product of formula (1 ). Examples of chloro formates 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 R3- is -(CH2)nη- NHRs in a suitable solvent, such as toluene, tetrahydrofuran, dimethylformamide, dichloromethane, pyridine, or chloroform. The reaction is carried out in the presence of an excess of 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.
For example, in an O-carbamoyl formation a compound of formula (9) in which
R is
-(CH2)m-i-CH2OH is contacted with an appropriate isocyanate, as defined above for urea formation, to give a compound of formula (10) in which R3 is -(CH2)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.
For example, in a sulfonamide formation to prepare a compound in which R3 is -(CH2)m-NR8 SO2-Y,, a compound of formula (9) in which R3- is -(CH2)m-NHR8 is contacted with an appropriate sulfonamide forming reagent. An appropriate sulfonamide forming reagent, such as a sulfonyl chloride, Y]S(O)2Cl, or sulfonyl anhydride, Yι(O)2S-O-S(O)2 Yi, is one which gives rise to Y, as desired in the final product. Examples of appropriate sulfonamide forming reagents are, 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 chloride, 2,5-dimethoxybenzenesulfonyl chloride, 4- ethylbenzenesulfonyl chloride, 3,4-dimethoxybenzenesulfonyl chloride, 2,6- dichlorobenzenesulfonyl chloride, 3-bromobenzenesulfonyl chloride, 4-n- butylbenzenesulfonyl chloride, benzenesulfonic anhydride, 4-toluenesulfonic anhydride, and 2-mesitylenesulfonic anhydride. 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. 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.
In Reaction Scheme B, optional step 3, a compound of formula (10) in which R3 is as desired in the final product of formula (1) undergoes a selective thiol deprotection to give a compound of formula (11). Such selective thiol deprotections using suitable protecting groups are well known and appreciated in the art as discussed in Reaction Scheme A, step 4, above.
In Reaction Scheme B, 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).
In Reaction Scheme B, optional step 5, a compound of formula (10), (11), or (12) is deprotected to give a compound of formula (1) as discussed in Reaction Scheme A, above.
Alternate routes for preparing the compounds of formula (2) in which Y is bromo are presented in Reaction Schemes C.l and C.2.
Reaction Scheme C.l
^υ (2 in which Y is bromo)
In Reaction Scheme C.l, an appropriate α-amino carboxylic acid of formula (20) is deaminobrominated to give a compound of formula (2) in which Y is bromo. An appropriate α-amino carboxylic acid of formula (20), and protected forms thereof, is one which is one in which R3 is as described above in Reaction Scheme A, step 8, above. In addition, α-amino carboxylic acid of formula (20) may also be one in which the stereochemistry at the R3 bearing carbon gives rise after displacement to the stereochemistry as desired at that carbon in the final product of formula (1). Such appropriate α-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. For example, L-alanine, D-alanine, L-valine, D-valine, D- norvaline, L-leucine, D-leucine, D-isoleucine, D-tert-leucine, glycine, L-glutamic acid, D-glutamic acid, L-glutamine, D-glutamine, L-lysine, D-lysine, L-ornithine, D- ornithine, (D)-(-)-2-aminobutyric acid, D-threonine, D-homoserine, D-allothreonine, D- serine, D-2-aminoadipic acid, D-aspartic acid, D-glutamic acid, D-lysine hydrate, 2,3- diaminopropionic acid monohydrobromide, D-ornithine hydrochloride, D,L-2,4- diaminobutyric acid dihydrochloride, L-meta-tyrosine, D-4-hydroxyphenylglycine, D- tyrosine, L-phenylalanine, D-phenylalanine, D,L-2-fluorophenylalanine, beta-methyl- D,L-phenylalanine hydrochloride, D,L-3-fluorophenylalanine, 4-bromo-D,L- phenylalanine, L-phenylalanine, L-phenylglycine, D-phenylglycine, D,L-4- fluorophenylalanine, 4-iodo-D-phenylalanine, D-homophenylalanine, D,L-2- fluorophenylglycine, D,L-4-chlorophenylalanine, and the like, are all commercially available and the methods in D. A. Evans, et al. J. Am. Chem. Soc, 112, 4011-4030 (1990); S. Ikegami et al. Tetrahedron, 44, 5333-5342 (1988); W.Oppolzer et al. Tet Lets. 30, 6009-6010 (1989); Synthesis of Optically Active α-Amino-Acids, R. M. Williams (Pergamon Press, Oxford 1989); M. J. O'Donnell ed.: α-Amino-Acid Synthesis, Tetrahedron Symposia in print, No. 33, Tetrahedron 44, No. 17 (1988); U. Schδllkopf, PureAppl. Chem. 55, 1799 (1983); U. Hengartner et al. J. QΓ . Chem., 44, 3748-3752 (1979); M. J. O'Donnell et al. Tet. Lets., 2641-2644 (1978); M. J. O'Donnell et al. Tet. Lets. 23, 4255-4258 (1982); M. J. O'Donnell et al. J. Am. Chem. Soc, 110, 8520-8525 (1988).
The deaminobromination described in Reaction Scheme C.1 can be performed utilizing conditions described in Compagnone, R.S. and Rapoport, H., J. Org. Chem.,
51, 1713-1719 (1986); U.S. Pat. No. 5,322,942, issued June 21, 1994; Overberger, C.G. and Cho, I., J. Org. Chem., 33, 3321-3322 (1968); or Pfister, K. et al., J. Am. Chem. Soc, 71 , 1096-1100 (1949). For example, an α-amino carboxylic acid of formula (20) and a suitable bromide, such as hydrogen bromide or potassium bromide in acidic solution, such as sulfuric acid, is treated with sodium nitrite. The reaction temperature is carried out a temperatures of from about -25°C to about ambient temperature and require about 1 to 5 hours. 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.
Reaction Scheme C.2
(21) Br
(2 in which Y is bromo) In Reaction Scheme C.2, 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 R3- is as defined in Reaction Scheme A, step 8, above. In addition, carboxylic acid of formula (21) may also be one in which the stereochemistry at the R3- bearing carbon gives rise after displacement to the stereochemistry as desired at that carbon in the final product of formula (1).
For example, 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.
Compounds of formula (20) and (21) in which R3- is a -(CH2)m-W for use in Reaction Schemes C.l and C.2 are prepared according to Reaction Scheme D.l and D.2.
Raction Scheme D.1
O
(22)
(21) in which R-,- is W-(CH2)m-
In Reaction Scheme D.l an appropriate ω-amino carboxylic acid of formula (22) is converted to an compound of formula (21) in which R3- is W-(CH )m-. An appropriate ω-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. For example, 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. 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 desired compound of formula (21) in which R3- is W-(CH2)m-. Reaction Scheme D.2
NHPgΛ
(25)
(20) in which Rot is W-(CH2)m-
Reaction Scheme D.2, step 1, an appropriate α,ω-diamino acid of formula (23) undergoes a selective N-α-protection to give an N-α-protected-ω-diamino acid of formula (24). An appropriate α,ω-diamino acid of formula (23) is one in which m is as desired in the final product of fomiula (1).
For example, a selective N-α-protection of a suitable α,ω-diamino acid, such as L-lysine (formula (23) in which m is 4), is accomplished by masking the ω-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-ω-benzylidene-L-lysine is recovered by filtration and evaporation. The α-amino group of the N-ω-benzylidene-L-lysine then 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-α-benzyloxy-carbonyl-L-lysine. Accordingly, N-ω-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-α-benzyloxycarbonyl-L-lysine, which corresponds to formula (24) where m is 4, is recovered by filtration evaporate and recrystallization.
In Reaction Scheme D.2, step 2, N-α-benzyloxycarbonyl-L-lysine or other compounds of formula (24) is converted to ω-phthalimido-α-benzyloxycarbonyl-L- lysine or other ω-phthalimido-α-aminoprotected carboxylic acid of formula (25) by the method described in Reaction Scheme D.1 , above.
In Reaction Scheme D.2, step 3, the ω-phthalimido-α-aminoprotected carboxylic acid of formula (25) is deprotected to give compound of formula (20) in which R3- is W-
(CH2)m-.
For example, ω-phthalimido-α-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. 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.
A route for preparing the compounds of formula (2) in which Y is protected thio is presented in Reaction Scheme F. The reagents and starting materials are readily available to one of ordinary skill in the art. In Reaction Scheme H all substituents, unless otherwise indicated, are as previously defined. 00/40564
-41.
Reaction Scheme F
(26) (27)
(2 in which Y is protected thio)
In Reaction Scheme F, step 1 , a bromoacetate of formula (26) is contacted with an appropriate thiol to give a protected acetic acid ester of formula (27). In a bromoacetate of formula (26) Pg5 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.
For example, a bromoacetate of formula (26) is contacted with an appropriate thiol in a suitable organic solvent, such as dimethylformamide. Advantageously, 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.
In Reaction Scheme F, step 2, the protected acetic acid ester of formula (27) is alkylated with an appropriate akylating agent to give a compound of formula (28). In Reaction Scheme F, step 2, an appropriate alkyl ating agent is one which transfers R3- which is R3 as desired in the final product of formula (1) or gives rise after deprotection to R3 as desired in the final product of formula (1) or gives rise to R3 - 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-bromoethyl)phthalimide, , N-(3-bromopropyl)phthalimide, N-(4- bromobutyl)phthalimide, and the like; l-bromo-2-phenylethane, l-bromo-3- phenylpropane, 1 -bromo-4-phenylbutane, and the like.
For example, 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.
In Reaction Scheme F, step 3, the compound of formula (28) the carboxy protecting group Pg5 is selectively removed to give a compound of formula (3b) in which Y is protected thio. Such deprotection of esters to acids in the presence of suitable thio protecting groups are well known and appreciated in the art.
A general preparation of compounds of formula (3) is set forth in Reaction Scheme G. Reaction Scheme G
o-
■Si (CH3) 3
(36) step 7 Reaction Scheme G, Cont.
O R,
(3 in which A' is O-t-Bu and as the 4-(S)-isomer)
In Reaction Scheme G, step 1 , an appropriate compound of structure (30) is functionalized to give the corresponding compound of structure (31). An appropriate compound of structure (30) in one in which R2 is as desired in the final product of formula (1).
For example, 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 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
In Reaction Scheme G, 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)
For example, 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 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-vιnyl-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 recovered from the reaction mixture by extractive methods as are known in the art
In Reaction Scheme G, step 3, a compound of formula (32) is subjected to an addition, elimination reaction with 2-(bιs-methylsulfonyl-methyleneammo)- 1 - (10,10-dιmethyl-3,3-dιoxo-3-thιa-4-aza-tπcyclo( 5 2 1 0 1 ,5)dec-4-yl)-ethanone to give the corresponding compound of formula (33)
For example, the anion of 2-(bιs-methylsulfonyl-methyleneamιno)- 1 -( 10,10- dιmethyl-3,3-dιoxo-3-thιa-4-aza-tπcyclo( 5 2 1 0 l,5)dec-4-yl)-ethanone is formed by treating 2-(bιs-methylsulfonyl-methyleneamιno)-l-(10,10- dιmethyl-3,3-dιoxo-3- thιa-4-aza-tπcyclo(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. 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.
In Reaction Scheme G, step 4, a compound of formula (33) is hydrolyzed to give a compound of formula (34).
For example, a compound of formula (33) is treated with 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. Evaporation of the solvent followed by treatment with 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. After acidification, the corresponding 2-amino- 3-(2-vinyl-phenyl)-propionic acid derivative of formula (34) was isolated by evaporation of solvents.
In Reaction Scheme G, step 5, the amino functionality of a compound of formula (34) is protected to give the corresponding compound of formula (35).
For example, 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. 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.
In Reaction Scheme G, step 6, the carboxylic acid functionality of a compound of formula (35) is esterified to give a compound of formula (36). For example, 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. 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.
In Reaction Scheme G, step 7, the vinyl functionality of a compound of formula (36) is oxidized to give a compound of formula (37).
For example, a compound of formula (36) is treated with ozone in 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. After purging the reaction with nitrogen and quenching by methods known in the art, such as addition of dimethylsulfide and pyridine, the product is recovered from the reaction zone by extractive methods as are known in the art and may be purified by chromatography.
In Reaction Scheme G, 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). In Reaction Scheme G, step 8, 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). In addition, an appropriate amino acid, tert-butyl ester derivative is one in which the stereochemistry is as desired in the final product of formula (1). As is appreciated by those skilled in the art, the use of amino acid, tert-butyl ester derivatives give rise to compounds of formula (3) in which A' is -O-tert-butyl. It is also understood that 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. For example, 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. As one skill in the art would realize, 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. The selection and utilization of 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).
In Reaction Scheme G, step 9, the ester functionality of a compound of formula (39) is hydrolyzed to give a compound of formula (40).
For example, a compound of formula (39) is treated with 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.
In Reaction Scheme G, step 10, a compound of formula (39) is subjected to a ring closure amination reaction to give a compound of formula (40).
For example, 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. 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.
In Reaction Scheme G, 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.
For example, the phthalimide protecting groups of a compound of formula (40) can be removed using hydrazine monohydrate in 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.
The following examples present typical syntheses as described in the Reaction
Schemes above. These examples and preparations are understood to be illustrative only and are not intended to limit the scope of the invention in any way.
PREPARATION 1 Synthesis of 2-(4-amino-3-oxo-l,3,4,5-tetrahvdro-benzorclazepin-2-yl)-4-methyl- valeric acid, tert-butyl ester
Dissolve homophthalic acid (22.2 g, 0.123 mmol) in tetrahydrofuran (250 mL) and add dropwise at room temperature to a slurry of lithium aluminum hydride (15.5 g, 0.407 mol) in tetrahydrofuran (500 mL). Heat at reflux for 18 hours, cool in an ice bath and carefully add, by dropwise addition, water (16 mL), followed by 50% sodium hydroxide (16 mL). Remove the ice bath, add water slowly with stirring and stir until the gray precipitate turns white and evolution of gas ceases. Filter, wash solids with methylene chloride, dry (MgSO4 ) and evaporate the solvent in vacuo to give 2-(2- hydroxymethyl-phenyl)-ethanol as a viscous oil (18.4 g, 98%). Mix 2-(2-hydroxymethyl-phenyl)-ethanol (12.0 g, 78.8 mmol) and collidine
(23 mL, 0.17mol) and treat with lithium chloride (7.35 g, 0.173 mmol) in dimethylformamide (125 mL). Cool in an ice bath and treat, by dropwise addition, with mesyl chloride (13.4 mL). Stir at 0°C for 4 hours, partition between ice water (300 mL) and a 1 :1 mixture of ether:pentane (2X400 mL). Wash the organic layer with a saturated solution of CuSO4 (2X200 L), dry (MgSO ) and purify by silica gel chromatography (2.5:1 hexane/ethyl acetate followed by 2:1 hexane/ethyl acetate followed by 3:2 hexane/ethyl acetate) to give methanesulfonic acid 2-(2- chloromethyl-phenyl)-ethyl ester as a pale yellow oil (8.8 g, 45%). Dissolve methanesulfonic acid 2-(2-chloromethyl-phenyl)-ethyl ester (8.8 g,
35.4 mmol) in ether (80 mL) and cool to -35° C. Add potassium t-butoxide (10 g, 89 mmol) and stir for 30 minutes. Add water (50 mL) and ether (150 mL), extract, dry (Na2SO ) and purify by silica gel chromatography (2:3 methylene chloride/pentane) to give 1 -chloromethyl-2-vinyl-benzene as a colorless oil (4.43 g, 82%). Dissolve l-chloromethyl-2-vinyl -benzene (4.0 g, 26 mmol) in acetone (100 mL) and add sodium iodide (4.5 g, 30 mmol). Heat at gentle reflux for 30 minutes. Cool, add water (150 mL) and extract with pentane (200 mL). Dry (MgSO4 ) and evaporate the solvent in vacuo to give l-iodomethyl-2-vinyl-benzene (95%).
Dissolve 2-(bis-methylsulfanyl-methyleneamino)- 1 -( 10, 10- dimethyl-3 ,3- dioxo-3-thia-4-aza-tricyclo(5.2.1.0 l,5)dec-4-yl)-ethanone (7.91 g, 21.0 mmol) in tetrahydrofuran (100 mL) and cool to -78°C. Treat, by dropwise addition, with 1.6 M n-butyllithium in hexane (13.1 mL, 21 mmol). Stir for 1.5 hours, then add hexamethylphosphotriamide (HMPA) (4.25 mL, 24.4 mmol). Stir for 15 minutes and add, via cannula, a solution of l-iodomethyl-2-vinyl-benzene (6.1 g, 25 mmol) in tetrahydrofuran (100 mL). Stir overnight at room temperature, partition between saturated ammonium chloride (2X75 mL) and ethyl acetate (400 mL). Dry (Na2S04) and purify by silica gel chromatography (2.5: 1 hexane/ethyl acetate) to give 2-(bis- methylsulfanyl-methyleneamino)-l-(10,10-dimethyl- 3,3-dioxo-3-thia-4-aza- tricyclo(5.2.1.0 l ,5)dec-4-yl)- 3-(2-vinyl-phenyl)-propan-l-one as a white solid (4.5g).
Dissolve 2-(bis-methylsulfanyl-methyleneamino)- 1 -( 10, 10- dimethyl-3, 3- dioxo-3-thia-4-aza-tricyclo(5.2.1.0 l,5)dec-4-yl)-3-(2-vinyl-phenyl)-propan-l -one (5.21 g, 10.6 mmol) in tetrahydrofuran (100 mL) and ) and 0.75 M hydrochloric acid (100 mL). Stir at room temperature for 24 hours, evaporate the solvent in vacuo to give the hydrochloride salt as a white solid. Dissolve in tetrahydrofuran (200 mL) and water (50m), add lithium hydroxide monohydrate (1.9 g, 4.5 mmol) and stir at room temperature under a nitrogen atmosphere for 4 hours. Extract into methylene chloride (200 mL) and wash with 2N sodium hydroxide (50 mL). Acidify to pH 2-3 while cooling in an ice bath and concentrate in vacuo to give 2-Amino-3-(2-vinyl- phenyl)-propionic acid as an off-white solid (3.40 g, 100%o).
Dissolve 2-amino-3-(2-vinyl-phenyl)-propionic acid (3.40g) in water (75 mL) and add sodium carbonate (1.97 g, 18.6 mmol) and N-carbethoxyphthalimide (2.81 g, 12.8 mmol). Stir for 2.5 hours, wash with methylene chloride (200 mL), acidify to pH 1 with cold concentrated hydrochloric acid and extract with ethyl acetate (3X200 mL), dry (Na S04), evaporate the solvent in vacuo and purify by silica gel chromatography (1 : 1 :0.02 hexane/ethyl acetate/acetic acid) followed by recrystallization (isopropanol) to give 2-(l ,3-dioxo-l,3-dihydro-isoindol-2-yl)-3- (2-vinyl-phenyl)- propionic acid as a pale yellow solid (2.47g).
Dissolve 2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)- propionic acid (2.47 g, 7.69 mmol) in tetrahydrofuran (35 mL) and cool in an ice bath. Treat with pyridine (1.6 mL, 20 mmol) and 2-(trimethylsilyl)ethanol (2.3 mL, 16 mmol). Stir for 30 minutes and add l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC) (2.21 g, 11.5 mmol). Stir for 22 hours at 5°C, then at room temperature for 1.5 hours. Cool to 0°C, add 0.6 times all reagents and stir at room temperature overnight. Dilute with ethyl acetate (150 mL), wash with 5% sulfuric acid (40 mL) and saturated sodium hydrogen carbonate (40 mL). Back extract with methylene chloride (100 mL), wash with brine (30 mL) and dry (Na2S04). Evaporate the solvent in vacuo and purify by silica gel chromatography (2:1 hexane/ethyl acetate) to give 2-(l,3-dioxo-l,3-dihydro- isoindol-2-yl)-3 -(2-vinyl-phenyl)- propionic acid, 2-trimethylsilanyl-ethyl ester (2.61 g, 81%).
Dissolve 2-(l,3-dioxo-l, 3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)- propionic acid, 2-trimethylsilanyl-ethyl ester (2.61 g, 6.19 mmol) in methylene chloride (70 mL) and methanol (75 mL). Cool to -78°C and treat with ozone until a blue color persists. Purge with nitrogen and add dimethylsulfide (7 mL) and pyridine (0.35 mL). Allow to warm to room temperature gradually overnight. Partition between methylene chloride (100 mL) and water (40 mL). Extract the aqueous with methylene chloride (50 mL), dry (Na2SO4) and purify by silica gel chromatography (2.5:1 hexane/ethyl acetate) to give the title compound as a colorless viscous oil (2.65 g, 100%). 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). Stir at room temperature for 2 hours with 3A molecular sieves, add sodium cyanoborohydride (0.6 mL of a 1.0M solution in tetrahydrofuran, 0.6 mmol), stir for 0.5 hours, add additional sodium cyanoborohydride (0.3 mL) and stir for 5 hours. Filter through filter aid, evaporate the solvent in vacuo and partition the residue between methylene chloride (100 mL) and saturated sodium hydrogen carbonate (40 mL). Dry (Na2SO4), evaporate the solvent in vacuo and purify by silica gel chromatography (5:1 hexane/ethyl acetate followed by 3:1 hexane/ethyl acetate) to give 2-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-3-(2-formyl- phenyl)-propionic acid, 2- trimethylsilanyl-ethyl ester (221 mg, 63%).
Dissolve 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 (221 mg, 0.372 mmol) in tetrahydrofuran (5 mL) and treat with tetrabutylammonium fluoride (0.43 mL of a 1.0M solution in tetrahydrofuran, 0.43 mmol). Stir for 1.5 hours, evaporate the solvent in vacuo and dissolve the residue in ethyl acetate (75 mL). Wash with IN hydrochloric acid (25 mL) and brine (25 mL). Dry (Na2SO4) and evaporate the solvent in vacuo to 2-(2-(2-carboxy-2-(l ,3-dioxo- l,3,dihydro-isoindol-2-yl)-ethyl)-benzylamino)-4-methyl-valeric acid, tert- butyl ester as a white solid (188mg).
Dissolve 2-(2-(2-carboxy-2-(l,3-dioxo-l,3,dihydro-isoindol-2-yl)-ethyl)- benzylamino)-4-methyl-valeric acid, tert-butyl ester (188mg) in tetrahydrofuran (10 mL) and cool in an ice bath. Add sequentially, N-methylmorpholine (86μL. 0.78 mmol), and isobutylchloroformate (55μL, 0.43 mmol). Stir for 2 hours, filter, wash salts with dry tetrahydrofuran, evaporate the solvent in vacuo and purify by silica gel chromatography (1 :1 hexane/ethyl acetate) to give 2-(4-((l,3-dioxo-l,3,dihydro- isoindol-2-yl)-3-oxo-l ,3,4,5- tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valeric acid, tert-butyl ester as a white solid (64 mg, 93%). Dissolve 2-(4-((l,3-dioxo-l,3,dihydro-isoindol-2-yl)-3-oxo-l,3,4,5- tetrahydro- benzo[c]azepin-2-yl)-4-rnethyl-valeric acid, tert-butyl ester (160 mg, 0.336 mmol) in methanol (3 mL) and treat with a solution of hydrazine monohydrate (0.40 mL, 0.40 mmol) in methanol. Stir at room temperature for 65 hours, filter through filter aid, wash with methylene chloride, filter through filter aid and dry (MgSO4 ). Evaporate the solvent in vacuo to give the title compound (93 mg, 80.2% for this step).
EXAMPLE 1 i 2-(4-(2-Benzoylsulfanyl-3-phenyl-propionyl-amino)- 3-oxo-l,3,4,5-tetrahydro- benzo clazepin-2-yl)-4-methyI- valeric acid
1.1 Synthesis of 2-(4-(2-benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo-l, 3,4,5- tetrahydro-benzorclazepin-2-yl)-4-methyl-valeric acid, tert-butyl ester Dissolve 2-(4-amino-3-oxo-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4- methyl-valeric acid, tert-butyl ester (93 mg, 0.27 mmol) in methylene chloride (3 mL) and treat with (S)-3-phenyl-2-benzoylthiopropionic acid (115 mg, 0.40 mmol) and EEDQ (100 mg, 0.40 mmol). Stir at room temperature for 18 hours, evaporate the solvent in vacuo, dissolve the residue in ethyl acetate (40 mL) and wash with 5% sulfuric acid (15 mL) when with saturated sodium hydrogen carbonate (15 mL). Dry (Na2S04), evaporate the solvent in vacuo and purify by silica gel chromatography (6:1 hexane/ethyl acetate followed by 2.5: 1 hexane/ethyl acetate) to give the title compound as a colorless oil (141 mg, 85%).
1.2 Synthesis of 2-(4-(2-benzoylsulfanyl-3 -phenyl -propionyl-amino)- 3-oxo-l, 3,4,5- tetrahydro-benzorclazepin-2-yl)-4-methyl- valeric acid
Dissolve 2-(4-(2-benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo-l, 3,4,5- tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valeric acid, tert-butyl ester (141 mg, 0.229 mmol) in methylene chloride (5 mL) and treat with anisole (0.12 mL, 1.15 mmol) then with trifluoroacetic acid (1.5M). Stir at room temperature for 15 hours, partition between ethyl acetate (25 mL) and brine (15 mL). Wash the organic layer with brine (15 mL), dry (Na2SO ) and purify by silica gel chromatography (1 :1 hexane/ethyl acetate followed by 1 :1 :0.01 hexane/ethyl acetate/acetic acid) to give the title compound as a white solid (157mg).
EXAMPLE 2 2-(4-(2-Mercapto-3-phenyl-propionyl-amino)-3-oxo- 1,3,4,5-tetrahydro- benzo|"c1azepin-2-yl)-4-methyl-valeric acid
2.1 Synthesis of 2-(4-(2-mercapto-3-phenyl-propionyl-amino)-3-oxo- 1,3,4,5- tetrahydro-benzo|"c1azepin-2-yl)-4-methyl-valeric acid
Dissolve 2-(4-(2-benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo- 1 ,3,4,5- tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valeric acid (0.229 mmol) in degassed methanol (3 mL) and cool in an ice bath. Treat with degassed IM aqueous lithium hydroxide (1.0 mL) and stir, allowing the ice bath to warm gradually over 3 hours. With the reaction at 0°C, acidify with 5% hydrochloric acid. Partition between methylene chloride (75 mL) and water (25 mL), dry (Na2SO4) and purify by silica gel chromatography (3:1 :0.01 hexane/ethyl acetate/acetic acid followed by 1 :1 :0.01 hexane/ethyl acetate/acetic acid to give the title compound as a white solid (84 mg, 80.8%).
PREPARATION 2 Synthesis of 2-bromo-6-phthalimidohexanoic acid
Combine 6-aminohexanoic acid (6-aminocaproic acid) (8.0 g, 60 mmol) and water (100 mL). Add sodium carbonate (6.84 g, 64 mmol) and N- carbethoxyphthalimide (14.0 g, 64 mmol). After 1.5 hours, extract the reaction mixture with ethyl acetate (100 mL). Cool the aqueous layer in an ice bath and acidify using concentrated hydrochloric acid to give a solid. Collect the solid by filtration, rinse with water, and dry to give 6-phthalimidohexanoic acid (12.7 g, 80%. yield). Combine 6-phthalimidohexanoic acid (12.7 g, 48 mmol) and dry red phosphorous (1.95 g, 63 mmol). Cool in an ice bath and add dropwise bromine (12.7 mL, 246 mmol). Warm to room temperature and then heat to 80°C. After 3 hours, cool the reaction mixture to ambient temperature, pour into water (300 mL) containing sodium bisulfite, and neutralize using solid sodium bicarbonate and extract with diethyl ether (about 150 mL). Acidify the aqueous layer with concentrated hydrochloric acid give a solid. Collect the solid by filtration and dry to give the title compound (15 g,
91.5% yield, 73.2% for both steps).
PREPARATION 3
Synthesis of (R)-2-bromo-6-phthalimidohexanoic acid
Combine (R)-2-N-carbobenzyloxy-6-aminohexanoic acid ((R)-Nα-Cbz-lysine)
(14.0 g, 50 mmol) and water (500 mL). Add sodium carbonate (5.65 g, 53 mmol) and N-carbethoxyphthalimide (13.15 g, 60 mmol). After 1.5 hours, acidify using concentrated hydrochloric acid to give a solid. Collect the solid by filtration, rinse with water, and dry to give (R)-2-N-carbobenzyloxy-6-phthalamidohexanoic acid.
Combine (R)-2-N-carbobenzyloxy-6-phthalamidohexanoic acid obtained above, methanol (200 mL), 10% palladium-on-carbon (1 g) and treat with hydrogen at atmospheric pressure. After 18 hours, filter, add to the filtrate a solution of hydrochloric acid in methanol (50 mL, 1 M, 50 mmol), and evaporate in vacuo to give (R)-2-amino-
6-phthalamidohexanoic acid hydrochloric acid salt.
Combine (R)-2-amino-6-phthalamidohexanoic acid hydrochloric acid salt (12.5 g, 40 mmol) and a 2.5 M aqueous sulfuric acid solution (40 mL). Cool in a salt-ice bath. Add 49% aqueous hydrobromic acid solution (13.2 g). Add dropwise over about 20 minutes, an aqueous solution of sodium nitrite (2.8 g, 40 mmol, in 20 mL of water).
After 3 hours, warm to ambient temperature. After 18 hours, collect the resultant solid by filtration, rinse with water and dry in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/dichloromethane containing 5% acetic acid to give the title compound.
EXAMPLE 3 2-(4-(2-Mercapto-6-phthalimidohexanoyl-amino)-3-oxo-l,3,4,5-tetrahydro- benzo c1azepin-2-yl)-4-methyl-valeric acid
3.1 Synthesis of 2-(4-(2-bromo-6-phthalimidohexanoyl-amino)-3-oxo-l , 3,4,5- tetrahydro-benzorc]azepin-2-yl)-4-mefhyl-valeric acid t-butyl ester
Combine 2-(4-amino-3-oxo-l, 3,4, 5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl- valeric acid, tert-butyl ester (0.34 mmol), 2-bromo-6-phthalimidohexanoic acid (0.189 g, 0.56 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.106 g, 0.55 mmol), and 1 -hydroxybenztriazole hydrate ((75 mg, 0.56 mmol) in dicloromethane (8 mL). After 17 hours, evapoarte in vacuo to give a residue, partition the residue between ethyl aceate and an aqueous 5% sulfuric acid solution (about 20 mL). Separate the layers, extract the organic layer with a saturate aqueiosu sodium bicarbonate solution and then brine, dry over Na SO , filter, and evaporate in vacuo to give the title compound.
3.2 Synthesis of 2-(4-(2-(p-methoxybenzylthio)-6-phthalimidohexanoyl-amino)-3-oxo- l,3,4,5-tetrahydro-benzo[clazepin-2-yl)-4-methyl-valeric acid t-butyl ester
Combine p-methoxybenzylmercaptan (0.08 mL, 0.57 mmol) and sodium hydride (17 mg, 60% oil dispersion, 0.42 mmol) in degassed dimethylformamide (3 mL). After 1 hour, tetra-n-butylammonium iodide (about 5 mg) and 2-(4-(2-bromo-6- phthalimidohexanoyl-amino)-3-oxo-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl- valeric acid t-butyl ester (0.27 mmol). After 20 hours, quench be the addition of a saturated aqueous ammonium chloride solution and dilute with water (about 5 mL). Extract with ethyl acetate (about 75 mL). Separate the layers and extract the orgainc layer with brine, dry over N 2S0 , filter, and evaporate in vacuo to give the title compound.
3.3 Synthesis of Σ-^-^-mercapto-ό-phthalimidohexanoyl-aminoVS-oxo- SAS- tetrahydro-benzofclazepin^-yl -methyl-valeric acid Combine 2-(4-(2-(p-methoxybenzylthio)-6-phthalimidohexanoyl-amino)-3-oxo- l,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valeric acid t-butyl ester (0.20 mmol), mercury (II) acetate (0.084 g, 0.26 mmol), and anisole (0.23 mL, 2.1 mmol) in dichloromethane (6.6 mL). Cool in an ice bath and degas by repeatedly cycles of vacuum and filling the vessel with nitrogen gas. Add trifluoroacetic acid (2.5 mL). After 1 hour, warm to ambient temperature. After 3 hours, purge with hydrogen sulfide (gas) for about 10 minutes. Filter and evaporate in vacuo to give a residue. Repeatedly, combine the residue and carbon tetrachloride and evaporate in vacuo to give the title compound.
PREPARATION 4
Synthesis of (L)-phenylalanine-N-methyl amide trifluoroacetic acid salt
Combine t-Boc-(L)-phenylalanine (8.00 g, 30.2 mmol) and tetrahydrofuran (20 mL). Cool to about -30°C and add sequentially N-methylmorpholine (3.5 mL, 32 mmol) and then isobutyl chloroformate (4.5 mL, 35 mmol). After 10 minutes, add 40% aqueous methylamine (13 mL, 380 mmol). After 2 hours, concentrate the reaction mixture in vacuo, combine the evaporated reaction mixture and dichloromethane (125 mL) and extract with an aqueous IM hydrochloric acid solution and then a saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO , filter, and evaporate in vacuo to give t-Boc-(L)-phenylalanine-N-methyl amide, which is used without further purification.
Combine t-Boc-(L)-phenylalanine-N-methyl amide (8.4 g, 30 mmol), methylene chloride (100 mL), and trifluoroacetic acid (20 mL). After 3 hours, evaporate in vacuo to give a residue. Repeatedly, combine the residue and carbon tetrachloride and toluene remove residual trifluoroacetic acid by coevaporation and evaporate in vacuo to give a residue. Triturate the residue with diethyl ether to yield the title compound as a solid (9.12 g, 100%).
PREPARATION 5 Synthesis of 2-(4-amino-3-oxo-l,3,4,5-tetrahydro-benzo["clazepin-2-yl)-3-phenyl- propionic acid, N-methyl amide
Prepare by the method of Preparation 1 using (L)-phenylalanine-N-methyl amide trifluoroacetic acid salt to give the title compound. EXAMPLE 4
2-(4-(2-Mercapto-6-phthalimidohexanoyl-amino)-3-oxo- 1,3,4, 5-tetrahydro- benzorclazepin-2-yl)- 3-phenyl-propionic acid, N-methyl amide
4.1 Synthesis of 2-(4-(2-bromo-6-phthalimidohexanoyl-amino)-3-oxo- 1,3,4,5- tetrahydro-benzo[clazepin-2-yl)- 3-phenyl-propionic acid, N-methyl amide
Prepare by the method of Example 3.1 using 2-(4-amino-3-oxo-l ,3,4,5- tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionic acid, N-methyl amide and 2- bromo-6-phthalimidohexanoic acid to give the title compound.
4.2 Synthesis of 2-(4-(2-(p-methoxybenzylthio)-6-phthalimidohexanoyl-amino)-3-oxo- l,3,4,5-tetrahydro-benzo[~clazepin-2-yl)- 3-phenyl-propionic acid, N-methyl amide
Prepare by the method of Example 3.2 using 2-(4-(2-bromo-6- phthalimidohexanoyl-amino)-3-oxo-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl- propionic acid, N-methyl amide and p-methoxybenzylmercaptan to give the title compound.
4.3 Synthesis of 2-(4-(2-mercapto-6-phthalimidohexanoyl-amino)-3-oxo- 1 ,3,4,5- tetrahydro-benzo clazepin-2-yl)- 3-phenyl-propionic acid, N-methyl amide Prepare by the method of Example 3.3 using 2-(4-(2-(p-methoxybenzylthio)-6- phthalimidohexanoyl-amino)-3-oxo-l,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl- propionic acid, N-methyl amide, mercury (II) acetate, anisole, and trifluoroacetic acid to give the title compound.
The present invention provides a method of inhibiting matrix metalloproteinase
(MMP) to a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of formula (1). As used herein, the term "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. For example, 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.
The identification of those patients who are in need of treatment to inhibit MMP is well within the ability and knowledge of one skilled in the art. A clinician skilled in the art can readily identify, by the use of clinical tests, physical examination and medical/family history, those patients who are suffering from disease states characterized by excessive tissue disruption or tissue degradation.
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. As used herein, "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. In 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.
A 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, follicullar reticulum, cell sarcoma and Hodgkin's Disease. Neoplastic disease states for which treatment with a compound of formula (1 ) will be particularly preferred include carcinomas and adenocarcinomas, particularly of the breast, prostate and lung.
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.
The term "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.
In effecting treatment of a patient, 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. For example, 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.
The pharmaceutical 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. For the purpose of oral therapeutic administration, a compound of formula (1) may be incoφorated 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, Pπmogel, 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 When 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 Thus, tablets or pills may be coated with sugar, shellac, or other entenc coating agents A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors Matenals used m preparing these vanous compositions should be pharmaceutically pure and non-toxic in the amounts used
For the puφose of parenteral therapeutic administration, the compounds of the present mvention may be incoφorated 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.
EXAMPLE A
Source and Activation of proMMP-1
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 μg/mL) at 37°C for 30 minutes, followed by addition of soybean trypsin inhibitor (50 μg/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-NH2, Knight, C.G. et al., FEBS Lett. 296, 263-266 (1992), 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, and 0.02% Brij-35. The increase in fluorescence due to cleavage of Gly-Leu peptide bond by MMP-3 was monitored with Perkin-Elmer LS50B Fluorimeter (λex 328 nm, λem 393 nm, excitation slit 2.5, emission slit 10). Substrate and inhibitor stock solutions were made in DMF. For determination of K, values for MMP-1 inhibitors, a series of intermediate inhibitor solutions were prepared in DMF and 1 or 2 μL of the diluted inhibitor solution was mixed with 1 μL of 2 mM substrate solution in DMF in a quartz cuvette containing 2 mL of assay buffer. The enzyme (10 μL of 0.2 μM MMP-3 dilution in assay buffer) was added at the last to start the reaction. For routine measurement of a K, value for a reversible, competitive inhibitor, the initial rates in the presence of at least four inhibitor concentrations (two concentrations above K, and two concentrations below K,) were measured using [S] = 1 μM (« Km) and [MMP-1] = 0.8 nM. Under these conditions, the measured K,, app is close to true K,. Calculation of K, Values
The K, for a competitive inhibitor is calculated using: v0/V| = (1 + [IJ/K^ app) and K, = KI> app/(l + [S]/Km), where v0 is the initial rate in the absence of inhibitor, v, is the initial rate in the presence of inhibitor at the concentration of [I], [S] is the substrate concentration, and Km is the Michaelis constant. If slow binding is observed (i.e. if the approach to the binding equilibrium is slow), the final steady-state rate rather than the initial rate is taken as v,.
EXAMPLE B Source and Activation of proMMP-2
Recombinant MMP-2 was purified from the fermentation broth of yeast Pichia pastoris that carries the integrated MMP-2 gene into its chromosome. In brief, 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 μM β- mercaptoethanol. The increase in fluorescence is monitored (λex 328 nm, λem 393 nm). Substrate and inhibitor stock solutions are made in DMF. The enzyme is added at the last to start the reaction. For routine measurement of a K, value for a reversible, competitive inhibitor, the initial rates in the presence of at least four inhibitor concentrations (two inhibitor concentrations above K, and two below K,) are measured using [S] = 1 μM («Km) and [MMP-2] = 0.4 nM. Under these conditions, the measured K„ app is close to true K,.
EXAMPLE C Source and Activation of proMMP-3
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 μg/mL) at 37°C for 30 minutes, followed by addition of soybean trypsin inhibitor (50 μg/mL). Aliquots of the activated MMP-3 were stored at -20°C.
Determination of Inhibition Constant (K,) for MMP-3
The activated MMP-3 is assayed 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 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. The increase in fluorescence due to cleavage of
Gly-Leu peptide bond by MMP-3 was monitored with Perkin-Elmer LS50B Fluorimeter (λex 328 nm, λen, 393 nm, excitation slit 2.5, emission slit 10). Substrate and inhibitor stock solutions were made in DMF and 0.1% HC1-DMF, respectively. For detennination of K, values for MMP-3 inhibitors, a series of intermediate inhibitor solutions were prepared in 0.1% HC1-DMF and 1 or 2 μL of the diluted inhibitor solution was mixed with 1 μL of 2 mM substrate solution in DMF in a quartz cuvette containing 2 mL of assay buffer. The enzyme (10 μL of 0.2 μM MMP-3 dilution in assay buffer) was added at the last to start the reaction. For routine measurement of a K, value for a reversible, competitive inhibitor, the initial rates in the presence of at least four inhibitor concentrations (two concentrations above K, and two concentrations below K,) were measured using [S] = 1 μM (« Km) and [MMP-3] = 1 nM. Under these conditions, the measured K,, app is close to true K,. Calculation of K, Values
The K, for a competitive inhibitor is calculated using: vo/v, = (1 + [I]/K,, app) and K, = K,j app/(1 + [S]/Km), where v0 is the initial rate in the absence of inhibitor, v, is the initial rate in the presence of inhibitor at the concentration of [I], [S] is the substrate concentration, and Km is the Michaelis constant. If slow binding is observed (i.e. if the approach to the binding equilibrium is slow), the final steady-state rate rather than the initial rate is taken as v,.
EXAMPLE D Source of MMP- 12 (macrophage metalloelastase) MMP-12 (EC 3.4.24.65) was cloned, expressed and purified according to
Shapiro, S.D. et al., J Biol. Chem. 268, 23824-23829 (1993). Autoactivation resulted in the fully processed active form of the enzyme. Aliquots of MMP-12 were stored at -
70C.
Determination of the inhibition constant (Ki) for MMP-12. 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. The increase in fluorescence due to cleavage of Gly-Leu peptide bond by MMP-12 was monitored with a Perkin-Elmer LS50B Fluorimeter (λex 328 nm, λem 393 nm, excitation slit 2.5, emission slit 10) for the cuvette assay and with a Molecular Devices Fmax fluorescence plate reader (λex 320 nm, λλem 405 nm) for the microtiter plate assay. Substrate and inhibitor stock solutions were made in N,N,dimethylformamide (DMF) and 0.1% HC1- DMF, respectively.
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 μM) 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. For routine measurement of a Ki value for a reversible competitive inhibitor, the initial rates in the presence of at least four inhibitor concentrations ( two concentrations above and two concentrations below the Ki) were measured [S] = 2 μM («Km) and [MMP-12] = 2 nM. Under these conditions, the measured Ki,app is close to the true Ki.
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 μl in assay buffer)of each compound were added to separate wells of a microtiter plate and substrate was added (100 μl) to get a final concentration of 4 mM. MMP-12 was added to a final concentration of 2 nM (50 μl) to start the reaction. Cleavage of substrate was recorded every 30 seconds for 30 minutes and progress curves were generated. Calculation of Ki values
The Ki for a competitive inhibitor was calculated using: Vo/Vi = (1+[I]/Ki,app) and Ki = Ki,app/(1+[S]/Km), where Vo is the initial rate in the absence of inhibitor, Vi is the initial rate in the presence of inhibitor at the concentration of [I], [S] is the substrate concentration, and Km is the Michaelis constant. If slow binding is observed (i.e. if the approach to the binding equilibium is slow), the final steady-state rate rather than the initial rate is taken as Vi.

Claims

WHAT IS CLAIMED IS:
1. A method of inhibiting matrix metallo-proteinases in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of the formula
wherein
A is selected from the group consisting of -OH and -NRR'; wherein
R and R' are independently selected from the group consisting of hydrogen and Cι-C6 alkyl or R and R' taken together with the nitrogen atom to which they are attached form a N-moφholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
Ri is selected from the group consisting of hydrogen, Cι-C6 alkyl, -(CH2)a-CO2R5, -(CH2)a-C(O)NH2, -(CH2)4NH2, -(CH2)3-NH-C(NH)NH2, -(CH2)2-S(O)b-CH3, -CH2- OH,
-CH(OH)CH3, -CH2-SH, -(CH2)d-Ar,, and -CH2-Ar2; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0 to 4;
R5 is selected from the group consisting of hydrogen, Ci.C-j alkyl, and benzyl;
A is a radical selected from the group consisting of wherein
R6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, d-C4 alkyl, hydroxy, and Cι-C4 alkoxy; R7 is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, and C]_C4 alkoxy; Ar2 is a radical selected from the group consisting of
R2 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy Cι-C4 alkyl, and Cι.C4 alkoxy;
R3 is selected from the group consisting of C]-C6 alkyl, -(CH2)m-W, -(CH2)P-Ar , -(CH2)k-C02R9, -(CH2)m-NR8-SO2-Yι, and -(CH2)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; Ar3 is selected from the group consisting of
wherein
R23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and C]-C4 alkoxy; R8- is hydrogen or C]-C6 alkyl; R9 is hydrogen or Cι-C6 alkyl;
Yi is selected from the group consisting of hydrogen, -(CH )j-Ar4, and -N(R24)2 wherein j is 0 or 1 ; R2 each time selected is independently hydrogen or Cι-C6 alkyl or are taken together with the nitrogen to which they are attached to form N- moφholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
Ar4 is
wherein
R s is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and C C4 alkoxy;
Z is selected from the group consisting of -0-, -NR8-, -C(O)NR8-, -NRgC(O)-, -NR8C(0)NH-, -NR8C(O)O -, and -OC(0)NH-; wherein R8 is hydrogen or Cι-C6 alkyl;
Q is selected from the group consisting of hydrogen, -(CH2)n-Y2, and -(CH2) Y3; wherein n is an integer from 0 to 4;
Y2 is selected from the group consisting of hydrogen, -(CH2)h-Ar and -(CH2)t-C(O)OR27 wherein Ars is selected from the group consisting of
wherein
R26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C]-C alkyl, and Cι-C4 alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6;
R27 is hydrogen or Cι-C alkyl; x is an integer from 2 to 4;
Y3 is selected from the group consisting of -N(R28)2, N-moφholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein
R28 each time taken is independently selected from the group consisting of hydrogen and C]-C6 alkyl;
R is selected from the group consisting of hydrogen, -C(O)Rιo, -C(O)-(CH2)q-K and - S-G wherein
Rio is selected from the group consisting of hydrogen, Cι-C4 alkyl, phenyl, and benzyl; q is 0, 1, or 2;
K is selected from the group consisting of
N — R,
Rn wherein
V is selected from the group consisting of a bond, -CH2-, -O-, -S(O),-, - NR21-, and -NC(O)R22; wherein r is 0, 1, or 2;
R21 is selected from the group consisting of hydrogen, Cι_C4 alkyl, and benzyl;
R22 is selected from the group consisting of hydrogen, -CF3, Ci-
C10 alkyl, phenyl, and benzyl; Ri i each time taken is independently selected from the group consisting of hydrogen, Cι-C4 alkyl, and benzyl;
G is selected from the group consisting of
C CH2 ^^R 12 : CH2 ) V, 1
R, V--
02R16
wherein w is an integer from 1 to 3;
R12 is selected from the group consisting of hydrogen, Cι-C6 alkyl,
-CH2CH2S(O)uCH3, and benzyl; wherein u is 0,1, or 2; Rπ is selected from the group consisting of hydrogen, hydroxy, amino, Cι-C6 alkyl, N-methylamino, N,N-dimethylamino, -CO2Ri7, and - OC(O)R18; wherein
R17 is hydrogen, -CH20-C(O)C(CH3)3, Cι-C4 alkyl, benzyl, or diphenylm ethyl;
Ris is hydrogen, Cι-C6 alkyl or phenyl; Rι4 is 1 or 2 substituents independently selected from the group consisting of hydrogen, C1-C4 alkyl, Cι-C4 alkoxy, or halogen; V| is selected from the group consisting of -O-, -S-, and -NH-; V2 is selected from the group consisting of -N- and -CH-; V3 is selected from the group consisting of a bond and -C(O)-; V4 is selected from the group consisting of -O-, -S-, -NRI 9-, and -
NC(O)R20-; wherein
Rι9 is hydrogen, Cι.C4 alkyl, or benzyl; R20 is hydrogen, -CF3, C1-C10 alkyl, or benzyl;
R15 is selected from the group consisting of hydrogen, Cι-C6 alkyl and benzyl;
Ri6 is selected from the group consisting of hydrogen and C1-C4 alkyl; and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof.
2. A method of treating neoplastic disease state in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of the formula
wherein
A is selected from the group consisting of -OH and -NRR'; wherein
R and R' are independently selected from the group consisting of hydrogen and Cι-C6 alkyl or R and R' taken together with the nitrogen atom to which they are attached form a N-moφholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
Ri is selected from the group consisting of hydrogen, Cι-C6 alkyl, -(CH2)a-C02R5, -(CH2)a-C(O)NH2, -(CH2)4NH2, -(CH2)3-NH-C(NH)NH2, -(CH2)2-S(O)b-CH3, -CH2- OH, -CH(OH)CH3, -CH2-SH, -(CH2)d-Ar, , and -CH2-Ar2; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0 to 4; R5 is selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl; Ari is a radical selected from the group consisting of
wherein
R6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, hydroxy, and C1-C4 alkoxy; R7 is selected from the group consisting of hydrogen, halogen, C].C alkyl, and Cι.C4 alkoxy; Ar is a radical selected from the group consisting of
R2 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy Cι_C4 alkyl, and Cι_C4 alkoxy;
R3 is selected from the group consisting of Cj-C6 alkyl, -(CH2)m-W, -(CH2)P-Ar3, -(CH2 -CO2R9, -(CH2)m-NR8.SO2-Y,, and -(CH2)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;
Ar3 is selected from the group consisting of
wherein R23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C]-C4 alkyl, and Cι-C alkoxy;
R8- is hydrogen or Cι-C6 alkyl;
R9 is hydrogen or Cι-C6 alkyl;
Yi is selected from the group consisting of hydrogen, -(CH )j-Ar , and -N(R 4)2 wherein j is 0 or 1 ;
R2 each time selected is independently hydrogen or Cι-C6 alkyl or are taken together with the nitrogen to which they are attached to form N- moφholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; Ar4 is
wherein
R25 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and Cι-C4 alkoxy;
Z is selected from the group consisting of -0-, -NR8-, -C(O)NR8-, -NR8C(O)-, -NR8C(O)NH-, -NR8C(O)0 -, and -OC(O)NH-; wherein
Rg is hydrogen or Cι-C6 alkyl;
Q is selected from the group consisting of hydrogen, -(CH2)n-Y2, and -(CH2),N3; wherein n is an integer from 0 to 4;
Y2 is selected from the group consisting of hydrogen, -(CH2)h-Ar and wherein
Ar5 is selected from the group consisting of
wherein R26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C alkyl, and Cι-C4 alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6; R 7 is hydrogen or C]-C6 alkyl; x is an integer from 2 to 4;
Y3 is selected from the group consisting of -N(R28)2, N-moφholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein
R28 each time taken is independently selected from the group consisting of hydrogen and Cι-C6 alkyl;
R4 is selected from the group consisting of hydrogen, -C(O)R! 0, -C(O)-(CH2)q-K and - S-G wherein
Rio is selected from the group consisting of hydrogen, Cι_C4 alkyl, phenyl, and benzyl; q is 0, 1, or 2;
K is selected from the group consisting of
N — R 1 1
Rιι wherein
V is selected from the group consisting of a bond, -CH2-, -O-, -S(O)r- wherein r is 0, 1 , or 2; R2ι is selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl;
R22 is selected from the group consisting of hydrogen, -CF3, Ci-
C10 alkyl, phenyl, and benzyl; Ri 1 each time taken is independently selected from the group consisting of hydrogen, Cι_C4 alkyl, and benzyl;
G is selected from the group consisting of
0 2 R_ S
wherein w is an integer from 1 to 3;
R12 is selected from the group consisting of hydrogen, Cι-C6 alkyl,
-CH2CH2S(O)uCH3, and benzyl; wherein u is 0,1, or 2; R13 is selected from the group consisting of hydrogen, hydroxy, amino, Ci-C(l alkyl, N-methylamino, N,N-dimethylamino, -CO2Rι7, and - OC(O)R,8; wherein
R,7 is hydrogen, -CH20-C(O)C(CH3)3, C,-C4 alkyl, benzyl, or diphenylmethyl;
Ri8 is hydrogen, Cι-C6 alkyl or phenyl; Ri is 1 or 2 substituents independently selected from the group consisting of hydrogen, Cι-C alkyl, Cι-C alkoxy, or halogen; Vi is selected from the group consisting of -0-, -S-, and -NH-; V? is selected from the group consisting of -N- and -CH-; V3 is selected from the group consisting of a bond and -C(O)-;
V is selected from the group consisting of -O-, -S-, -NR] 9-, and - NC(O)R20-; wherein
R]9 is hydrogen, Cι-C4 alkyl, or benzyl; R2o is hydrogen, -CF3, Ci-Cio alkyl, or benzyl;
Ri5 is selected from the group consisting of hydrogen, Cj-C6 alkyl and benzyl;
Ri6 is selected from the group consisting of hydrogen and Cι-C alkyl; and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof
3. A method of treating atherosclerosis in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of the formula
wherein
A is selected from the group consisting of -OH and -NRR'; wherein
R and R' are independently selected from the group consisting of hydrogen and Ci-Cό alkyl or R and R' taken together with the nitrogen atom to which they are attached form a N-moφholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
Ri is selected from the group consisting of hydrogen, Cι-C6 alkyl, -(CH2)a-C02R5, -(CH2)a-C(O)NH2, -(CH2)4NH2, -(CH2)3-NH-C(NH)NH2, -(CH2)2-S(O)b-CH3, -CH2- OH, -CH(OH)CH3, -CH2-SH, -(CH2)d-Ar,, and -CH2-Ar2; wherein a is 1 or 2; b is 0, 1 , or 2; d is an integer from 0 to 4;
R5 is selected from the group consisting of hydrogen, Cι-C4 alkyl, and benzyl; Ari is a radical selected from the group consisting of
wherein
R6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι_C4 alkyl, hydroxy, and Cι-C4 alkoxy; R7 is selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and Cι-C alkoxy; Ar2 is a radical selected from the group consisting of
R2 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy Cι-C4 alkyl, and Cι-C4 alkoxy;
R3 is selected from the group consisting of Cι-C6 alkyl, -(CH2)m-W, -(CH2)P-Ar3, -(CH2)k-CO2R9, -(CH2)m-NR8 SO2-Y,, and -(CH2)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;
Ar3 is selected from the group consisting of wherein
R23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and C C4 alkoxy;
R8 is hydrogen or Cι-C6 alkyl;
R9 is hydrogen or Cι-C6 alkyl;
Yi is selected from the group consisting of hydrogen, -(CH2)j-Ar4, and -N(R2 )2 wherein j is 0 or 1 ;
R24 each time selected is independently hydrogen or Cι-C6 alkyl or are taken together with the nitrogen to which they are attached to form N- moφholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; Ar is
wherein
R25 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and Cι-C4 alkoxy;
Z is selected from the group consisting of -O-, -NR8-, -C(O)NR8-, -NR8C(0)-, -NR8C(O)NH-, -NR8C(O)O -, and -OC(0)NH-; wherein
R8 is hydrogen or Cι-C6 alkyl;
Q is selected from the group consisting of hydrogen, -(CH2)n-Y2, and -(CH )XY3; wherein n is an integer from 0 to 4; Y is selected from the group consisting of hydrogen, -(CH2)h-Ar5 and wherein Ar5 is selected from the group consisting of
wherein
R26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C]-C4 alkyl, and C]-C4 alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6;
R27 is hydrogen or Cι-C6 alkyl; x is an integer from 2 to 4;
Y3 is selected from the group consisting of -N(R28)2, N-moφholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein
R28 each time taken is independently selected from the group consisting of hydrogen and Cι-C6 alkyl;
RA is selected from the group consisting of hydrogen, -C(O)Rι0, -C(O)-(CH2)q-K and - S-G wherein
Rio is selected from the group consisting of hydrogen, Cι_C4 alkyl, phenyl, and benzyl; q is 0, 1, or 2; K is selected from the group consisting of
N — R,
R . wherein
V is selected from the group consisting of a bond, -CH2-, -O-, -S(O),-, -
NR21-, and -NC(O)R22; wherein r is 0, 1, or 2;
R21 is selected from the group consisting of hydrogen, Cι_C alkyl, and benzyl;
R22 is selected from the group consisting of hydrogen, -CF3, Ci-
C10 alkyl, phenyl, and benzyl; Ru each time taken is independently selected from the group consisting of hydrogen, Cι-C4 alkyl, and benzyl;
G is selected from the group consisting of
02R16
wherein w is an integer from 1 to 3;
Ri2 is selected from the group consisting of hydrogen, C]-C6 alkyl,
-CH2CH2S(O)uCH3, and benzyl; wherein u is 0,1, or 2; Rπ is selected from the group consisting of hydrogen, hydroxy, amino,
C|-C6 alkyl, N-methylamino, N,N-dimethylamino, -CO2Rπ, and - OC(O)R,8; wherein
R,7 is hydrogen, -CH2O-C(O)C(CH3)3, C,_C4 alkyl, benzyl, or diphenylmethyl ;
Ri8 is hydrogen, Cι-C6 alkyl or phenyl; R]4 is 1 or 2 substituents independently selected from the group consisting of hydrogen, Cι-C alkyl, Cι_C alkoxy, or halogen; V) is selected from the group consisting of -O-, -S-, and -NH-; V2 is selected from the group consisting of -N- and -CH-;
V3 is selected from the group consisting of a bond and -C(O)-; V is selected from the group consisting of -O-, -S-, -NRι9-, and -
NC(O)R20-; wherein Ri9 is hydrogen, Cι_C alkyl, or benzyl;
R2o is hydrogen, -CF3, Ci-Cio alkyl, or benzyl; Ris is selected from the group consisting of hydrogen, Cι-C6 alkyl and benzyl;
Ri6 is selected from the group consisting of hydrogen and Cι_C alkyl; and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof.
4. A method of treating chronic inflammatory disease in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of the formula wherein
A is selected from the group consisting of -OH and -NRR'; wherein
R and R' are independently selected from the group consisting of hydrogen and Cι-C6 alkyl or R and R' taken together with the nitrogen atom to which they are attached form a N-moφholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
Ri is selected from the group consisting of hydrogen, Cι-C6 alkyl, -(CH )a-CO2R5, -(CH2)a-C(O)NH2, -(CH2)4NH2, -(CH2)3-NH-C(NH)NH2, -(CH2)2-S(O)b-CH3, -CH2- OH, -CH(OH)CH3, -CH2-SH, -(CH2)d-Ar,, and -CH2-Ar2; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0 to 4;
R5 is selected from the group consisting of hydrogen, Cι„C alkyl, and benzyl;
Ari is a radical selected from the group consisting of
wherein
R6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, hydroxy, and Cι-C4 alkoxy;
R7 is selected from the group consisting of hydrogen, halogen, Cι-C alkyl, and Cι-C alkoxy; Ar2 is a radical selected from the group consisting of
R is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy Cι_C4 alkyl, and Cι-C alkoxy;
R3 is selected from the group consisting of Cι-C6 alkyl, -(CH2)m-W, -(CH2)P-Ar3, -(CH2)k-CO2R9, -(CH2)m-NR8 SO2-Y,, and -(CH2)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;
Ar3 is selected from the group consisting of
wherein
R23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and Cι-C4 alkoxy;
R8- is hydrogen or Cι-C6 alkyl;
R9 is hydrogen or Cι-C6 alkyl;
Yi is selected from the group consisting of hydrogen, -(CH2)j-Ar4, and -N(R24)2 wherein j is 0 or 1 ;
R each time selected is independently hydrogen or Cι-C6 alkyl or are taken together with the nitrogen to which they are attached to form N- moφholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; Ar is wherein
R25 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C]-C4 alkyl, and C]-C4 alkoxy;
Z is selected from the group consisting of -0-, -NR8-, -C(O)NR8-, -NR8C(0)-, -NR8C(0)NH-, -NR8C(O)0 -, and -OC(O)NH-; wherein
R8 is hydrogen or Cι-C6 alkyl;
Q is selected from the group consisting of hydrogen, -(CH2)n-Y2, and -(CH2)XY3; wherein n is an integer from 0 to 4;
Y2 is selected from the group consisting of hydrogen, -(CH2)h-Ar5 and wherein
Ar5 is selected from the group consisting of
wherein
R26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and Cι-C4 alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6; R27 is hydrogen or Cι-C6 alkyl; x is an integer from 2 to 4;
Y3 is selected from the group consisting of -N(R28)2, N-moφholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein R28 each time taken is independently selected from the group consisting of hydrogen and Cι-C6 alkyl;
1^ is selected from the group consisting of hydrogen, -C(O)Rι0, -C(0)-(CH2)q-K and - S-G wherein
Rio is selected from the group consisting of hydrogen, Cι-C alkyl, phenyl, and benzyl; q is 0, 1, or 2;
K is selected from the group consisting of
Rιι wherein
V is selected from the group consisting of a bond, -CH2-, -O-, -S(O),-, - wherein r is 0, 1, or 2;
R21 is selected from the group consisting of hydrogen, Cι-C4 alkyl, and benzyl;
R22 is selected from the group consisting of hydrogen, -CF3, -
C10 alkyl, phenyl, and benzyl; Ri 1 each time taken is independently selected from the group consisting of hydrogen, Cι-C4 alkyl, and benzyl;
G is selected from the group consisting of wherein w is an integer from 1 to 3;
R12 is selected from the group consisting of hydrogen, Cι-C6 alkyl,
-CH2CH2S(O)llCH3, and benzyl; wherein u is 0,1, or 2; Ri3 is selected from the group consisting of hydrogen, hydroxy, amino, Ci-Cό alkyl, N-methylamino, N,N-dimethylamino, -CO2R17, and - OC(O)R! 8; wherein
Rπ is hydrogen, -CH20-C(O)C(CH3)3, C,-C4 alkyl, benzyl, or diphenylmethyl;
Rig is hydrogen, Cι-C6 alkyl or phenyl; R]4 is 1 or 2 substituents independently selected from the group consisting of hydrogen, Cι_C4 alkyl, Cι_C alkoxy, or halogen; Vi is selected from the group consisting of -0-, -S-, and -NH-; V2 is selected from the group consisting of -N- and -CH-; V3 is selected from the group consisting of a bond and -C(O)-; V4 is selected from the group consisting of -O-, -S-, -NR) 9-, and -
NC(O)R20S wherein
Rι9 is hydrogen, Cι-C4 alkyl, or benzyl; R20 is hydrogen, -CF3, C1-C10 alkyl, or benzyl; R15 is selected from the group consisting of hydrogen, C)-C6 alkyl and benzyl;
Ri6 is selected from the group consisting of hydrogen and Cj-C4 alkyl; and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof.
5. A method of treating smoking-induced emphysema in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of the formula
wherein
A is selected from the group consisting of -OH and -NRR'; wherein
R and R' are independently selected from the group consisting of hydrogen and Cι-C6 alkyl or R and R' taken together with the nitrogen atom to which they are attached form a N-moφholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
Ri is selected from the group consisting of hydrogen, C]-C6 alkyl, -(CH )a-CO2R5, -(CH2)a-C(O)NH2, -(CH2)4NH2, -(CH2)3-NH-C(NH)NH2, -(CH2)2-S(O)b-CH3, -CH2- OH,
-CH(OH)CH3, -CH2-SH, -(CH2)d-Ar,, and -CH2-Ar2; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0 to 4;
R5 is selected from the group consisting of hydrogen, Cι-C alkyl, and benzyl;
Ari is a radical selected from the group consisting of wherein
R6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, hydroxy, and Cι-C4 alkoxy; R7 is selected from the group consisting of hydrogen, halogen, Cι-C alkyl, and Cι-C alkoxy; Ar2 is a radical selected from the group consisting of
R2 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy Ci.C-j alkyl, and Cι-C4 alkoxy;
R3 is selected from the group consisting of d-C6 alkyl, -(CH2)m-W, -(CH2)P-Ar , -(CH2)k-CO2R9, -(CH2)m-NR8 SO2-Y,, and -(CH2)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; Ar3 is selected from the group consisting of
wherein
R23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and Cι-C4 alkoxy; R - is hydrogen or C]-C6 alkyl; R9 is hydrogen or Cι-C6 alkyl;
Yi is selected from the group consisting of hydrogen, -(CH2)j-Ar , and -N(R 4)2 wherein j is 0 or 1; R24 each time selected is independently hydrogen or CpC6 alkyl or are taken together with the nitrogen to which they are attached to form N- moφholino, N-piperidmo, N-pyrrolidino, or N-isoindolyl; Ar4 is
wherein
R25 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C]-C4 alkyl, and Cι-C4 alkoxy;
Z is selected from the group consisting of -O-, -NRg-, -C(O)NR8-, -NR8C(O)-, -NR8C(O)NH-, -NR8C(O)0 -, and -OC(O)NH-; wherein R8 is hydrogen or Cj-C6 alkyl;
Q is selected from the group consisting of hydrogen, -(CH2)n-Y2, and -(CH2)XY ; wherein n is an integer from 0 to 4;
Y2 is selected from the group consisting of hydrogen, -(CH )h-Ar5 and -(CH2),-C(O)OR27 wherein Ars is selected from the group consisting of
wherein
R26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and Cι-C4 alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6;
R27 is hydrogen or Cι-C6 alkyl; x is an integer from 2 to 4;
Y3 is selected from the group consisting of -N(R28)2, N-moφholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein
R28 each time taken is independently selected from the group consisting of hydrogen and Cι-C6 alkyl;
-Rt is selected from the group consisting of hydrogen, -C(0)R,o, -C(O)-(CH2)q-K and - S-G wherein
Rio is selected from the group consisting of hydrogen, Cι_C4 alkyl, phenyl, and benzyl; q is 0, 1 , or 2;
K is selected from the group consisting of
N— R,
Rιι wherein
V is selected from the group consisting of a bond, -CH2-, -0-, -S(O),-, - wherein r is 0, 1 , or 2;
R21 is selected from the group consisting of hydrogen, C1-C alkyl, and benzyl;
R22 is selected from the group consisting of hydrogen, -CF3, d-
C10 alkyl, phenyl, and benzyl; Rn each time taken is independently selected from the group consisting of hydrogen, Cι-C alkyl, and benzyl;
G is selected from the group consisting of
02R 16
wherein w is an integer from 1 to 3;
R12 is selected from the group consisting of hydrogen, Cι-C6 alkyl,
-CH2CH2S(O)uCH3, and benzyl; wherein u is 0,1, or 2; Ri3 is selected from the group consisting of hydrogen, hydroxy, amino, Cι-C6 alkyl, N-methylamino, N,N-dimethylamino, -CO2R17, and - OC(0)R,8; wherein
R,7 is hydrogen, -CH20-C(O)C(CH3)3, C,_C4 alkyl, benzyl, or diphenylmethyl;
Rig is hydrogen, Cι-C6 alkyl or phenyl; R]4 is 1 or 2 substituents independently selected from the group consisting of hydrogen, Cι-C4 alkyl, Ct.C4 alkoxy, or halogen; V] is selected from the group consisting of -O-, -S-, and -NH-; V2 is selected from the group consisting of -N- and -CH-; V3 is selected from the group consisting of a bond and -C(O)-; V is selected from the group consisting of -0-, -S-, -NR] 9-, and -
NC(O)R20-; wherein
Rι9 is hydrogen, Cι-C alkyl, or benzyl;
R2o is hydrogen, -CF3, Ci-Cio alkyl, or benzyl; Ri5 is selected from the group consisting of hydrogen, Cι-C6 alkyl and benzyl;
Ri6 is selected from the group consisting of hydrogen and Cι-C alkyl; and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof.
6. A method according to any one of Claims 1-5 wherein Ri is selected from the group of Cι-C6 alkyl and -(CH2)dA .
7. A method according to any one of Claims 1-5 wherein Ri is -(CH2)dA and Ari is phenyl or substituted phenyl.
8. A method according to any one of Claims 1-5 wherein R4 is selected from the group consisting of hydrogen, -C(O)Rιo and -S-G.
9. A method according to any one of Claims 1-5 wherein R is hydrogen.
10. A method according to any one of Claims 1-5 wherein R4 is -C(O)Rι0 and Rio is C1-C4 alkyl.
11. A method according to any one of Claims 1-5 wherein A is -OH.
12. A method according to any one of Claims 1 -5 wherein A is -NRR" wherein R is hydrogen and R' is methyl.
13. A compound of the formula wherein
Aa is -NRR'; wherein
R and R' are independently selected from the group consisting of hydrogen and C1-C6 alkyl or R and R' taken together with the nitrogen atom to which they are attached form a N-moφholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
Ri is selected from the group consisting of hydrogen, Cι-C6 alkyl, -(CH )a-CO R5, -(CH2)a-C(O)NH2, -(CH2)4NH2, -(CH2)3-NH-C(NH)NH2, -(CH2)2-S(O)b-CH3, -CH2- OH, -CH(OH)CH3, -CH2-SH, -(CH2)d-Ar,, and -CH2-Ar2; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0 to 4;
R5 is selected from the group consisting of hydrogen, Cι_C alkyl, and benzyl;
Aτι is a radical selected from the group consisting of
wherein
R6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, hydroxy, and d-C alkoxy;
R7 is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, and Cι-C4 alkoxy; Ar2 is a radical selected from the group consisting of
R2 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy Cι-C alkyl, and Cι-C alkoxy;
R3 is selected from the group consisting of Cι-C6 alkyl, -(CH2)m-W, -(CH2)P-Ar3, -(CH2)k-C02R9, -(CH2)m-NR8 SO2-Y,, and -(CH2)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;
Aτ3 is selected from the group consisting of
wherein
R23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, Cι-C4 alkyl, and Cι-C4 alkoxy;
R8 is hydrogen or Cι-C6 alkyl;
R is hydrogen or Cι-C6 alkyl;
Yi is selected from the group consisting of hydrogen, -(CH2)j-Ar4, and -N(R24)2 wherein j is 0 or 1 ;
R2 each time selected is independently hydrogen or Cι-C6 alkyl or are taken together with the nitrogen to which they are attached to form N- moφholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; Ar is wherein
R25 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C]-C alkyl, and Cι-C4 alkoxy;
Z is selected from the group consisting of -0-, -NRg-, -C(0)NR8-, -NRgC(O)-, -NR8C(O)NH-, -NR8C(O)0 -, and -OC(O)NH-; wherein
R8 is hydrogen or C)-C6 alkyl;
Q is selected from the group consisting of hydrogen, -(CH2)n-Y2, and -(CH2)XY3; wherein n is an integer from 0 to 4;
Y2 is selected from the group consisting of hydrogen, -(CH2)h-Ar5 and -(CH2)t-C(O)OR27 wherein
ATJ is selected from the group consisting of
wherein
R26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, and Cι-C4 alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6; R27 is hydrogen or Cι-C6 alkyl; x is an integer from 2 to 4;
Y3 is selected from the group consisting of -N(R28)2, N-moφholino, N- piperidino, N-pyrrolidino, and N-isoindolyl; wherein R28 each time taken is independently selected from the group consisting of hydrogen and C|-C6 alkyl;
R is selected from the group consisting of hydrogen, -C(O)Rι0, -C(0)-(CH2)q-K and - S-G wherein
Rio is selected from the group consisting of hydrogen, Cι-C4 alkyl, phenyl, and benzyl; q is 0, 1, or 2;
K is selected from the group consisting of
N — ,
wherein
V is selected from the group consisting of a bond, -CH2-, -O-, -S(0)r-, - wherein r is 0, 1, or 2;
R21 is selected from the group consisting of hydrogen, Cι-C alkyl, and benzyl;
R22 is selected from the group consisting of hydrogen, -CF3, Ci-
C10 alkyl, phenyl, and benzyl; Ru each time taken is independently selected from the group consisting of hydrogen, Cι-C alkyl, and benzyl;
G is selected from the group consisting of wherein w is an integer from 1 to 3;
R12 is selected from the group consisting of hydrogen, C]-C6 alkyl,
-CH2CH2S(O)uCH3, and benzyl; wherein u is 0,1, or 2; R] 3 is selected from the group consisting of hydrogen, hydroxy, amino, Cι-C6 alkyl, N-methylamino, N,N-dimethylamino, -CO2R17, and - OC(O)Rι8; wherein
R,7 is hydrogen, -CH2O-C(O)C(CH3)3, C,.C4 alkyl, benzyl, or diphenylmethyl;
Rig is hydrogen, C]-C6 alkyl or phenyl; R] is 1 or 2 substituents independently selected from the group consisting of hydrogen, C1-C4 alkyl, Cι_C alkoxy, or halogen; Vi is selected from the group consisting of -O-, -S-, and -NH-; V2 is selected from the group consisting of -N- and -CH-; V3 is selected from the group consisting of a bond and -C(O)-; V is selected from the group consisting of -O-, -S-, -NR1 -, and -
NC(O)R20-; wherein
R)9 is hydrogen, Cι-C alkyl, or benzyl; R20 is hydrogen, -CF3, Ci-Cio alkyl, or benzyl; R15 is selected from the group consisting of hydrogen, Cι-C6 alkyl and benzyl;
Ri6 is selected from the group consisting of hydrogen and Cι-C4 alkyl; and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof.
14. A compound according to Claim 13 wherein Ri is selected from the group consisting of Cι-C6 alkyl and -(CH )dArι .
15. A compound according to Claim 13 wherein Ri is -(CH2)dArι and An is phenyl or substituted phenyl.
16. A compound according to Claim 13 wherein R4 is selected from the group consisting of hydrogen, -C(O)Rιo and -S-G.
17. A compound according to Claim 13 wherein R-4 is hydrogen.
18. A compound according to Claim 13 wherein 1^ is -C(O)Rιo and R]0 is C].C alkyl.
19. A compound according to Claim 13 wherein Aa is -NRR' wherein R is hydrogen and R' is methyl.
20. A pharmaceutical composition comprising an effective matrix metallo- proteinases inhibitory amount of a compound of any one of Claims 13-19 in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.
EP99961877A 1998-12-31 1999-11-30 N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase Withdrawn EP1150957A1 (en)

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