EP1051407A1 - Acides 2,3,4,5-tetrahydro-1h-[1,4]-benzodiapezine-3-hydroxamiques utilises en tant qu'inhibiteurs de metalloproteases matricielles - Google Patents

Acides 2,3,4,5-tetrahydro-1h-[1,4]-benzodiapezine-3-hydroxamiques utilises en tant qu'inhibiteurs de metalloproteases matricielles

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Publication number
EP1051407A1
EP1051407A1 EP99902417A EP99902417A EP1051407A1 EP 1051407 A1 EP1051407 A1 EP 1051407A1 EP 99902417 A EP99902417 A EP 99902417A EP 99902417 A EP99902417 A EP 99902417A EP 1051407 A1 EP1051407 A1 EP 1051407A1
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EP
European Patent Office
Prior art keywords
alkyl
tetrahydro
benzodiazepine
methoxybenzenesulfonyl
carboxylic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP99902417A
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German (de)
English (en)
Inventor
Jay Donald Albright
Efren Guillermo Delos Santos
Xuemei Du
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Wyeth Holdings LLC
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American Cyanamid Co
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Publication of EP1051407A1 publication Critical patent/EP1051407A1/fr
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P19/00—Drugs for skeletal disorders
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • 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
    • C07D403/10—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 carbon chain containing aromatic rings
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to 4-(4-substituted-benzenesulfonyl)-2,3,4,5-tetrahydro- lH-[l,4]benzodiazepine-3-hydroxyamic acids which act as matrix metalloproteinase
  • the compounds of the present invention are useful in disease conditions mediated by matrix metalloproteinases, such as tumor growth, osteoarthritis, rheumatoid arthritis and degenerative cartilage loss.
  • MMPs Matrix metalloproteinases
  • These zinc-containing endopeptidases consist of several subsets of enzymes, including collagenases, stromelysins and gelatinases. Of these, the gelatinases have been shown to be the MMPs most intimately involved with the growth
  • gelatinase For example, it is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis.
  • Angiogenesis required for the growth of solid tumors, has also 25 recently been shown to have a gelatinase component to its pathology as reported in "Matrix Metalloproteinases, Novel Targets for Directed Cancer Therapy", Drugs and Aging. 11:229-244 (1997).
  • MMPs diseases mediated by MMPs
  • Other conditions mediated by MMPs include restenosis, MMP-mediated 30 osteopenias, inflammatory diseases of the central nervous system, skin aging, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal 35 membranes, inflammatory bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of - 2 -
  • TNF- ⁇ converting enzyme catalyzes the formation of TNF- from membrane bound TNF- ⁇ precursor protein.
  • TNF- ⁇ is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance and HIN infection, in addition to its well-documented antitumor properties.
  • Research with anti-T ⁇ F- ⁇ antibodies in transgenic animals has demonstrated that blocking the formation of T ⁇ F- ⁇ inhibits the progression of arthritis. This observation has recently been extended to humans as described in "T ⁇ F- ⁇ in Human Diseases", Current Pharmaceutical Design. 2:662-667 (1996).
  • MMPs and TACE small molecule inhibitors of MMPs and TACE would have the potential for treating a variety of disease states. Although a variety of MMP and TACE inhibitors are known, many of these molecules are peptidic and peptide-like which demonstrate bioavailability and pharmacokinetic problems. Long acting, orally bioavailable non-peptide inhibitors of MMPs and/or TACE would thus be highly desirable for the treatment of the disease states discussed above.
  • U.S. Patent No, 5,455,258 discloses 2-substituted-2-(arylsulfonylamino) hydroxyamic acids and their use as MMP inhibitors.
  • WO 97/18194 discloses N- (arylsulfonyl)tetrahydroisoquinolone-hydroxyamic acids and related bicyclic derivatives thereof and their use as MMP inhibitors.
  • WO 97/20824 discloses l-(arylsulfonyl)-4- (substituted)piperazine-2-hydroxyamic acids, 4-(arylsulfonyl) morpholine-3- hydroxyamic acids, 4-(arylsulfonyl)-tetrahydro-2HJ,4-thiazine-3-hydroxyamic acids, 3-(substituted-l-(arylsulfonyl)hexahydro-2 -hydroxyamic acids and related compounds as useful MMP inhibitors. - 3 -
  • This invention relates to novel derivatives of substituted 2.3,4.5-tetrahydro-lH- [l,4]benzodiazepine-3-carboxylic acid hydroxyamide which exhibit inhibitory activity against MMPs.
  • the compounds of the present invention are represented by the following formula 1
  • R is selected from hydrogen, (Cj - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 -OCF 3 , Cl, F, NH 2 , NH(C j - C 3 )alkyl, -N ⁇ CO ⁇ - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), or -N(R')COCH 2 O-(C 1 - C 3 )alkyl, wherein R' is (C l - C 3 ) alkyl or hydrogen;
  • R 4 is (Ci - C 6 ) alkyl-O-, (C, - C 6 ) alkyl-S-, o ⁇ s -R.
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • Rl and R 2 are each, independently, hydrogen or CH 3 ;
  • R 3 is (C, - C 8 )alkyl, NH 2 CH 2 CO-, (Cj - C 6 )alkylNHCH 2 CO-. HO(CH 2 ) m CO-,
  • HCO- Aryl(CH 2 ) n CO-, Heteroaryl(CH 2 ) n CO-, (C x - C 3 )alkyl-O-(CH 2 ) n CO-,
  • L is hydrogen, (C r C 3 )alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl , F, NH 2 , -NH-(C, - C 3 )alkyl, -N(R')CO(C ⁇ - C 3 )alkyl, N(R')(R'), -NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), -N(R')COCH 2 O-(C ⁇ - C 3 )alkyl,
  • W is O, S, NH or N(C, - C 3 )alkyl
  • Y is hydrogen, F, Cl, CF 3 or OCH 3 ; and X' is halogen, hydrogen, (C j - C 3 )alkyl, O-
  • (C ! - C 3 )alkyl or -CH 2 OH; and pharmaceutically acceptable salts thereof.
  • -C3 alkyl covers methyl, ethyl, n-propyl and i-propyl groups.
  • -C6 alkyl covers, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and pentyl groups.
  • C3-C7 cycloalkyl covers saturated and unsaturated cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl and 2-cyclobutenyl.
  • R is suitably hydrogen, halogen or (Ci-C3)alkyl, for example hydrogen, chloro or methyl.
  • Rl is suitably hydrogen.
  • R2 is suitably hydrogen.
  • R4 is suitably ( -C alkyl)-O-, for example methoxy.
  • R3 is suitably selected from the group: (C ⁇ -C3)alkyl- SO2-, aryl(CH2)nSO2-, (C ⁇ -C3)alkyl-CO-, aryl(CH2)nCO-, heteroaryl(CH2)nCO-, - 7 -
  • the compounds of the present invention are those of formula 1 wherein R is hydrogen, (C ⁇ - C 3 ) alkyl, -CN, -OR', -SR', -CF 3; -OCF 3 , Cl, F, NH 2 , NH(C ⁇ - C 3 )alkyl, -N(R')CO(C ⁇ - C 3 )alkyl, -N(R')(R'), NO 2 ,
  • R 4 is (C, - C 6 ) alkyl-O-, (Ci - C 6 ) alkyl-S-,
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • Rl and R 2 are each, independently, hydrogen or CH 3 ;
  • X is hydrogen, halogen, (C ⁇ - C 3 ) alkyl or -OCH 3 wherein R and R' are as defined above; and pharmaceutically acceptable salts thereof.
  • the compounds of the present invention are those of formula 1 wherein R is hydrogen, (C ⁇ - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 -OCF 3 , Cl, F, NH 2 ,
  • R 4 is (C j - C 6 ) alkyl-O-, (C, - C 6 ) alkyl-S-, - 9 -
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • R l and R 2 are each, independently, hydrogen or CH 3 ; R 3 is
  • the compounds of the present invention include those of formula 1 wherein R is hydrogen, (C, - C 3 ) alkyl, -CN, -OR', -SR'. -CF 3 ⁇ -OCF 3 , Cl, F, NH 2 , NH(C ⁇ - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), or -N(R')COCH 2 O-(C ⁇ - C 3 )alkyl, wherein R' is (C j - C 3 ) alkyl or hydrogen;
  • R 4 is ( - C 6 ) alkyl-O-, (C ] - C 6 ) alkyl-S-,
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • R ] and R 2 are each, independently hydrogen or CH 3 ;
  • R' R' wherein X is hydrogen, halogen, (Ci - C 3 ) alkyl or -OCH 3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
  • a further, more preferred embodiment of the present invention includes compounds represented by formula 1 wherein
  • R is selected from hydrogen, (Cj - C 3 ) alkyl, -CN, -OR', -SR', -CF 3
  • R 4 is (C j - C 6 ) alkyl-O-, (Ci - C 6 ) alkyl-S-,
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • R ] and R 2 are each, independently hydrogen or CH 3 ;
  • R' R' wherein X is hydrogen, halogen, (C j - C 3 ) alkyl or -OCH 3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof.
  • R is hydrogen, ( - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 -OCF 3 , Cl, F, NH 2 .
  • R 4 is (C j - C 6 ) alkyl-O-, (Ci - C 6 ) alkyl-S-,
  • R is hydrogen, halogen, cyano, methyl or -OCH 3 ;
  • Ri and R 2 are each, independently hydrogen or CH 3 ; 13 -
  • L is hydrogen, (C x - C 3 )alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 ,
  • W is O, S, NH or N(C, - C 3 )alkyl
  • Y is hydrogen, F, Cl, CF 3 or OCH 3 ; and X' is halogen, hydrogen, (Ci - C 3 )alkyl, O- (Ci - C3)alkyl, or -CH 2 OH; and pharmaceutically acceptable salts thereof.
  • the compounds of the invention may be prepared by reacting an appropriate acid halide such as the acid chloride or bromide with hydroxylamine.
  • the acid halide may be prepared by reacting the corresponding acid or a metal salt thereof with an activating agent such as oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, (chloromethylene)dimethylammoniumchloride or (bromomethylene)dimethyl ammonium bromide.
  • an activating agent such as oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, (chloromethylene)dimethylammoniumchloride or (bromomethylene)dimethyl ammonium bromide.
  • the subsequent reaction of the acid halide with hydroxylamine may suitably be performed in situ.
  • Metal salts may be prepared by reacting a ester of formula I
  • R 2J is (C ⁇ alkyl, benzyl or arylalkyl and all other groups are as defined above, with a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide or barium hydroxide.
  • a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide or barium hydroxide.
  • This may suitably be performed in a solvent such as a (C j -Cg) alcohol, tetrahydrofuran, N,N-dimethylformide or p-dioxane in the presence or absence of water.
  • the resulting metal salt may be directly converted to the desired product or it may first be converted to the acid, e.g. by treating it with aqueous hydrochloric acid or acetic acid.
  • the ester of formula I a may be converted to its acid by treatment with an aqueous mineral acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid and the acid converted to the desired product as described
  • the compounds of formula 1 may be advantageously prepared according to Reaction Schemes 1 to 7. Variations in these schemes may be made to improve productivity without negatively impacting the amount and nature of the product, by - 15 -
  • reactive groups may be blocked with suitable blocking moieties which may then be deblocked under standard conditions (for instance, hydroxy groups may be protected with trimethylsilyl or t-butyl-dimethylsilyl moieties which are then removed in a later reaction step).
  • suitable blocking moieties for instance, hydroxy groups may be protected with trimethylsilyl or t-butyl-dimethylsilyl moieties which are then removed in a later reaction step.
  • the compounds of Formula 1 are synthesized from an alkyl ester
  • Ester derivatives 8 (where the ester function is a t-butyl ester) are converted to the acid with trifluoroacetic acid under standard conditions.
  • Rj (Ci - C 3 )alkyl;
  • R Hydrogen; halogen; OCH 3 ; NO 2 ; NH 2 ; CF 3 ; NHCOCH 3 ; NHCOCH 2 OCH 3 ; CONH 2 ; -N(R')(R'), -N(R')CO(C ⁇ - C 3 )alkyl; (C!
  • R 3 Ar(CH 2 ) n CO-; Heteroaryl(CH 2 ) n CO-, Ar(CH 2 ) n SO 2 -; Heteroaryl(CH 2 ) n SO 2 -: Alkyl-O-CH 2 ) n CO-; Alkyl-O-(CH 2 ) m SO 2 -; AlkylCO-; AlkylSO 2 -; AlkylCO- NHCH 2 CO-; and cycloalkyl(C 3 - C 7 )CO-; and R 4 is as defined herein. 17
  • R 5 -N0 2 t-BocNH- CH OCONH-
  • R 6 Ar(CH 2 ) n -; Alkyl-; Heteroaryl(CH 2 ) n -;Alkyl-O-(CH 2 ) n -; Cycloalkyl(C 3 - C 7 );
  • R 7 Ar(CH 2 ) n -; Alkyl-; Heteroaryl(CH 2 ) n -; Alkyl-O-(CH 2 ) m -;
  • Rg Ar(CH 2 ) n CO-; Ar(CH 2 ) n SO 2 -; AlkylCO-; AlkylSO 2 -; Heteroaryl(CH 2 ) n CO-;
  • arylmethyl-2,3,4,5-tetrahydro-lH [1.4]-benzodiazepines may be prepared in the manner illustrated in Reaction Schemes 3 and 4.
  • Reaction Scheme 3 the methyl 3-hydroxy-2-[4-methoxybenzenesulfonyl)-(2-aminobenzyl)amino]- propionates 6 are subjected to reductive alkylation with arylcarboxaldehydes and heteroaiylcarboxaldehydes to provide intermediates 17.
  • Standard reaction conditions such as reactions with triphenylphosphine and diethyl azodicarboxylate (DEAD) or triplenylphosphine with either carbon tetrachloride or carbon tetrabromide, results in the
  • N- aroyl derivatives 22 are reduced with reducing agents such as borane or lithium aluminum hydride to reduce both the ester and amide functions.
  • R 9 Ar R ° t rfllA ⁇ R i ⁇ o or
  • R-o ; and 9 and R 10 are: Cl, Br, F, OCH 3 , OEt , SCH 3 , CO CH
  • R 9 and RJO are hydrogen ,C1, Br, F, OCH3 , OEt
  • R 8 alkyl, arylalkyi, aryloxyalkyl, heterocyclicalkyl, or alkyloxyalkyloxyalkyl.
  • preferred compounds of the present invention are those with basic moieties in the 1 -(substituted carbonyl) group which may be prepared in the manner shown in Reaction Scheme 5.
  • the intermediates 25 may also be synthesized by reaction of methyl 2-[(2-aminobenzyl)-(4- methoxybenzenesulfonyl) amino]-3-hydroxypropionates 6 with acid chlorides to give "dehydroalanine" derivatives 28.
  • mild bases such as NaHCO3 can be reacted with these derivatives to cause ring closure via a 1.4- addition to the double bond in intermediate 28 to provide the 7-membered 2,3.4,5-tetrahydro- 1H-[1 ,4] diazepines 25.
  • R 8 o N- ⁇ CH.)- ⁇ / 2 n -(CH 2 )-
  • aryl-heteroarylcarbonyl, heteroaryl-heteroarylcarbonyl derivatives 30 may be synthesized by standard palladium catalysed coupling of bromoaiOyl or bromheteroaroyl derivatives 29 with appropriate arylstannanes, heteroarylstannanes, arylboronic acids, heteroarylboronic acids, aryl triflates, heteroaryl triflates and the like. under known conditions. For example, see Synthesis. 563-566 (1997); J. Org. Chem.. 62:3405-3406, (1997); Tetrahedron Lett.. 36:5247-5250, ( 1995);
  • aryl-aryl, heteroaryl-aryl, aryl- heteroaryl and heteroaryl-heteroaryl carboxylic ester derivatives can be prepared and these derivatives converted to carboxylic acid intermediates.
  • the acids are then converted to acid chlorides which are reacted with esters of 2- [(2-aminobenzyl)-(4- substituted-benzenesulfonyl)amino]-3-hydroxypropionate as illustrated for conversion of derivatives 6 to intermediates 31.
  • esters of 2- [(2-aminobenzyl)-(4- substituted-benzenesulfonyl)amino]-3-hydroxypropionate as illustrated for conversion of derivatives 6 to intermediates 31.
  • the following references describe procedures for the synthesis of methyl 3-arylpyrrole-4-carboxylates as in J. Org. Chem..
  • Y is H, F, Cl, CF 3 , CH 3 , or OCH 3 ;
  • X is halogen, hydrogen, or (C j - C 3 )alkyl
  • R and R' are as defined herein; and R4 is as defined herein. - 25
  • the intermediates 2.4,5.6-tetrahydro- l H-[ l J]benzod ⁇ azep ⁇ nes 39 and 38 may be prepared from glycine esters in the manner exemplified in Reaction Scheme 7
  • 10.160-161, 8 194 affords the dimethylaminomethyl (Mannich type) compounds as intermediates for elimination to the "dehydroalanine" derivatives 37 or direct ring closure of 36 to 39 via an e minauon- addition reaction Ring closure of compounds 37 provides intermediates 38 for conversion to hydroxamic acids Variations of the reactions conditions for conversion of 36 to 39 involve heating in the presence of Lewis acids, such as BF3, or heating an acid salt of 36 to effect the elimination-addition reacuon.
  • Lewis acids such as BF3
  • an acid salt of 36 to effect the elimination-addition reacuon.
  • inte ⁇ nediate carboxylic acids for conversion to the tetrahydro[ 1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamides may be synthesized via different routes as shown in Schemes 1-8.
  • alternate routes may be preferred as shown in Scheme 8.
  • intermediate carboxylate esters of Intermediate 41 or acids of Intermediate 44 wherein the R 4 substituent is an OH group are prepared.
  • Intermediates with R 4 an OH group may be prepared from derivatives wherein the OH group is protected by a group which can be selectively removed.
  • Derivatives 40 wherein R 4 is an OCH 3 moiety are suitable precursors to the desired phenolic compounds 41 and 44 through cleavage of the oxygen methyl bond.
  • the anion of the phenolic OH group may be prepared in situ and then alkylated.
  • Suitable bases are alkaline metal carbonates, hydrides, alkoxides and organic bases.
  • Reaction with an alkylating moiety represented by the Formula (C r C 6 )alkyl-X wherein X is a reactive leaving group such as a chloride, bromide, iodide, O-mesylate of an O-to.sylate gives the derivatives 42 and 45.
  • the alkylation reaction may be carried out with caboxylate esters such as 41 or with the carboxylic acids such as 44.
  • the phenolic compounds 41 and 44 may be reacted under Mitsunobe Reaction conditions to afford the O-alkylated derivatives 42 and 45.
  • Standard Mitsunobe Reaction conditions such as those described in the following literature references, may be used in the coupling reactions: J. Heterocvclic Chem. 34:349 (1997); Tetrahedron Lett. 37:6439 (1996); J. Org. Chem.. 56:7173 (1991); Tetrahedron Lett. 5709 (1989); Synthesis 1:28 (1981).
  • the compounds of the present invention which have a basic moiety may be used in the form of salts derived from pharmaceutically or physiologically acceptable acids.
  • These salts include, but are not limited to, salts with inorganic acids (such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid) or organic acids (such as acetic acid, oxalic acid, succinic acid, and maleic acid).
  • Other salts of compounds with an acidic moiety include those with alkali metals or alkaline earth metals (such as sodium, potassium, calcium, and magnesium) or organic bases.
  • compositions containing the present compounds may be administered orally, in the form of tablets, capsules, dispersible powders, granules, suspensions, syrups or elixirs; parentally, in the form of a sterile injectable solution or suspension; or topically, in the form of creams, lotions, ointments, etc.
  • Such pharmaceutical compositions may contain from about 1 to about 100 mg of active in "gt>r A edient in combination with the carrier.
  • the effective dosage of the present compounds utilized to treat a specific condition will vary depending upon the particular compound employed, the mode of administration and the type and severity of the condition being treated. However, in general, satisfactory results are obtained when the present compounds are administered at a dosage of about 0.001 to 1000 mg kg of body weight.
  • the compounds of the present invention may be administered orally, as well as by intravenous, intramuscular, subcutaneous or topical routes.
  • Solid carriers useful for preparing tablets, capsules, etc. include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin.
  • Liquid carriers useful for preparing compositions of the present compounds include sterile water, polyethylene, glycols, non-ionic surfactants, and edible oils such as corn, sesame, and peanut oils.
  • Adjuvants conventionally used in the preparation of pharmaceutical compositions may also be included, such as flavoring agents, coloring agents, preservatives and antioxidants.
  • the compounds of the present invention were tested for biological activity according to the following procedures. - 30 -
  • the assay is based on the cleavage of the thiopeptide substrate ((Ac-Pro-Leu- Gly(2-mercapto-4-methyl-pentanoyl)-Leu-Gly-OEt), available from Bachem Bioscience) by the enzyme gelatinase, releasing the substrate product which reacts colorimetrically with DTNB ((5,5'-dithio-bis(2-nitro-benzoic acid)).
  • DTNB (5,5'-dithio-bis(2-nitro-benzoic acid)
  • the thiopeptide substrate was made up fresh as a 20 mM stock in 100% DMSO and the DTNB was dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature.
  • the substrate and the DTNB were diluted together to 1 mM with substrate buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2) before use.
  • substrate buffer 50 mM HEPES, pH 7.5, 5 mM CaCl2
  • the stock of human neutrophil gelatinase B was diluted with assay buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij) to a final concentration of 0J5 nM.
  • the assay buffer, enzyme, DTNB/substrate (500 ⁇ M final concentration) and vehicle or inhibitor were added to a 96 well plate (total reaction volume of 200 ⁇ l) and the increase in color was monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader.
  • the increase in OD405 was plotted and the slope of the line was calculated.
  • the slope represents the reaction rate.
  • the lineaiity of the reaction rate was confirmed (fi >0.85) and the mean (x ⁇ sem) of the control rate was calculated and compared for statistical significance (p ⁇ 0.05) with drug-treated rates using Dunnett's multiple comparison test.
  • Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression (IPRED, HTB).
  • This assay was based on the cleavage of a peptide substrate ((Dnp-Pro-Cha- Gly-Cys(Me)-His-Ala-Lys(NMa)-NH2), available from Peptide International, Inc.) by collagenase releasing the fluorescent NMa group which was quantitated on the fluorometer as disclosed in Bickett et al., "A High Throughput Fluorogenic Substrate - 31 -
  • MMP-1 Interstitial Collagenase
  • MMP-2 Gelatinase
  • Dnp quenches the NMa fluorescence in the intact substrate.
  • the substrate was dissolved in methanol and stored frozen in 1 mM aliquots. Collagenase was stored frozen in buffer in 25 ⁇ M aliquots.
  • the substrate was dissolved in HCBC buffer to a final concenttation of 10 ⁇ M and collagenase to a final concentration of 5 nM.
  • the compounds being examined were dissolved in methanol, DMSO, or HCBC.
  • the methanol and DMSO were diluted in HCBC to ⁇ 1.0%.
  • the compounds were added to a 96 well plate containing enzyme and the reaction was started by the addition of substrate.
  • the reaction was read (excitation 340 nm. emission 444 nm) for 10 min. and the increase in fluorescence over time was plotted as a linear line. The slope of the line was calculated representing the reaction rate. The linearity of the reaction rate was confirmed (r ⁇ >0.85). The mean (x ⁇ sem) of the control rate was calculated and compared for statistical significance (p ⁇ 0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression.
  • each well received a solution composed of 10 ⁇ L TACE (available from Immunex) at a final concentration of l ⁇ g/mL, 70 ⁇ L Tris buffer, have a pH of 7.4 and containing 10% glycerol (final concentration 10 mM), and 10 ⁇ L of test compound solution in DMSO (final concentration l ⁇ M, DMSO concentration ⁇ 1%).
  • the plates were incubated for 10 minutes at room temperature.
  • the reaction was initiated by addition of a fluorescent peptidyl substrate (final concentration 100 ⁇ M) to each well with shaking on a shaker for 5 sec.
  • the reaction was read (excitation 340 nm, emission 420 nm) for 10 min. and the increase in fluorescence over time was plotted as a linear line. The slope of the line was calculated and this represents the reaction rate. The linearity of the reaction rate was confirmed (r ⁇ >0.85). The mean (x ⁇ sem) of the control rate was calculated and compared for statistical significance (p ⁇ 0.05) with drug-treated rates using Dunnett's -32-
  • the following intermediate compounds can be prepared from the appropriately unsubstituted methyl 2- [(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate or the appropriately substituted methyl 2-[(substituted-2-aminobenzyl)-(4-methoxybenzene- sulfonyl)amino]-3-hydroxypropionate.

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Abstract

L'invention se rapporte à des composés représentés par la formule (I) dans laquelle R, R1, R2, R3 et R4 sont définis dans la description. Ces composés présentent une activité inhibitrice vis à vis des métalloprotéases matricielles.
EP99902417A 1998-01-27 1999-01-22 Acides 2,3,4,5-tetrahydro-1h-[1,4]-benzodiapezine-3-hydroxamiques utilises en tant qu'inhibiteurs de metalloproteases matricielles Withdrawn EP1051407A1 (fr)

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US14374 1998-01-27
PCT/US1999/001325 WO1999037625A1 (fr) 1998-01-27 1999-01-22 Acides 2,3,4,5-tetrahydro-1h-[1,4]-benzodiapezine-3-hydroxamiques utilises en tant qu'inhibiteurs de metalloproteases matricielles

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US6458783B1 (en) 1997-09-29 2002-10-01 Bristol-Myers Squibb Company Non-imidazole benzodiazepine inhibitors of farnesyl protein transferase
AR022423A1 (es) * 1999-01-27 2002-09-04 American Cyanamid Co Compuestos derivados de acidos 2,3,4,5-tetrahidro-1h-[1,4]benzodiazepina-3-hidroxamicos, composicion farmaceutica que los comprenden, y el uso de losmismos para la manufactura de un medicamento
US6544984B1 (en) 1999-01-27 2003-04-08 American Cyanamid Company 2,3,4,5-tetrahydro-1H-(1,4)benzodiazepine-3-hydroxamic acids
US6808902B1 (en) 1999-11-12 2004-10-26 Amgen Inc. Process for correction of a disulfide misfold in IL-1Ra Fc fusion molecules
US7766013B2 (en) 2001-06-05 2010-08-03 Alexza Pharmaceuticals, Inc. Aerosol generating method and device
US20070122353A1 (en) 2001-05-24 2007-05-31 Hale Ron L Drug condensation aerosols and kits
KR20040023630A (ko) 2001-06-26 2004-03-18 아브게닉스, 인크. Ｏｐｇｌ에 결합하는 항체
ES2594867T3 (es) 2007-03-09 2016-12-23 Alexza Pharmaceuticals, Inc. Unidad de calentamiento para usar en un dispositivo de administración de fármaco
FR2950057B1 (fr) 2009-09-17 2011-08-26 Galderma Res & Dev Nouveaux composes benzene-carboxylamides, leur procede de synthese et leur utilisation en medecine ainsi qu'en cosmetique
FR2950056B1 (fr) 2009-09-17 2011-08-26 Galderma Res & Dev Nouveaux composes benzene-carboxylamides, leur procede de synthese et leur utilisation en medecine ainsi qu'en cosmetique
BR112021006407A8 (pt) 2018-10-04 2022-12-06 Inst Nat Sante Rech Med uso de inibidores do egfr para ceratodermas

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RU2164914C2 (ru) * 1995-11-13 2001-04-10 Хехст Акциенгезелльшафт ЦИКЛИЧЕСКИЕ И ГЕТЕРОЦИКЛИЧЕСКИЕ N-ЗАМЕЩЕННЫЕ α-ИМИНОГИДРОКСАМОВЫЕ И КАРБОНОВЫЕ КИСЛОТЫ
DE69633947T2 (de) * 1995-12-08 2005-12-01 Agouron Pharmaceuticals, Inc., San Diego Zwischenprodukte zur Herstellung von Metallproteinasehemmern

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AR017230A1 (es) 2001-08-22
AU2240299A (en) 1999-08-09
CA2317546A1 (fr) 1999-07-29
KR20010034406A (ko) 2001-04-25
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ZA99569B (en) 2000-07-26
BR9907746A (pt) 2000-10-17
CN1293663A (zh) 2001-05-02
PL342045A1 (en) 2001-05-21
JP2002501056A (ja) 2002-01-15

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