Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/16—Benzazepines; Hydrogenated benzazepines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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

Definitions

• This invention relates to novel bicyclic compounds which inhibit platelet aggregation, pharmaceutical compositions containing the compounds and methods of using the compounds.
• GPIIb-IIIa platelet receptor complex which is a member of a family of adhesion receptors referred to as integrins. It has been found that frequently the natural ligands of integrin receptors are proteins which contain an Arg-Gly-Asp sequence. Von Willebrand factor and fibrinogen, which are considered to be natural ligands for the GPIIb-IIIa receptor, possess an Arg-Gly-Asp (RGD in single letter amino acid code) sequence in their primary structure.
• these proteins are able to bind and crosslink GPIIb-IIIa receptors on adjacent platelets and thereby effect aggregation of platelets.
• Fibronectin, vitronecrin and thrombospondin are RGD-containing proteins which have also been demonstrated to bind to GPIIb-IIIa.
• Fibronectin is found in plasma and as a structural protein in the intracellular matrix. Binding between the structural proteins and GPIIb-IIIa may function to cause platelets to adhere to damaged vessel walls.
• Linear and cyclic peptides which bind to vitronectin and contain an RGD sequence are disclosed in WO 89/05150 (PCT US88/04403).
• EP 0275748 discloses linear tetra- to hexapeptides and cyclic hexa- to octapeptides which bind to the GPIIb-IIIa receptor and inhibit platelet aggregation.
• Other linear and cyclic peptides are reported in EP-A 0341 915.
• the peptide like structures of such inhibitors often pose problems, such as in drug delivery, metabolic stability and selectivity.
• Inhibitors of the fibrinogen receptor which are not constructed of natural amino acid sequences are disclosed in EP-A 0372,486, EP-A 0 381 033 and EP-A 0478 363.
• WO 92/07568 discloses fibrinogen receptor antagonists which mimic a conformational ⁇ -turn in the RGD sequence by forming a monocyclic seven-membered ring structure.
• novel fibrinogen receptor antagonists e.g., inhibitors of the GPIIb-IIIa protein
• the present invention discloses novel bicyclic compounds, including benzazepines and benzodiazepines. These compounds inhibit the GPIIb-IIIa receptor and inhibit platelet aggregation. Summary of the Invention
• this invention is a bicyclic compound comprising a substituted seven-membered ring fused to an aromatic six-membered ring as described hereinafter in formula (I).
• This invention is also a pharmaceutical composition for inhibiting platelet aggregation or clot formation, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier.
• This invention is further a method for inhibiting platelet aggregation in a mammal in need thereof, which comprises internally administering an effective amount of a compound of formula (I).
• this invention provides a method for inhibiting reocclusion of an artery or vein in a mammal following fibrinolytic therapy, which comprises internally administering an effective amount of a fibrinolytic agent and a compound of formula (I).
• This invention is also a method for treating stroke, transient ischemia attacks, or myocardial infarction.
• the novel bicyclic compounds comprise a seven-membered ring fused to an aromatic six-membered ring and having a nitrogen-containing substituent on the seven-membered ring and an aliphatic substituent, preferably containing or being an acidic moiety, on the aromatic six-membered ring.
• the seven-membered ring may contain heteroatoms, such as nitrogen, oxygen and sulfur, and the aromatic six-membered ring may be carbocyclic or contain up to two nitrogen atoms.
• the fused 7-6 ring system is believed to interact favorably with the GPIIb-Ula receptor and to orient the substituent sidechains on the seven and the aromatic six-membered rings so that they may also interact favorably with the receptor.
• these compounds are believed to inhibit the binding of fibrinogen to the platelet-bound fibrinogen receptor GPIIb-IIIa, and may interact with other adhesion proteins via antagonism of a putative RGD binding site.
• the compounds of mis invention are compounds of formula (I):
• a 1 to A 5 form an accessible substituted seven-membered ring, which may be saturated or unsaturated, optionally containing up to two heteroatoms chosen from the group of O, S and N wherein S and N may be optionally oxidized;
• D 1 to D 4 form an accessible substituted six membered ring, optionally containing up to two nitrogen atoms;
• R* is H, Q-C 1-6 dkyl, Q-C 1-6 oxoalkyl, Q-C 2-6 alkenyl, Q-C 3-4 oxoalkenyl, Q-C 3-4 oxoalkynyl, Q-C 2-4 alkynyl, Q-C 1-4 alkylamino, Q-C 1-4 alkyloxy,
• Q is H, C 3-6 cycloa-kyl, Het or Ar;
• R 6 is W-(CR , 2)q-Z-(CR , R 10 ) r -U-(CR , 2 ) s -V-;
• R 7 is -COR 8 , -COCR' 2 R 9 , -C(S)R 8 , -S(O) m OR', -S(O) m NR'R", -PO(OR'), -PO(OR') 2 , -B(OR') 2 , -NO 2 and Tet;
• R 8 is -OR', -NR'R", -NR'SO 2 R', -NR'OR', -OCR' 2 C(O)OR', -OCR' 2 OC(O)-R', -OCR' 2 C(O)NR' 2 , CF 3 or AA1;
• R 9 is -OR', -CN, -S(O) r R', S(O) m NR 2 . -C(O)R' C(O)NR 2 or -CO 2 R';
• R 10 is H, C 1-4 alkyl or -NR'R";
• R 11 is H, halo, -OR 12 , -CN, -NR'R 12 , -NO 2 , -CF 3 , CF 3 S(O) r -, -CO 2 R', -CONR' 2 , Q-C 0-6 alkyl-, Q-C 1-6 oxoalkyl-, Q-C 2-6 alkenyl-, Q-C 2-6 alkynyl-,
• R 12 is R", -C(O)R', -C(O)NR' 2 , -C(O)OR 15 , -S(O) m R' or S(O) m NR' 2 ;
• R 13 is R', -CF 3 . -SR', or -OR';
• R 14 is R', C(O)R', CN, NO 2 , SO 2 R' or C(O)OR 15 ;
• R 15 is H, C 1-6 alkyl or Ar-C 0-4 alkyl
• R' is H, C 1- 6 alkyl, C 3-7 cycloalkyl-C 0-4 alkyl or Ar-C 0-4 alkyl;
• R" is R', -C(O)R' or -C(OOR 15 ;
• R'" is R" or AA2
• AA1 is an amino acid attached through its amino group and having its carboxyl group optionally protected
• AA2 is an amino acid attached through its carboxyl group, and having its amino group optionally protected
• Y is absent, S or O;
• Z is (CH 2 ) t , Het, Ar or C 3-7 cycloalkyl
• n 1 or 2;
• n 0 to 3;
• p is 0 or 1;
• q 0 to 3;
• r is 0 to 2;
• s is 0 to 2;
• t is 0 to 2;
• Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
• this invention includes each unique nonracemic compound which may be synthesized and resolved by conventional techniques. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, such as and , and tautomers of guanidine-type groups, such as - and , each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or locked in one form by appropriate substitution with R'. The meaning of any substiment at any one occurrence is independent of its meaning, or any other substiment's meaning, at any other occurrence, unless specified otherwise.
• a 1 is CR 1 R 1' ,NR 1 , O or S(O) x ;
• a 2 is CR 2 R 2' or NR 2 ;
• a 3 is CR 3 R 3 ', CR 3 , NR 3 , N, O or S(O) x ;
• a 4 is CR 4 R 4 ', CR 4 , NR 4 , or N;
• a 5 is CR 5 R 5' , CR 5 , NR 5 , N, O or S(O) x ;
• D 1 -D 4 are CR, CR * or N;
• R 4 and R 4' are hydrogen or R 4 is R 9 and R 4' is absent or present as hydrogen;
• a 1 is CR 1 R 1' , NR 1 , O or S
• a 2 is CR 2 R 2' , NR 2 or CR 2
• a 3 is
• a 4 is CR 4 R 4' , CR 4 , NR 4 or N
• a 5 is CR 5 R 5' , CR 5 , NR 5 , N or O
• D 1 and D 4 are CH
• D 2 is CR*
• D 3 is CR.
• a 1 is CR 1 R 1' , NR" or S
• a 2 is CR 2 R 2' or NR 2
• a 3 is CR 3 R 3'
• a 4 is CR 4 R 4' or NR 4
• a 5 is CR 5 R 5' .
• (CR'R 10 ) r -U-(CR , 2 ) s -V is CO, CONR', NR'CO, CH 2 CHOH,
• a 2 is NR 6
• a 3 , A 4 and A 5 are CH 2 .
• a 1 is NH
• a 3 is CHR 6
• a 4 is
• NC(O)R 1-6 alkyl and R 5 is CH 2 .
• Z is phenyl, a six-membered Het or (CH 2 ) t ;
• R 6 Preferred illustrative examples of R 6 are:
• R' are H or C 1-4 alkyl.
• Preferred compounds of this inventions are:
• W represents a nitrogen-containing group which is capable of making a hydrogen bond.
• W is a basic nitrogen moiety.
• R 7 represents a group with a non-bonding pair of electrons which is capable of forming a hydrogen bond or chelating with a metal cation.
• R 7 is acidic.
• Arg refers to arginine
• MeArg refers to N ⁇ -methyl-arginine
• HArg refers to homoarginine
• NArg refers to norarginine
• (Me 2 )Arg refers to N',N"-dimethyl arginine
• (Et 2 )Arg refers to N',N"-diethyl arginine
• Orn refers to omithine.
• These radicals are suitable components of the substituent R 6 .
• N ⁇ -Substituted derivatives of these amino acid are also useful in this invention. Representative methods for preparing ⁇ -substituted derivatives are disclosed in U.S. Patent No.
• PEPTIDES PROCEEDINGS OF THE 7TH AMERICAN PEPTIDE SYMPOSIUM, Rich, D., Gross, E., Eds, Pierce Chemical Co.,
• C 1-4 alkyl as applied herein is meant to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.
• C 1-6 alkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
• C 0-4 alkyl and C 0-6 -dkyl additionally indicates that no alkyl group need be present
• C 2-6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
• C 2-6 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
• C 2-6 alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
• C 2-6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
• C 1-4 oxoalkyl refers to an alkyl group of up to four carbons wherein a CH 2 group is replaced by a C(O), or carbonyl, group. Substituted formyl, acetyl, 1-propanal, 2-propanone, 3-propanal, 2-butanone, 3-butanone, 1- and 4-butanal groups are representative.
• C 1-6 oxoalkyl includes additionally the higher analogues and isomers of five and six carbons substituted by a carbonyl group.
• C3-6oxoalkenyl and C3-6oxoalkynyl refers to a C 3-6 alkenyl or C 3-6 alkynyl group wherein a CH 2 group is replaced by C(O) group.
• C 3-4 oxoalkenyl includes 1-oxo-2-propenyl, 3-oxo-1-propenyl, 2-oxo-3-butenyl and the like.
• a substiment on a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 oxoalkyl group, such as R 11 may be on any carbon atom which results in a stable structure, and is available by conventional synthetic techniques.
• Q-C 1-6 alkyl refers to a C 1-6 alkyl group wherein in any position a carbonhydrogen bond is replaced by a carbon-Q bond.
• Q-C 2-6 alkenyl and Q-C 2-6 alkynyl have a similar menaing with respect to C 2-6 alkenyl and C 2-6 alkynyl.
• Ar, or aryl as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three moieties R 11 .
• R 11 may be C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkthio, trifluoroalkyl, OH, F, CI, Br or I.
• Het, or heterocycle indicates an optionally substituted five or six membered monocyclic ring, or a nine or ten-membered bicyclic ring containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis.
• Illustrative heterocycles are benzofuryl, benzimidazole, benzopyran, benzothiophene, furan, imidazole, indoline, morpholine, piperidine, piperazine, pyrrole, pyrrolidine,
• a six membered ring heterocycle containing one or two nitrogens such as piperidine, piperazine, tetrahydropyridine and pyridine, are preferred heterocycles for the moiety Z. Any accessible combination of up to three substituents, such as chosen from R 11 , on the Het ring that is available by chemical synthesis and is stable is within the scope of this invention.
• a six membered monocyclic ring heterocycle containing one or two nitrogens, such as piperidine, piperazine, tetrahydropyridine and pyridine, are preferred heterocycles for the moiety Z.
• C 3-7 cycloalkyl refers to an optionally substituted carbocyclic system of three to seven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds.
• Typical of C 3-7 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents, such as chosen from R 11 , on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention.
• An accessible substituted seven-membered ring as referred to herein is any saturated or unsaturated seven-membered ring which (i) has up to five substituents, such as R 6 or R 9 , wherein the substituents may be present on any atom or heteroatom that results in a stable strucmre, and (ii) contains up to two heteroatoms selected from the group of N, O and S, wherein S and N may optionally be oxidized, and (iii) is stable and may be synthesized by one skilled in the chemical arts in a form fused via two adjacent ring carbon atoms to a phenyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl ring.
• Typical of accessible six-membered rings are the common saturated and unsaturated rings of cycloheptane, thiepin, oxapin, azepine, diazepine, thiazepin, oxazepin, dioxepin, oxathiepin, and dithiepin.
• no two adjacent atoms in the seven-membered ring are simultaneously heteroatoms.
• An accessible substituted aromatic six-membered ring as referred to herein is an unsaturated (e.g. aromatic) six-membered ring which (i) has one to three substituents, such as chosen from R and R * , (ii) optionally contains up to two nitrogens, (iii) is fused via two adjacent carbon atoms to an accessible substituted seven-membered ring, and (iv) is stable and may be prepared by one skilled in the chemical arts.
• Typical of accessible aromatic six-membered rings are phenyl, pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl ring.
• Representative bicyclic rings formed by the combination of the accessible seven and six-membered rings are: 1,2-benzo-1-cycloheptene, 1,2-benzo-1,3-cycloheptadiene and 1,2-benzo-1,4-cycloheptadiene compounds; 1-, 2- and 3-benzazepine, dihydrobenzazepine and tetrahydrobenzazepine compounds; 1,2-, 1,3-, 1,4-, 1,5-, 2,3- and 2,4-benzodiazepine, dihydrobenzodiazepine and tetrahdyrobenzodiazepine compounds;, 1,2-, 1,3-, 1,4-, 1,5-, 2,1-, 2,3-, 2,4-, 2,5-, 3,1-, 3,2-, and 4,1-benzoxazepine, dihydrobenzoxazepine and tetrabenzoxazepine compounds; 1,2-, 1,3-, 1,4-, 1,5-, 2,1-, 2,3-, 2,5-, 3,
• Phenyl is a preferred accessible six-membered ring, and di- or tetrahydroazepine, diazepine, thiazepine and oxazepine are preferred accessible seven-membered rings.
• preferred ring systems are the benzazepine and benzodiazepine systems.
• a 1 -A 5 , CR 1 -CR 5 and N represent an unsaturated sp 2 carbon or nitrogen atom, which may be connected by an endocyclic double bond to an adjacent atom in the ring, provided such arrangement results in the creation of a stable compound.
• N as used herein indicates a nitrogen heterocycle, which may be a saturated or unsaturated stable five-, six- or seven-membered monocyclic ring, or a seven- to ten-membered bicyclic ring containing up to three nitrogen atoms or containing one nitrogen atom and a heteroatom chosen from oxygen and sulfur, and which may be substituted on any atom that results in a stable structure.
• the nitrogen atom in such ring may be substituted so as to result in a quaternary nitrogen.
• the nitrogen heterocycle may be substituted in any stable position by R 20 , for instance H, C 1-4 alkoxy, F, CI, Br, I, NO 2 , NR' 2 , OH, CO 2 R', CONHR', CF 3 , Q- C 0-4 alkyl, Q-C 1-4 alkyl-S(O) u (e.g., where u is 0, 1 or 2) or C 1-4 alkyl substituted by any of the aforementioned sustituents.
• Representative of N are pyrroline, pyrrolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline,
• N may be pyridyl, pyrolidinyl, piperidinyl, piperazinyl, azetidinyl, quinuclidinyl or tetrahy dropyridinyl.
• N is preferably 4-pyridyl, 4-(2-amino-pyridyl), 4-tetrahydropyridyl, 4-piperidinyl or 4-piperazinyl.
• AA1 as referred to herein is an amino acid with its carboxyl group optionally protected, wherein the amino acid may be any of the natural ⁇ -amino acids or penicillamine.
• the unprotected carboxyl group is a free carboxylic acid group.
• Protecting groups for the carboxyl are esters or amides which are formed, for instance, when the OH of the carboxy group is replaced by R 8 .
• AA2 is an amino acid, as above, with its amino group optionally protected. Amino protecting groups are well known in the art, for instance, when the amino group is substituted by R 12 .
• An unprotected amino group is a free NH 2 group.
• C(O) indicates a carbon doubly bonded to oxygen (e.g., carbonyl)
• C(S) indicates a carbon doubly bonded to sulfur (e.g., thiocarbonyl).
• t-Bu refers to the tertiary butyl radical
• Boc refers to the t-butyloxycarbonyl radical
• Fmoc refers to the fluorenylmethoxycarbonyl radical
• Ph refers to the phenyl radical
• Cbz refers to the benzyloxycarbonyl radical
• BrZ refers to the o-bromobenzyloxycarbonyl radical
• ClZ refers to the o-chlorobenzyloxycarbonyl radical
• Bzl refers to the benzyl radical
• 4-MBzl refers to the 4-methyl benzyl radical
• Me refers to methyl
• Et refers to ethyl
• Ac refers to acetyl
• Alk refers to C 1-4 alkyl
• Nph refers to 1- or 2-naphthyl
• cHex refers to cyclohexyl.
• MeArg is N ⁇ -methyl argin
• DCC refers to dicyclohexylcarbodiimide
• DMAP refers to
• DIEA diisopropylethyl amine
• EDC N-ethyl-N'(dimethylaminopropyl)-carbodiimide.
• HOBt refers to 1-hydroxybenzotriazole
• THF tetrahydrofuran
• DIEA diisopropylethylamine
• DMF dimethyl formamide
• NBS N-bromo-succinimide
• Pd/C a palladium on carbon catalyst
• PPA 1-propanephosphonic acid cyclic anhydride
• DPPA diphenylphosphoryl azide
• BOP refers to benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
• HF refers to hydrofluoric acid
• TEA triethylamine
• TFA trifluoroacetic acid
• PCC pyridinium chlorochromate.
• the compounds of formula (I) are generally prepared by reacting a compound of the formula (IV) with a compound of the formula (V):
• L 1 and L 2 are functional groups which are capable of reacting to form the linkage -(CR'R 10 ) r -U-(CR' 2 ) s -V-;
• R 6- is W-(CR' 2 ) q -Z- and any portion of the group -(CR'R 10 ) r -U-(CR' 2 ) s -V-which is connected to L 2 , with any reactive functional groups protected;
• L 1 and L 2 will be dependent upon the site of the linkage being formed.
• General methods for preparing the linkage -(CR'R 10 ) r -U-(CR , 2 ) s -V- are described, for example, in EP-A 0372486 and EP-A 0381 033 and EP-A 0478 363, which are incorporated herein by reference.
• L 1 may be -NH 2
• L 2 may be OH (as in an acid) or CI (as in an acid chloride)
• R 6" may be W-(CR , 2 ) q -Z-(CR , R 10 ) r -U-(CR , 2 ) s -C(O), with any functional groups optionally protected.
• R 6" may be (benzyloxycarbonyl-amidino)benzoyl- or (N ⁇ -Boc,N guan -Tos)arginyl-.
• L 2 is OH
• a coupling agent is used.
• L 1 may be -CO 2 H or CO-Cl
• L 2 may be -NH 2
• R 6" may be W-(CR' 2 ) q -Z-(CR'R 10 ) r -U-(CR , 2 ) s -.
• R 6" may be
• L 1 may be SO 2 Cl
• L 2 may be -NH 2 and R 6" may be as above.
• V is SO 2 NH
• L 1 may be -NH 2
• L 2 may be SO 2 CI.
• L 1 may be -CHO
• R 6" may be W-(CR' 2 ) q -Z-(CR'R 10 ) r -U-(CR' 2 ) s -.
• L 2 may be CHO, e.g., R 6" may be W-(CR' 2 ) q -Z-(CR'R 10 ) r -U-(CR' 2 ) s-1 -CHO.
• V is CH 2 CH 2
• L 1 may be -OH, -NH or - C ⁇ CH, respectively; L 2 may be -Br; and R 6" may be W-(CR' 2 ) q -Z-(CR'R 10 ) r -U-(CR' 2 ) s -.
• R 6" may be (benzyloxycarbonylamino)-methylbenzyl- or 2-(N-benzyl-4-piperidinyl)-ethyl.
• U or V is OCH 2 , NR'CH 2 or
• L 1 may be -CH 2 Br and L 2 may be -OH, -NH or -H, respectively.
• U or V is C ⁇ C
• L 1 may be Br, I or CF 3 SO 3
• L 2 may be C ⁇ CH and the coupling may be catalyzed by palladium and a base.
• V is CHOHCH 2
• V is CH 2 CHOH
• the compounds of formula (TV), wherein two of A 1 to A 5 are nitrogen, are benzodiazepines and are prepared by the general methods illustrated by Scheme I.
• Representative methods for preparing benzodiazepines are well known in the art (e.g., Hynes, et al., J. Het. Chem., 25: 1173 (1988); Muller, et al., Helv. Chim. Acta., 65:2118 (1982): Mori, et al.. Heterocycles, 16:1491 (1981)).
• the methylene acetal group of the formula 1 compound is converted to the corresponding diol compound of formula 2 by reacting the formula 1 compound with a Lewis Acid, such as aluminum chloride, in a suitable solvent, such as 1,2-dichloroethane, followed by reaction with aqueous hydrobromic acid.
• a Lewis Acid such as aluminum chloride
• a suitable solvent such as 1,2-dichloroethane
• the Boc protecting group on the 4-nitrogen of the formula 7 1,4-benzodiazepine compound is removed under acidic conditions, using, for example, trifluoroacetic acid in methylene chloride.
• Acetylation of the 4-nitrogen of the formula 8 compound using, for example, acetyl chloride in the presence of a base, such as
• a TOS group on a nitrogen atom may be removed by condensing the formula 9 compound with hydrogen fluoride to give the formula 10 compound, which is also a formula (I) compound, and a C 1- 6 alkyl ester group on a carboxylic acid moiety may be removed by saponification using base, for example, sodium hydroxide in a suitable solvent system, such as water/methanol, to give the formula 11 compound, which is also a formula (I) compound.
• base for example, sodium hydroxide in a suitable solvent system, such as water/methanol
• Scheme II presents a method for the preparation of the benzazepine ring system. Generally the synthesis is begun with a tetralone, substituted by R and R*, or precussors thereto, such as a nitro group, which are commercially available or are well known in the art.
• the tetralone of formula 12 is treated with a base, such as lithium bis(trimethylsilyl)amide, followed by reaction with a C 1 -4 alkyl chloroformate, such as methyl chloroformate, to give the corresponding enol carbonate.
• a base such as lithium bis(trimethylsilyl)amide
• a C 1 -4 alkyl chloroformate such as methyl chloroformate
• Cyclization to form the azepine ring is accomplished by hydrolyzing the ester of the formula 14 compound, for example, using base, such as sodium hydroxide, followed by reaction with a peptide-coupling agent, such as benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate, in the presence of 1-hydroxybenzotriazole and a base, such as N-methylmorpholine, in a suitable solvent, such as dimethylformamide, to give the formula 15 compound. Reduction of the nitro group in the formula 15 compound using, for example, hyrogenation in the presence of a catalyst, such as palladium on carbon, gives the formula 16 amino compound.
• base such as sodium hydroxide
• a peptide-coupling agent such as benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate
• 1-hydroxybenzotriazole and a base such as N
• the amine group is further elaborated to give the desired R-substituent on the benzazepine ring.
• the formula 16 amine is reacted with dimethylacetylene dicarboxylate to give the corresponding enamine, which is then reduced to the formula 17a compound, which is also a formula (I) compound.
• formula 16 amine may be reacted with imine-forming reagents, such as benzyl 3-keto-5-phenyl-pentanoate, which may be reduced using, for example, sodium triacetoxyborohydride to give a compound represented by formula 17b, which is also a formula (I) compound.
• imine-forming reagents such as benzyl 3-keto-5-phenyl-pentanoate
• Protecting groups such as those for amino or carboxy groups, are selectively removed by methods known in the an to give the formula 18 compound, which is also a formula (I) compound.
• Coupling reagents as used herein denote reagents which may be used to form peptide bonds. Typical coupling methods employ carbodiimides, activated anhydrides and esters and acyl halides. Reagents such as EDC, DCC, DPPA, PPA, BOP reagent, HOBt, N-hydroxysuccinimide and oxalyl chloride are typical.
• Coupling methods to form peptide bonds are generally well known to the art.
• the methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer- Verlag, Berlin, 1984, Ali et al. in J. Med. Chem., 29, 984 (1986) and J. Med. Chem., 30, 2291 (1987) are generally illustrative of the technique and are incorporated herein by reference.
• the amine or aniline is coupled via its free amino group to an appropriate carboxylic acis substrate using a suitable carbodiimide coupling agent, such as N,N' dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP).
• a suitable carbodiimide coupling agent such as N,N' dicyclohexyl carbodiimide (DCC)
• catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP).
• HABT 1-hydroxybenzotriazole
• DMAP dimethylamino pyridine
• Other methods such as the formation of activated esters, anhydrides or acid halides, of the free carboxyl of a suitably protected acid substrate, and subsequent reaction with the free amine of a suitably protected amine, optionally in the presence of a base, are also suitable.
• tetrahydrofuran(THF) in the presence of a base, such as N-methyl morpholine, DMAP or a trialkylamine, with isobutyl chloroformate to form the "activated anhydride", which is subsequently reacted with the free amine of a second protected amino acid or aniline.
• a base such as N-methyl morpholine, DMAP or a trialkylamine
• W is a generally a basic functional group attached to Z, optionally via an alkyl chain, and is protected during the synthesis of R 6 or is introduced into the molecule after the -(CR'R 10 ) r -U-(CR , 2 ) s -V-linkage has been formed.
• Useful intermediates of formula (V) include compounds of the formula W- (CR' 2 ) q -Z-(CR'R 10 ) r -U-(CR , 2 ) s -L 2 , wherein Z, R', R", R 10 , U, q, r, and s are as defined for formula (I); L 2 is CHO, CO 2 R', , OH, Cl, Br, I, CH 2 -T or NR'R", and T is CF 3 SO 3 , OH, NHR", CI, Br or I; and W is W with any reactive basic nitrogen group protected as herein described.
• R'SO 2 , R'OCO and R'CO are typical nitrogen protecting groups. Particular examples of such intermediates are:
• R 20 is hydrogen, amino, mono or di-C 1-4 alkylamino, hydroxy or C 1-4 alkyl.
• the reactive functional groups of the sidechains of each synthetic fragment are suitably protected as known in the an. Suitable protective groups are disclosed in Greene, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, John Wiley and Sons, New York, 1981.
• the Boc, Cbz, phthaloyl or Fmoc group may be used for protection of an amino or amidino group.
• the Boc group is generally preferred for protection of an ⁇ -amino group.
• a t-Bu, cHex or benzyl ester may be used for the protection of the side chain carboxyl.
• a benzyl group or suitably substituted benzyl group (e.g., 4-methoxy-benzyl or 2,4-dimethoxy-benzyl) is used to protect the mercapto group or the hydroxyl group.
• the tosyl group may be used for protection of the imidazolyl group and tosyl or nitro group for protection of the guanidino group.
• a suitably substituted carbobenzyloxy group or benzyl group may be also be used for the hydroxyl group or amino group.
• Suitable substitution of the carbobenzyloxy or benzyl protecting groups is ortho and/or para substitution with chloro, bromo, nitro or methyl, and is used to modify the reactivity of the protective group.
• the protective groups for the amino moiety are, most conveniently, those which are not removed by mild acid treatment. These protective groups are removed by such methods as catalytic hydrogenation, sodium in liquid ammonia or HF treatment, as known in the art.
• Modification of amino groups especially on the six-membered ring of the bicyclic system may be accomplished by alkylation, sulfonylation, cyanation or acylation as is generally known in the art.
• Acid addition salts of the compounds of this invention are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic.
• the acetate salt form is especially useful.
• Certain of the compounds form inner salts or zwitterions which may be acceptable.
• Canonic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li+, Na+, K+, Ca++, Mg-H- and NH 4 + are specific examples of cations present in pharmaceutically acceptable salts.
• This invention provides a pharmaceutical composition which comprises a compound according to formula (I) and a pharmaceutically acceptable carrier.
• the compounds of formula (I) may be used in the manufacture of a medicament.
• Pharmaceutical compositions of the compounds of formula (I) prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
• the liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
• Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpynolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
• excipients such as polyvinylpynolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
• the compounds of this invention may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration.
• Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
• Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
• Liquid carriers include syrup, peanut oil, olive oil, saline and water.
• the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
• the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
• the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
• a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
• Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
• the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
• excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
• the compounds of this invention may be used in vitro to inhibit the aggregation of platelets in blood and blood products, e.g., for storage, or for ex vivo manipulations such as in diagnostic or research use.
• This invention also provides a method of inhibiting platelet aggregation and clot formation in a mammal, especially a human, which comprises the internal administration of a compound of formula (I) and a pharmaceutically acceptable carrier.
• Indications for such therapy include acute myocardial infarction (AMI), deep vein thrombosis, pulmonary embolism, dissecting anurysm, transient ischemia attack (TIA), stroke and other infarct-related disorders, and unstable angina.
• DIC disseminated intravascular coagulation
• septicemia surgical or infectious shock
• post-operative and post-partum trauma cardiopulmonary bypass surgery
• incompatible blood transfusion abruptio placenta
• thrombotic thrombocytopenic purpura TTP
• snake venom immune diseases
• the compounds of this invention may be useful in a method for the prevention of metastatic conditions, the prevention or treatment of fungal or bacterial infection, inducing immunostimulation, treatment of sickle cell disease, and the prevention or treatment of diseases in which bone resorption is a factor.
• the compounds of formula (I) are administered either orally or parenterally to the patient, in a manner such that the concentration of drug in the plasma is sufficient to inhibit platelet aggregation, or other such indication.
• composition containing the compound is administered at a dose between about 0.2 to about 50 mg/kg in a manner consistent with the condition of the patient.
• parenteral administration is preferred.
• an intravenous infusion of the peptide in 5% dextrose in water or normal saline is most effective, although an intramuscular bolus injection may be sufficient.
• a capsule or tablet, or a bolus intramuscular injection is suitable.
• the compound of this invention is administered one to four times daily at a level of about 0.4 to about 50 mg/kg to achieve a total daily dose of about 0.4 to about 200 mg/kg/day.
• This invention further provides a method for inhibiting the reocclusion of an anery or vein following fibrinolytic therapy, which comprises internal
• fibrinolytic agent is intended to mean any compound, whether a natural or synthetic product, which directly or indirectly causes the lysis of a fibrin clot.
• Plasminogen activators are a well known group of fibrinolytic agents.
• Useful plasminogen activators include, for example, anistreplase, urokinase (UK), pro-urokinase (pUK), streptokinase (SK), tissue plasminogen activator (tPA) and mutants, or variants, thereof, which retain plasminogen activator activity, such as variants which have been chemically modified or in which one or more amino acids have been added, deleted or substituted or in which one or more or functional domains have been added, deleted or altered such as by combining the active site of one plasminogen activator with the fibrin binding domain of another plasminogen activator or fibrin binding molecule.
• Other illustrative variants include tPA molecules in which one or more
• tPA Growth factor variants are disclosed, e.g., by Robinson et al., EP-A 0 297589 and Browne et al., EP-A 0240 334.
• Other variants include hybrid proteins, such as those disclosed in EP 0 028 489, EP 0 155 387 and EP 0297 882, all of which are incorporated herein by reference.
• Anistreplase is a prefened hybrid protein for use in this invention. Fibrinolytic agents may be isolated from natural sources, but are commonly produced by traditional methods of genetic engineering.
• the fibrinolytic agent may be formulated in an aqueous, buffered, isotonic solution, such as sodium or ammonium acetate or adipate buffered at pH 3.5 to 5.5. Additional excipients such as polyvinyl pyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene, glycol, mannitol and sodium chloride may also be added. Such a composition can be lyophilized.
• the pharmaceutical composition may be formulated with both the compound of formula (I) and fibrinolytic in the same container, but formulation in different containers is preferred.
• both agents are provided in solution form they can be contained in an infusion/injection system for simultaneous administration or in a tandem arrangement.
• Indications for such therapy include myocardial infarction, deep vein thrombosis, pulmonary embolism, stroke and other infarct-related disorders.
• the compound of formula (I) is administered just prior to, at the same time as, or just after parenteral administration of tPA or other fibrinolytic agent. It may prove desirable to continue treatment with the peptide for a period of time well after reperfusion has been established to maximally inhibit post-therapy reocclusion.
• the effective dose of tPA, SK, UK or pUK may be from 0.5 to 5 mg/kg and the effective dose of the compound of this invention may be from about 0.1 to 25 mg/kg.
• a kit for convenient administration of the inhibitor and the fibrinolytic agent at the same or different times, comprising, in a single container, such as a box, carton or other container, individual bottles, bags, vials or other containers each having an effective amount of the inhibitor for parenteral administration, as described above, and an effective amount of tPA, or other fibrinolytic agent, for parenteral administration, as described above.
• kit can comprise, for example, both pharmaceutical agents in separate containers or the same container, optionally as lyophilized plugs, and containers of solutions for reconstitution.
• a variation of this is to include the solution for reconstitution and the lyophilized plug in two chambers of a single container, which can be caused to admix prior to use.
• the fibrinolytic and the compound of this invention may be packaged separately, as in two containers, or lyophilized together as a powder and provided in a single container.
• both agents When both agents are provided in solution form, they can be contained in an infusion/Injection system for simultaneous administration or in a tandem
• the platelet aggregation inhibitor may be in an i.v.
• injectable form, or infusion bag linked in series, via tubing to the fibrinolytic agent in a second infusion bag.
• a patient can receive an initial bolus-type injection or infusion, of the peptide inhibitor followed by an infusion of the fibrinolytic agent.
• the pharmacological activity of the compounds of this invention is assessed by their ability to inhibit the binding of 3 H-SK&F 107260, a known RGD-fibrinogen antagonist, to the GPIIbllla receptor, their ability to inhibit platelet aggregation, in vitro, and their ability to inhibit thrombus formation in vivo.
• the column was washed with 50 mL cold buffer A.
• the lectin-retained GPIIb-IIIa was eluted with buffer A containing 10% dextrose. All procedures were performed at 4°C.
• the GPIIb-IIIa obtained was >95% pure as shown by SDS polyacrylamide gel electrophoresis.
• a mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polar Lipids) were dried to the walls of a glass tube under a stream of nitrogen.
• Purified GPIIb-IIIa was diluted to a final concentration of 0.5 mg/mL and mixed with the phospholipids in a proteinrphospholipid ratio of 1:3 (w:w). The mixture was resuspended and sonicated in a bath sonicator for 5 min.
• the mixture was then dialyzed overnight using 12,000-14,000 molecular weight cutoff dialysis mbing against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaCl2 (with 2 changes).
• the GPIIb-IIIa-containing liposomes wee centrifuged at 12,000g for 15 min and resuspended in the dialysis buffer at a final protein concentration of approximately 1 mg/mL. The liposomes were stored at -70C until needed.
• the binding to the fibrinogen receptor (GPIIb-IIIa) was assayed by an indirect competitive binding method using [ 3 H]-SK&F- 107260 as an RGD-type ligand.
• the binding assay was performed in a 96- well filtration plate assembly (Millipore Corporation, Bedford, MA) using 0.22 um hydrophilic durapore membranes.
• the wells were precoated with 0.2 mL of 10 ⁇ g/mL polylysine (Sigma Chemical Co., St. Louis, MO.) at room temperature for 1 h to block nonspecific binding.
• Various concentrations of unlabeled benzadiazapines were added to the wells in quadruplicate.
• [ 3 H]-SK&F-107260 was applied to each well at a final concentration of 4.5 nM, followed by the addition of 1 ⁇ g of the purified platelet GPIIb-IIIa-containing liposomes. The mixtures were incubated for 1 h at room temperature. The GPIIb-IIIa-bound [3H]-SK&F- 107260 was seperated from the unbound by filtration using a Millipore filtration manifold, followed by washing with ice-cold buffer (2 times, each 0.2 mL).
• IC50 concentration of the antagonist which inhibits specific binding of [ 3 H]-SK&F- 107260 by 50% at equilibrium.
• the compounds of this invention inhibit [3H]-SK&F 107260 binding with Ki in the range of about 40 uM to about 100 uM.
• Platelet rich plasma, PRP was prepared by centrifugation at 150 ⁇ g for 10 min at room temperature. Washed platelets were prepared by centrifuging PRP at 800 ⁇ g for 10 min. The cell pellet thus obtained was washed twice in Tyrode's buffer (pH 6.5) without Ca ++ and resuspended in Tyrode's buffer (pH 7.4) containing 1.8 mM Ca ++ at 3 ⁇ 10 5 cells/ml. Peptides were added 3 min prior to the agonist in all assays of platelet aggregation.
• % aggregation [(90-CR) ⁇ (90-10)] ⁇ 100, where CR is the chart reading, 90 is the baseline, and 10 is the PRP blank reading.
• IC50's were determined by plotting [% inhibition of aggregation] vs. [concentration of peptide]. Peptides were assayed at 200 mM and diluted sequentially by a factor of 2 to establish a suitable dose response curve.
• the compounds were incubated for 3 h (rather than 3 min) in the PRP prior to addition of the agonist.
• (+)-4-N-(BOC)-1,3,5-trihydro-3(R)-(propyl-3-guanidine(tos))-2-oxo-7,8-dibutyrloxy-1,4-benzodiazapine bis ethyl ester was N-deprotected according to the procedure of Example 1(g). MS(ES) m/e 676(m+H) + . g) (+)-4-N-acetyl- 1,3,5-trihydro-3(R)-(propyl-3-guanidine(tos))-2-oxo-7,8-diobutyrloxy-1,4-benzodiazapine bis ethyl ester
• (+)-4-N-1,3,5-trihydro-3(R)-(propyl-3-guanidine(tos))-2-oxo-7,8-dibutyrioxy-1,4-benzodiazapine bis ethyl ester was N-acetylated according to the procedure of Example 1(h) to afford the title compound (30%).
• (+)-4-N-acetyl-1,3,5-trihydro-3(R)-(propyI-3-guanidine(tos))-2-oxo-7,8-diobutyrloxy-1,4-benzodiazapine bis ethyl ester was hydrogen fluoride (HF) deprotected according to the procedure of Example 1(i) to afford the title compound (80%).
• (+)-4-N-acetyl-1,3,5-trihydro-3(R)-(propyl-3-guanidine)-2-oxo-7,8-dibuturloxy-1,4-benzodiazapine was saponified according to the procedure of Example 2(a) to afford the title compound. MS(ES) m/e 508(m+H) + .
• p-Xylenediamine (10 g, 73.4 mmol, was dissolved in methylene chloride (150 mL) and was treated at room temperature with di-tert-butyl dicarbonate (5.36 g, 24.5 mmol) and stirred for 50 hours. The reaction was diluted with chloroform, washed with 5% sodium carbonate, dried over magnesium sulfate, filtered and evaporated at reduced pressure. The residue was dissolved in a minimum of 1N aqueous hydrochloric acid (10 mL) and was washed 2 times with diethyl ether.
• reaction mixture was diluted with chloroform, washed with 1N hydrochloric acid (aqueous), dried over anhydrous magnesium sulfate and evaporated at reduced pressure.
• the residue was dissolved in dry toluene (250 mL) with benzyl alcohol (11 mL, 100 mmol) and the mixture was heated at 127 °C (bath temperature) for 20 hours and at reflux for 48 hours.
• the reaction mixture was evaporated and the residue was taken into ethyl acetate. This solution was washed with 5% sodium bicarbonate
• a preparation which contains 20 mg of the compound of Example 1 as a sterile dry powder is prepared as follows: 20 mg of the compound is dissolved in 15 mL of distilled water. The solution is filtered under sterile conditions into a 25 mL multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 mL of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume. Subsequent dilution may be made by addition of a metered volume of this dosage unit to another volume of D5W for injection, or a metered dose may be added to another mechanism for dispensing the drug, as in a bottle or bag for IV drip infusion or other injection-infusion system.
• D5W dextrose in water
• a capsule for oral administration is prepared by mixing and milling 50 mg of the compound of Example 1 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule.
• a tablet for oral administration is prepared by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of Example 1 with a 10% gelatin solution.
• the wet granules are screened, dried, mixed with 10 mg starch, 5 mg talc and 3 mg stearic acid; and compressed into a tablet

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