Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • 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
  • C07D401/14—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 three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• This invention relates to pharmaceutically active compounds which bind to integrins, such as dual antagonists of the vitronectin receptor and the fibrinogen receptor. Such compounds are useful for inhibiting platelet aggregation, treating restenosis and atherosclerosis and are useful in vascular remodeling.
• Integrins are a family of heterodimeric proteins which generally mediate cell adhesion. Typical of such proteins are the vitronectin receptor (an ⁇ 3 heterodimer) and the fibrinogen receptor (an ⁇ b ⁇ 3 heterodimer).
• the natural ligands of these receptors e.g., vitronectin and fibrinogen
• vitronectin and fibrinogen have been found to share a common -Arg-Gly-Asp- amino acid sequence, which appears to be critical for binding.
• many of the integrin receptors appear to cross react with ligands which possess such an amino acid sequence.
• the ⁇ n b ⁇ 3 receptor reacts with fibronectin and vitronectin, thrombospondin and von Willebrand factor, as well as fibrinogen.
• fibrinogen a dimer having two binding sites for ⁇ b ⁇ 3 , reacts with activated receptors found on the surface of platelets.
• the binding of 0C ⁇ b ⁇ 3 receptors on adjacent platelets, by fibrinogen leads to crosslinking and is considered to be a major factor in platelet aggregation.
• Compounds which inhibit the binding of the ⁇ b ⁇ 3 receptor to fibrinogen have been shown to inhibit the platelet aggregation in vitro, and thrombus formation in vivo.
• the vitronectin receptor oty ⁇ ⁇ is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions. It has been reported that the ⁇ v B 3 receptor expressed on human aortic smooth muscle cells stimulates their migration into neointima, which leads to the formation of atherosclerosis and restenosis after angioplasty. Brown, et al., Cardiovascular Res., 1994, 28, 1815. Additionally, a study has shown that a ⁇ y ⁇ ⁇ antagonist is able to promote tumor regression by inducing apoptosis of angiogenic blood vessels. Brooks, et al., Cell, 1994, 79, 1157.
• agents that block the vitronectin receptor and the fibrinogen receptor would be useful in treating diseases mediated by these receptors, such as atherosclerosis, restenosis (Topol. et al., J. Am. Coll. Cardiol, 1996, 28, 1643.) and cancer.
• This invention is also a pharmaceutical composition
• a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically carrier.
• This invention is also a method of treating diseases in which the pathology may be modified by binding to integrin receptors, especially the vitronectin and the fibrinogen receptors.
• the compounds of this invention are useful for treating atherosclerosis and restenosis, and conditions in which it is desirable to inhibit platelet aggregation, such as stroke, transient ischemia attacks, myocardial infarction and rethrombosis following thrombolytic therapy.
• This invention comprises compounds of formulae (I) or (II):
• A is NR', CHR', O or S
• R 1 is R 7 , or D-Co-4alkyl, D-C2-4alkenyl, D-C2-4alkynyl,
• R 2 is -(CH 2 )t-CO R 3 ;
• R 3 isH, Ci_6alkylor(CHRVAr;
• W is -(CHRg)a-U- (CHRg)b-;
• Rg is H, C j ⁇ alkyl, Het-C()-6alkyl, C3-7cycloalkyl-C _6alkyl or Ar-CQ-6alkyl;
• R k is Rg, -C(O)Rg, or -C(O)OR f ;
• Ri is is H, C j .galkyl, Het-C ⁇ - ⁇ alkyl, C3-7cycloalkyl-Co-6alkyl, Ar-Co-6 a lkyl, or C j.galkyl substituted by one to three groups chosen from halogen, CN, NRg 2 , ORg, SRg, CO 2 Rg, and CON(Rg) 2 ; R f is H, C ⁇ _6alkyl or Ar-Cj.galkyl;
• R e is H, Ci.galkyl, Ar-C ⁇ galkyl, Het-C ⁇ galkyl.
• Cs- cycloalkyl-C galkyl, Rb and R c are independently selected from H, C j.galkyl, Ar-Co- ⁇ alkyl,
• Q . Q ⁇ » Q 3 n d Q ⁇ are independently N or C-RY, provided that no more than one of Q ⁇ Q 2 , Q 3 and Q 4 is N;
• RY is H, halo, -ORg, -SRg, -CN, -NRgR k , -NO 2 , -CF3, CF 3 S(O) r , -CO 2 Rg, -CORg or -CONRg 2 , or C 1 _6alkyl optionally substituted by halo, -ORg, -SRg, -CN, -NRgR", -NO 2 , -CF3, R'S(O) r , -CO 2 Rg, -CORg or -CONRg 2 ;
• R5 is W'-(CR , 2)q-Z-(CR'RlO) r -U'-(CR'2)s;
• N CR', C(O) or O
• Y is absent, S or O
• Z is (CH 2 )t, Het. Ar or C3-7cycloalkyl
• R 7 is -COR 8 , -COCR'2R 9 , -C(S)R 8 , -S(0) m OR , , -S(0) m NR'R", -PO(OR'), -PO(OR')2, ⁇ (OR ⁇ , -N0 2 and Tet;
• R 8 is -OR', -NRR", -NR'SO2R', -NR'OR', -OCR'2C(O)OR', -OCR'2OC(O)- R', -OCR'2C(O)NR'2 or CF3;
• R 9 is -OR', -CN, -S(O) r R', S(O) m NR'2, -C(O)R' C(O)NR'2 or -CO2R';
• R 10 is H, C alkyl or -NRR"; each R u independently is H, halo, -OR 12 , -CN, -NR'R 12 , -NO 2 , -CF3, CF3S(O) r , -CO2R', -CONR'2, D-C ⁇ -6alkyl-, D-C ⁇ _6oxoalkyl-, D-C2-6alkenyl-, D-C2-6alkynyl-, D-C ⁇ -6alkyloxy-, D-C ⁇ -6alkylamino- or D-C ⁇ -6alkyl-S(O) r ;
• 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', -CF3, -SR', or -OR';
• R 14 is R', C(0)R', CN, NO 2 , SO 2 R' or C(O)OR 15 ;
• R 15 is H, Ci-6alkyl or Ar-C ⁇ -4alkyl
• D is H, C3-6cycloalkyl, Het or Ar
• R' is H, Ci-6alkyl, Ar-C ⁇ -6alkyl or C3_6cycloalkyl-C ⁇ -6alkyl;
• R" is R -C(O)R' or -C(O)OR';
• R'" is H, C ⁇ alkyl, Ar-Co-6alkyl, Het-C ⁇ - ⁇ alkyl, or C3-6cycloalkyl-C()- 6 alkyl, halogen, CF 3 , OR f , S(O) k R f , COR f , NO 2 , N(Rf) 2 , CO(NR f ) 2 , CH 2 N(Rf) 2 ; n is 0 to 3; q is 0 to 3; t is 0 to 2; a is 0, 1 or 2; b is 0, 1 or 2; k is 0, 1 or 2; m is 1 or 2; r is 0, 1 or 2; s is 0, 1 or 2; u is 0 or 1 ; and v is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
• this invention comprises formula (I) compounds of formula (la):
• Y is C(O), C(S) or CH 2 ;
• R 1 is R 7 , or D-Co-4alkyl, D-C2-4alkenyl, D-C2-4alkynyl, D-C3-4oxoalkenyl, D-C3_4oxoalkynyl, D-Cj_4aminoalkyl, D-C3_4aminoalkenyl, D-C3_4aminoalkynyl, optionally substituted by any accessible combination of one or more of R 1 * or R 7 ;
• R is -(CH 2 ) r CO2R 3 ;
• R 3 is H, C ⁇ _ 6 alkyl or (CHR ⁇ -Ar;
• W is -(CHRg)a-U- (CHRg)b-;
• G is NR e , S or O;
• Rg is H, Cj.galkyl, Het-Co_6alkyl, C3_7cycloalkyl-C()-6alkyl or Ar-Co-6alkyl;
• R k is Rg, -C(O)R8, or -C(O)OR f ;
• R 1 is is H, Cj.galkyl, Het-C()-6alkyl, C3-7cycloalkyl-Co-6alkyl, Ar-Co-6 a l k y k or Cj.galkyl substituted by one to three groups chosen from halogen, CN, NRg 2 , ORg, SRg, CO 2 Rg, and CON(Rg) 2 ;
• R f is H, C ⁇ galkyl or Ar-C ⁇ alkyl
• R e is H, C ⁇ _6alkyl, Ar-C ⁇ galkyl, Het-Ci.galkyl, C3-7cycloalkyl-C ⁇ _6alkyl, or (CH 2 ) k CO 2 Rg;
• R b and R c are independently selected from H, Cj.galkyl, Ar-C )-6alkyl, Het-Co-6alkyl, or C3-6cycloalkyl-Co_6alkyl, halogen, CF 3 , OR f , S(O) k R , COR f , NO2, N(R f )2, CO(NR ) 2 , CH 2 N(R f ) 2 , or R b and R c are joined together to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up to three substituents chosen from halogen, CF3, C ⁇ _4alkyl, OR f , S(O) k R f , COR f , CO 2 R f , OH, NO 2 , N(R f ) 2) CO(NR f ) 2 , and CH2N(Rf) 2 ; or methylenedioxy;
• Ci-6alkyl optionally substituted by halo, -ORg, -SRg, -CN, -NRgR", -NO 2 , -CF 3 , R'S(O) , -CO 2 Rg, -CORg or -CONRg 2 ;
• R5 is W'-(CR'2) q -Z-(CR'RlO) r u'-(CR'2) s ;
• Y is absent, S or O;
• Z is (CH2)t, Het, Ar or C3-7cycloalkyl
• R 7 is -COR 8 , -COCR'2R 9 , -C(S)R 8 , -S(O) m OR', -S(0) m NR'R", -PO(OR'), -PO(OR')2, -B(OR') 2 , -NO 2 and Tet;
• R 8 is -OR', -NRTT, -NR'SO R', -NR'OR', -OCR' C(O)OR', -OCR' 2 OC(O)- R', -OCR' 2 C(O)NR'2 or CF3;
• R 9 is -OR', -CN, -S(O) r R', S(O) m NR'2, -C(O)R' C(O)NR'2 or -CO2R';
• R 10 is H, C i-4alkyl or -NRH";
• R 1 1 is H, halo, -OR 12 , -CN, -NR'R 12 , -NO2, -CF3, CF3S(O) r , -CO2R',
• 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', -CF3, -SR', or -OR';
• R 14 is R', C(O)R', CN, NO2, SO2R' or C(O)OR 15 ;
• R 15 is H, Ci-6alkyl or Ar-C ⁇ -4alkyl
• D is H, C3-6cycloalkyl, Het or Ar;
• R' is H, C ⁇ _6alkyl, Ar-C ⁇ -6alkyl or C3-6cycloalkyl-C()-6alkyl;
• R" is R', -C(O)R' or -C(O)OR';
• 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.
• compounds may have unsaturated carbon- carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.
• compounds may exist in tautomeric forms, such as
• keto-enol tautomers such as - ⁇ " ⁇ - and -""" ⁇
• tautomers of guanidine-type NR' NR' 2 groups such as R"R'N A NR'-X- and R"R'N A N-X-
• 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 substituent at any one occurrence is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
• the compounds of formula (I) inhibit the binding of vitronectin and other
• RGD-containing peptides to the vitronectin ( ⁇ v ⁇ 3 ) receptor.
• Inhibition of the vitronectin receptor on osteoclasts inhibits osteoclastic bone resorption and is useful in the treatment of diseases wherein bone resorption is associated with pathology, such as osteoporosis and osteoarthritis.
• the compounds of the instant invention inhibit vitronectin receptors on a number of different types of cells, said compounds would be useful in-the treatment of inflammatory disorders, such as rheumatoid arthritis and psoriasis, and cardiovascular diseases, such as atherosclerosis and restenosis.
• the compounds of Formula (I) of the present invention may be useful for the treatment or prevention of other diseases including, but not limited to, thromboembolic disorders, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplant rejection, septic shock, eczema, contact dermatitis, inflammatory bowel disease, and other autoimmune diseases.
• the compounds of the present invention may also be useful for wound healing.
• the compounds of the present invention are useful for the treatment, including prevention, of angiogenic disorders.
• the term angiogenic disorders as used herein includes conditions involving abnormal neovascularization.
• angiogenisis will reduce the deleterious effects of the disease.
• An example of such a disease target is diabetic retinopathy.
• inhibition of angiogenisis will reduce the blood supply to the tissue and thereby contribute to reduction in tissue mass based on blood supply requirements. Examples include growth of tumors where neovascularization is a continual requirement in order that the tumor grow and the establishment of solid tumor metastases.
• the compounds of the present invention inhibit tumor tissue angiogenesis, thereby preventing tumor metastasis and tumor growth.
• the inhibition of angiogenesis using the compounds of the present invention can ameliorate the symptoms of the disease, and, in some cases, can cure the disease.
• a preferred therapeutic target for the compounds of the instant invention are eye diseases chacterized by neovascularization.
• eye diseases include corneal neovascular disorders, such as corneal transplantation, herpetic keratitis, luetic keratitis, pterygium and neovascular pannus associated with contact lens use.
• Additional eye diseases also include age-related macular degeneration, presumed ocular histoplasmosis, retinopathy of prematurity and neovascular glaucoma.
• the dual fibrinogen/vitronectin receptor antagonists of the present invention in the inhibition of platelet aggregation and smooth muscle cell migration following vascular injury from percutaneous transluminal coronary angioplasty (PTC A).
• PTC A percutaneous transluminal coronary angioplasty
• the instant compounds are useful in vascular remodeling.
• Y is C(O).
• X 1 is CH2
• A is NR'.
• R 1 is H, CH3, CH2CH3, CH2CF3, (CH2)i-2Phenyl, in which the phenyl group is unsubstituted or substituted by C ⁇ -4 alkoxy, C ⁇ -4 alkthio, CF3, OH, or halo.
• Suitable substituents for R 5 when fibrinogen antagonist acitivity is desired are:
• R"HNC( NH)NH-(CH 2 ) 3 (CHR 10 )-, and R"HN-(CH 2 ) 5 -, wherein E is N or CH, and R 20 is hydrogen, amino, mono or
• R' is H or C ⁇ -4 alkyl and R" is H.
• Particularly preferred of such groups for R 5 are:
• R" is H
• Preferred substituents for the group attached to W in R 4 when vitronectin binding activity is desired are:
• R b and R c are joined to form a cyclohexyl, phenyl or pyridyl ring.
• R', R" and Rg are each H and s is 0 or 1.
• R 4 A particularly preferred of such groups for R 4 is:
• fibrinogen antagonist activity will be favored by an intramolecular distance of about 16 intervening covalent bonds via the shortest path between the oxygen of the carbonyl moiety of the R 2 group attached to the seven- membered ring, and the basic nitrogen moiety of R ⁇ ; while vitronectin antagonist activity will be favored by about 14 intervening covalent bonds via the shortest path between the oxygen of the carbonyl moiety attached to the seven-membered ring, and the basic nitrogen moiety of R 4 .
• C ⁇ -4 alkyl as applied herein is meant to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.
• Ci ⁇ alkyl additionally includes pentyl, n- pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any C ⁇ alkyl or Ci ⁇ alkyl group may be optionally substituted by R 1 unless otherwise indicated.
• Co- 4 alkyl and Co-6alkyl additionally indicates that no alkyl group need be present (e.g., that a covalent bond is present).
• C -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. Any C 2-6 alkenyl group may be optionally substituted by R 1 ' unless otherwise indicated.
• C _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. Any sp 3 carbon atom in the C 2 _ 6 alkynyl group may be optionally substituted by R 1 *.
• 4 ⁇ xoalkyl refers to an alkyl group of up to four carbons wherein a CH 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 ⁇ _ 6 ⁇ xoalkyl includes additionally the higher analogues and isomers of five and six carbons substituted by a carbonyl group.
• C 3- 6 ⁇ xoalkenyl and C 3 .60xoalkynyl refers to a C 3 _6alkenyl or Cs ⁇ alkynyl group wherein a CH 2 group is replaced by C(O) group.
• C 3 - 4 ⁇ xoalkenyl includes l-oxo-2-propenyl, 3-oxo-l- propenyl, 2-oxo-3-butenyl and the like.
• a substituent on a Cj-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl or C ⁇ _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.
• D-Ci- 6 alkyl refers to a Cj. 6 alkyl group wherein in any position a carbon- hydrogen bond is replaced by a carbon-D bond.
• D-C 2-6 alkenyl and D-C 2- 6 alkynyl have a similar meaning 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
• R 1 J may be Ci-4alkyl, C1.4aU.oxy, CF3, OH, or halo
• Het, or heterocycle indicates an optionally substituted five or six membered monocyclic ring, or a nine or ten-membered bicychc 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 benzofuran, benzimidazole, benzopyran, benzothiophene, furan, lmidazole indole, indoline, morphohne, pipe ⁇ dine, p ⁇ erazine, pyrrole, pyrrohdine, tetrahydropyndine, py ⁇ dine, thiazole, thiophene, quinoline, isoquinoline, and tetra- and perhydro- quinoline and isoquinoline
• C3-7cycloalkyl 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 C3 7cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl Any combination of up to three substituents, such as chosen from R 1 !, on the cycloalkyl ring that is available by conventional chemical synthesis and is stable, is within the scope of this invention
• - indicates a nitrogen heterocycle which may be a saturated or unsaturated stable five-, six- or seven-membeied monocyclic ring, or a seven- to ten-membeied bicychc 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 21 , for instance H, C alkoxy, F, Cl, Br, I, NO 2 , NR' 2 , OH, CO 2 R', CONHR', CF 3 , D-C 0-4 alkyl, D-Ci-4alkyl-S(O) u (e g , where u is 0, 1 or 2) or Ci ⁇ alkyl substituted by any of the
• aforementioned sustituents Representative of — ' are pyrrohne, pyrrohdine, lmidazole, lmidazohne, lmidazohdine, pyrazole, pyrazo ne, pyrazohdine, pipe ⁇ dine, piperazine, morphohne, py ⁇ dine, py ⁇ dinium, tetrahydropyndine, tetrahydro- and hexahydro-azepine, quinuchdine, quinuc dinium, quinoline, or tetrahydropyridinyl.
• v ⁇ --) is preferably 4-pyridyl, 4-(2-amino-pyridyl), 4- tetrahydropyridyl, 4-piperidinyl or 4-piperazinyl.
• R b and R c are joined together to form a five- or six-membered aromatic or non-aromatic ring fused to the ring to which R b and R c are attached, the ring formed will generally be a five- or six-membered heterocycle selected from those listed above for Het, or will be a phenyl, cyclohexyl or cyclopentyl ring.
• Benzimidazolyl, 4-azabenzimidazolyl, 5-azabenzimidazolyl and substituted derivatives thereof are prefe ⁇ ed moieties for the group attached to W in R 4 .
• 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
• CIZ refers to the o-chlorobenzyloxycarbonyl radical
• Bn 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 Cj ⁇ alkyl
• Nph refers to 1- or 2-naphthyl
• cHex refers to cyclohexyl.
• MeArg is N ⁇ -methyl arginine. Tet refers to 5-tetrazolyl. Certain reagents are abbreviated herein.
• DCC refers to dicyclohexylcarbodiimide
• DMAP refers to dimethvlaminopyridine
• DIEA diisopropylethylamine
• EDC N-ethyl-N'(dimethylaminopropyl)- carbodiimide.
• HOBt refers to 1-hydroxybenzotriazole
• THF refers to tetrahydrofuran
• DMF refers to dimethyl formamide
• NBS refers to N-bromo- succinimide
• Pd/C refers to a palladium on carbon catalyst.
• DPPA diphenylphosphoryl azide
• BOP refers to benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate
• HF hydrofluoric acid
• PPA refers to polyphosphoric acid
• TEA triethylamine
• TFA trifluoroacetic acid
• PCC pyridinium chlorochromate
• a suitably protected benzazepine or benzodiazepine such as II-l (prepared as described in Bondinell, et al., PCT application WO 93/00095, published January 7, 1993 and Bondinell, et al., PCT application WO 94/14776, published July 7, 1994) is converted to an activated form using, for example, EDC and HOBt, and the activated form is subsequently reacted with a suitably protected arginine mimic, such as 1-5 (prepared as above), in a suitable solvent such as DMF or C ⁇ C ⁇ - Depending on whether acid nuetralization is required, an added base, such as diisopropylethylamine, may be used.
• a suitably protected benzazepine or benzodiazepine such as II-l (prepared as described in Bondinell, et al., PCT application WO 93/00095, published January 7, 1993 and Bondinell, et al., PCT application WO 94/14776
• the methyl ester of II-2 is hydrolyzed with aqueous base, such as, NaOH in aqueous MeOH and the t-butyl carbamate is removed with a strong acid, such as TFA in CH2CI2 or HCl in dioxane.
• a strong acid such as TFA in CH2CI2 or HCl in dioxane.
• the intermediate carboxylate salt is acidified with a suitable acid, such as TFA or HCl to afford the carboxylic acid II-3.
• the tricyclic core of the compounds of formula (II) are prepared as described in Bondinell, et al., PCT Application WO 97/01540, published January 16, 1997. Reference should be made to said patent application, the entire disclosure of which is incorporated by reference.
• the formula (II) compounds are prepared by methods analogous to those detailed in Scheme II. Coupling methods to form amide 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 /. Med. Chem., 29, 984 (1986) and J. Med.
• Coupling reagents as used herein denote reagents which may be used to form amide bonds.
• Typical coupling methods employ carbodiimides, activated anhydrides and esters and acyl halides.
• Reagents such as EDC, DCC, DPPA, BOP reagent, HOBt, N- hydroxysuccinimide and oxalyl chloride are typical.
• the amine or aniline is coupled via its free amino group to an appropriate carboxylic acid 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.
• Boc-amino acid or Cbz-amidino benzoic acid is treated in an anhydrous solvent, such as methylene chloride or tetrahydrofuran(THF), in the pre sence of a base, such as N-methyl mo ⁇ holine, 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.
• Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hvdrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic. succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable.
• Cationic 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 ++ and NH4+ are specific examples of cations present in pharmaceutically acceptable salts.
• compositions of 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.
• these compounds 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.
• the compounds described herein which are antagonists of the vitronectin receptor are useful for treating diseases wherein the underlying pathology is attributable to ligand or cell which interacts with the vitronectin receptor. For instance, these compounds are useful for the treatment of diseases wherein loss of the bone matrix creates pathology.
• the instant compounds are useful for the treatment of ostoeporosis, hype ⁇ arathyroidism, Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastasis, bone loss due to immobilization or sex hormone deficiency.
• the compounds of this invention are also believed to have utility as antitumor, antiinflammatory, anti-angiogenic and anti-metastatic agents, and be useful in the treatment of cancer, atherosclerosis and restenosis.
• the compounds of this invention are useful for inhibiting restenosis following angioplasty.
• the compounds of this invention which inhibit fibrinogen binding provide 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 pu ⁇ ura TTP
• snake venom and 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 reso ⁇ tion is a factor.
• This invention further provides a method for inhibiting the reocclusion of an artery or vein following fibrinolytic therapy, which comprises internal administration of a compound of formula (I) and a fibrinolytic agent.
• Administration of a compound of formula (I) in fibrinolytic therapy either prevents reocclusion completely or prolongs the time to reocclusion.
• 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.
• the compounds of this invention may also 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.
• the compound is administered either orally or parenterally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone reso ⁇ tion, or inhibit platelet aggregation or other such indication.
• the pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.
• parenteral administration is preferred.
• An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful.
• the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg.
• the compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
• the precise level and method by which the compounds are administered is readily determined by one routinely skilled in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
• the compounds may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
• the wells were washed once with buffer A and were incubated with 0.1 mL of 3.5% bovine serum albumin in the same buffer for 1 hr at room temperature. Following incubation the wells were aspirated completely and washed twice with 0.2 mL buffer A.
• the IC 50 concentration of the antagonist to inhibit 50% binding of [ 3 H]-SK&F- 107260
• the Kj dissociation constant of the antagonist
• c i b ⁇ 3 was diluted to a final concentration of 0.5 mg/mL and mixed with the phospholipids in a protein:phospholipid 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 tubing against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaC12 (with 2 changes).
• ⁇ b ⁇ 3 -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 -70°C until needed.
• the binding to the fibrinogen receptor ( ⁇ b ⁇ 3) 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 Co ⁇ oration, 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 ⁇ b ⁇ 3-containing liposomes. The mixtures were incubated for 1 h at room temperature. The 0t ⁇ ⁇ 3- bound [3HJ-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). Bound radioactivity remaining on the filters was counted in 1.5 mL Ready Solve (Beckman Instruments, Fullerton, CA) in a Beckman Liquid
• Inhibition of platelet aggregation may be measured by the method described in WO 93/00095 (PCT/US/92/05463).
• In vivo thrombus formation is demonstrated by recording the systemic and hemodynamic effects of infusion of the peptides into anesthetized dogs according to the methods described in Aiken et al., Prostaglandins, 19, 620 (1980).
• the compounds of the instant invention were tested for their ability to inhibit the migration and proliferation of smooth muscle tissue in an artery or vein in order to assess their ability to prevent restenosis of an artery, such as that which typically occurs following angioplasty.
• Rat or human aortic smooth muscle cells were used. The cell migration was monitored in a Transwell cell culture chamber by using a polycarbonate membrane with pores of 8 um (Costar). The lower surface of the filter was coated with vitronectin. Cells were suspended in DMEM supplemented with 0.2% bovine serum albumin at a concentration of 2.5 - 5.0 x 10 6 cells/mL, and were pretreated with test compound at various concentrations for 20 min at 20°C. The solvent alone was used as control. 0.2 mL of the cell suspension was placed in the upper compartment of the chamber. The lower compartment contained 0.6 mL of DMEM supplemented with 0.2% bovine serum albumin.
• Incubation was carried out at 37°C in an atmosphere of 95% air/5% CO 2 for 24 hr. After incubation, the non-migrated cells on the upper surface of the filter were removed by gentle scraping. The filter was then fixed in methanol and stained with 10% Giemsa stain. Migration was measured either by a) counting the number of cells that had migrated to the lower surface of the filter or by b) extracting the stained cells with 10% acetic acid followed by determining the absorbance at 600 nM.
• the efficacy of the compounds of formula (I) to prevent tumor growth may be determined using several transplantable mouse tumor models. See U. S. Patent Nos. 5,004,758 and 5,633,016 for details of these models.
• Nuclear magnetic resonance spectra were obtained using either a Bruker AM 250 or Bruker AC 400 spectrometer. Chemical shifts are reported in parts per milliom ( ⁇ ) downfield from the internal standard tetramethylsilane. Mass spectra were taken on either VG 70 FE or VG ZAB HF instruments using fast atom bombardment (FAB) or electrospry-(ES) ionization techniques. Elemental analyses were performed by Quantitative Technologies Inc., Whitehouse, New Jersey.
• (+/-)-2,3,4,5-tetrahydro-3-oxo-8- [[/V-(4-N-f-butoxycarbonylpiperidinylpropyl-/V-( 1 H-benzimidazol-2- ylmethyl)]aminocarbonyl]-2-methyl-lH-2-benzazepine-4-acetic acid, methyl ester (0.19 g, 0.29 mmol) gave 0.23 g of the desired product as a white foam after reverse phase flash chromatography (step gradient: H2O + 0.1% TFA then 30% CH3CN/H2O + 0.1% TFA, Analytichem Bond-Elut® C-8 column, 50 mL size).
• 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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• 1998
  • 1998-08-04 WO PCT/US1998/016246 patent/WO1999006049A1/en not_active Application Discontinuation
  • 1998-08-04 CA CA002298544A patent/CA2298544A1/en not_active Abandoned
  • 1998-08-04 AU AU86897/98A patent/AU8689798A/en not_active Abandoned
  • 1998-08-04 JP JP2000504863A patent/JP2001511452A/ja not_active Withdrawn
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