IL155202A - Biaryl compounds as serine protease inhibitors - Google Patents

Biaryl compounds as serine protease inhibitors

Info

Publication number
IL155202A
IL155202A IL155202A IL15520203A IL155202A IL 155202 A IL155202 A IL 155202A IL 155202 A IL155202 A IL 155202A IL 15520203 A IL15520203 A IL 15520203A IL 155202 A IL155202 A IL 155202A
Authority
IL
Israel
Prior art keywords
mmol
reaction mixture
group
alkyl
vacuo
Prior art date
Application number
IL155202A
Other languages
Hebrew (he)
Original Assignee
Biocryst Pharm Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from PCT/US2001/032582 external-priority patent/WO2002034711A1/en
Application filed by Biocryst Pharm Inc filed Critical Biocryst Pharm Inc
Publication of IL155202A publication Critical patent/IL155202A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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]
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
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    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
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    • C07C259/20—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines with at least one nitrogen atom of hydroxamidine groups bound to another nitrogen atom
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    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract

Compounds of formula (I) are useful as inhibitors of trypsin like serine protease enzymes such as thrombin, factor VIIa, factor Xa, TF/FVIIa, and trypsin. These compounds could be useful to treat and/or prevent clotting disorders, and as anticoagulating agents.

Description

tNtnia γιυ ^ω jmattin BIARYL COMPOUNDS AS SERINE PROTEASE INHIBITORS INT. APPL. NO.: PCTUSOl/032582 INT. FIL. DATE: October 22, 2001 INT.PUB.NO.: WO 02/34711 PAT/5346 Technical Field The present invention relates to the identification, through synthesis and testing, of heretofore unreported compounds which, in appropriate pharmaceutical compositions, exert a therapeutic effect through reversible inhibition of serine proteases.
Background of Invention Serine proteases make up the largest and most extensively studied group of proteolytic enzymes. Their critical roles in physiological processes extend over such diverse areas as blood coagulation, fibrinolysis, complement activation, reproduction, digestion, and the release of physiologically active peptides. Many of these vital processes begin with cleavage of a single peptide bond or a few peptide bonds in precursor protein or peptides. Sequential limited proteolytic reactions or cascades are involved in blood clotting, fibrinolysis, and complement activation. The biological signals to start these cascades can be controlled and amplified as well. Similarly, controlled proteolysis can shut down or inactivate proteins or peptides through single bond cleavages.
While serine proteases are physiologically vital, they also can be hazardous. Their proteolytic action, if uncontrolled, can destroy cells and tissues through degradation of proteins. As a natural safeguard in normal plasma, 10% of the protein matter is composed of protease inhibitors. The major natural plasma inhibitors are specific for serine proteinases. Diseases (associated protease given in the parentheses) such as pulmonary emphysema (cathepsin G), adult respiratory distress syndrome (chymases), and pancreatitis (trypsin, chymotrypsin, and others) are characterized by uncontrolled serine proteases. Other proteases appear to be involved in tumor invasion (plasmin, plasminogen activator), viral transformation, and inflammation (kallikrein). Thus the design and synthesis of specific inhibitors for this class of proteinases could offer major therapeutic benefits.
Thrombus formation, that is blood coagulation, is normally initiated by tissue injury; its normal purpose is to slow or prevent blood loss and facilitate wound healing. There are other conditions, however, not directly connected with tissue injury that may promote the coagulation process and lead instead to harmful consequences; examples of such conditions are atherosclerosis and inflammation.
The complex pathways of blood coagulation involve a series of enzyme reactions in which plasma coagulation factors, actually enzyme precursors or zymogens, are sequentially activated by limited proteolysis. Blood coagulation, or the coagulation cascade, is viewed mechanistically as two pathways, the extrinsic and the intrinsic (Fig. 1). Each pathway proceeds through a sequence of the Roman-numeral-designated factors until they converge at the activation of factor X after merger of the pathways. Thrombin generation proceeds stepwise through a common pathway. Thrombin then acts on the solution plasma protein, fibrinogen, to convert it to stable insoluble fibrin clots, thus completing the coagulation cascade.
The extrinsic pathway is vital to the initiation phase of blood coagulation while the intrinsic pathway provides necessary factors in the maintenance and growth of fibrin. The initiation of the coagulation cascade involves the release of tissue factor (TF) from injured vessel endothelial cells and subendothelium. TF then acts upon factor VII to form the TF/FVTIa complex (where Vila designates the activated factor rather than the zymogen form). This complex initiates coagulation by activating factors DC and X. The resulting factor Xa forms a prothrombinase complex that activates prothrombin to produce the thrombin that converts fibrinogen to insoluble fibrin. In contrast, the mtrinsic system is activated in vivo when certain coagulation proteins contact subendothelial connective tissue. In the sequence that follows, contact factors ΧΠ and XI are activated. The resulting factor XIa activates factor ΓΧ; then factor D a activates factor X thereby intersecting with the extrinsic pathway.
With time, the TF/FVTHa complex (of the extrinsic pathway) loses activity due to the action of tissue factor pathway inhibitor (TFPI), a Kunitz-type protease inhibitor protein which, when complexed with factor Xa, can inhibit the proteolytic activity of TF/FVEa. If the extrinsic system is inhibited, additional factor Xa is produced through the thrombin-mediated action in the mtrinsic pathway. Thrombin, therefore, exerts a dual catalytic role in (a) the conversion of fibrinogen to fibrin and (b) mediating its own production. The autocatalytic aspect of thrombin production affords an important safeguard against excessive blood loss, and, assuming presence of a threshold level of prothrombinase, ensures that the blood coagulation process will go to completion.
While the ability to form blood clots is vital to survival, there are disease states · wherein the formation of blood clots within the circulatory system can cause death.
When patients are afflicted with such disease states, it is not desirable to completely inhibit the clotting system because Ufe-threatening hemorrhage would follow. Thus, it is highly desirable to develop agents that inhibit coagulation by inhibition of factor Vila without directly inhibiting thrombin.
Need for th e prevention of intravascular blood clots or for anti-coagulant treatment in many clinical situations is well known. Drugs in use today are often not satisfactory. A high percentage of patients who suffer internal injuries or undergo certain surgical procedures develop intravascular blood clots which, if unchecked, cause death. In total hip replacement surgery, for example, it is reported that 50% of the patients develop deep vein thrombosis (DVT). Current approved therapies involve administration of heparin in various forms, but results are not entirely satisfactory, 10-20% of patients suffer DVT and 5-10% have bleeding complications- Along these lines, see International Publication No. WO 00/15658.
Other examples of clinical situations for which better anticoagulants would be of great value are when patients undergo transluminal coronary angioplasty and treatment for myocardial infarction or crescendo angina. The present therapy for these conditions is aciiniiustration of heparin and aspirin, but this treatment is associated with a 6-8% abrupt vessel closure rate within 24 hours of the procedure. Transfusion therapy due to bleeding complications is required in approximately 7% of cases following the use of heparin. Occurrences of delayed vessel closures are also significant, but adniimstration of heparin after tennination of the procedure affords little beneficial effect and can be detrimental.
Heparin and certain derivatives thereof are the most commonly used anti-clotting agents. These substances exert their effects mainly through inactivation of thrombin, which is inactivated 100 times faster than factor Xa. Two other thrombin-specific anticoagulants, hirudin and hirulog, are in clinical trials (as of September 1999).
However, bleeding complications are associated with these agents.
In preclinical studies in baboons and dogs, the targeting of enzymes involved in earlier stages of the coagulation cascade, such as factor Vila or factor Xa, prevents clot formation and does not produce bleeding side effects observed with direct thrombin inhibitors.
Several preclinical studies reveal that inhibition of TF/FVTIa offers the widest window of therapeutic effectiveness and safety with respect to bleeding risk of any anticoagulant approach tested including thrombin, platelet, and factor Xa inhibition.
A specific inhibitor of factor Vila would provide clinicians with a valuable and needed agent that would be safe and effective in situations where the present drugs of choice, heparin and related sulfated polysaccharides, are no better than marginally effective.
There exists a need for a low molecular weight specific serine protease inhibitors specific toward various enzymes, particularly for factor Vila that does not cause unwanted side effects.
Figure 1. Pathways of Coagulation Extrinsic Pathway Intrinsic Pathway Release of TF Release of Contact Factors XII and XI Common Pathway Prothrombin »- Thrombin *- Fibrinogen ^Fibrin The figure illustrates the extrinsic and intrinsic pathways of blood coagulation.
Summary of Invention An aspect of the present invention relates to compounds represented by the formula: ; pharmaceutically acceptable salts thereof; and prodrugs thereof.
Each E and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which maybe substituted with one or more hetero groups selected from N, 0, S, S(O), and S(C>2) which may be saturated or unsaturated. The bicyclic rings typically contain 7-13 atoms in the ring.
R is -CH=CH:R2, -C≡C-R2, -C(R2)=CH2, -C(R2)=C(R3), -CHN R2, -C(R )=N-R3, 4-7 membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from Rl, R2, or R3. 02/34711 PCT/USOl/32582 R1 is H} -R, -N02, -CN, -halo, -N3, -C M alkyl, -(CH2)NC02R2, -C2-8 alkenyl-C02R2, -0(CH2)NC02R2, -C(0)NR2R3, -P(0)(OR2)2, alkyl substituted tetrazol-5-yl, -(CH2)NO(CH2)N aryl, -NR2R3, -(CH2)„ OR2, -(CH2)N SR2, -N(R2)C(0)R3, -S(02)NR2R3, -N(R2)S(02)R3, -(CHR2)N NR2R3, -C(0)R3, (CH2)N N(R3)C(0)R3, -N(R2)CR2R3 substituted or unsubstituted (CH2)n-cycloalkyl, substituted or unsubstituted (C¾)n-• phenyl, or substituted or unsubstituted (CH2)n-heterocycle which may be saturated or unsaturated. m is 1 except that when El is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring.
R2 is H, -halo, -alkyl, -haloalkyl, -(W -phenyl, -(CH^-a-biphenyl, -(CH2) -Ph- N(S02-Q-2-alkyl)2, -C.C CHR OR1, -(CHR^n-heterocycle, -(CHR^-NH-CO-R1, -(CHR NH-S02R\ -(CHR^n-Ph-NCSOa-Ca-alkyl^, -(CHR CCOXCHR^NHR1, -(CHR^n-CCSXCHR^- HR1, -(CH2)„0(CH2)NCH3, ~CF3, -C2-5 acyl, -(CHR^OH, -(CHRL)NC02RL, -(CHR^n-O-alkyl, -(CHRL)N-0-(CH2)N-0-alkyl, -(CHR'VS-alkyl, -(CHRVS(0)-a]kyl, -(CHR^n-SiO^-alkyl, -(CHR')N-S(02)-NHR3, -(CHR3)„-N3, -(CHR3)NNHR4, 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted- (CHR3)n heterocycle, or substituted or unsubstituted-(CHR3)N cycloalkyl which may be saturated or unsaturated.
When n is more than 1, the substitutions R1 and R3 may be same or different.
R3 is H, -OH, -CN, substituted alkyl, -C2.8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R! )R2, or 5-6 membered saturated substituted or unsubstituted hetero ring.
-NR R3 may form a ring system having 4 to 7 atoms or may be bicyclic ring. The ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted. 711 PCTYUS01/32582 W is a direct bond, -CHR2-, -CH=CR2-, -CR2=CH-, -CR2=CR2-, -C-C-, -O-CHR2-, -CHR2-0-, -N(R2)-C(0)-, -C(0)-N(R2)-, -N(R2)-CH-(R3)-, -C¾-N(R2)-, -CH(RL)-N(R2)-, -S-CHR2-, -CHR2-S-, -S(02)-N(R2)-, -C(0)N(R2)-(CHR2)n-, -C(RLR2)n-NR2-, -N(R2)-S(02)-, -R2C(0)NR2-, -R2NC(0)NR2-, -CONR2CO-, -C(=NR2) R2-, -NR2C(=NR2)NR2-, -NR20-, -N=NCHR2-, or -C(0)NR2S02-.
E2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Ci-g alkyl, C2.s alkenyl, C2-8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino. each X individually is a direct bond, substituted or unsubstituted C1- methylene chain; O, S, NR2 , S(O), S(02), or N(0) containing one or two CM substituted or unsubstituted methylene chains. X at different places may be same or different.
B is H, -halo, -CN, -NH2, -(CH2)N-C(=NR4) HR5, -(CH2)N-NHR4, -(CH2)„NHC(=NR )NR5, -(C¾)„-OR4, CW substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated.
B1 is selected from B; B1 and B may be same or different.
There may be more man one similar or different R2 groups present on E2, when E2 is a cyclic group of more than 5 atoms. In particular, p is 1 except that when E2 is a cyclic ring of more than 5 atoms, p is 1 or higher depending upon the size of the ring. n is 0-4 A is selected from R1. o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring.
Each V and V1 individually is selected from R1 and N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; Ν,Ν-disubstituted carboxamidyl (-CONR1R2 where R\ and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or -SO2NR1R2); and methylene- or polymethylene chain-extended variants thereof.
Each R4 and R5 individually is H, -(C¾)nOH, -C(0)OR6, -C(0)SR6, -(CH2)„ C(0)NR7R8, -0-C(0)-0-R7, an amino acid or a o¾eptide, Each R6 is H, R7, -C(R7)(R8)-(CH2)n-0-C(0)-R9, -(CH2)n-C(R7)(R8)-0-C(0)R9, -(CH2)„-C(R7)(R8)-0-C(0)-0-R9, or -C(R7)(R8)-(CH2)„-0-C(0)-0-R9, Each R7, R8 and R9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH2C02alkyl.
The present invention also relates to pharmaceutical compositions containing at least one of the above disclosed compounds and their prodrugs.
A further aspect of the present invention relates to a method for inhibiting trypsin-like serine protease enzymes, such as thrombin, factor Xa, factor Vila, TF/VIIa, and trypsin in a patient which comprises administering to the patient an effective serine protease inhibiting amount of at least one of the above disclosed compounds.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accor<iingly, the description is to be regarded as illustrative in nature and not as restrictive.
Best: and Various Modes for Carrying Out Invention An aspect of the present invention relates to compounds represented by the formula: pharmaceutically cceptable salts thereof; nd prodrugs thereof.
Each E1 and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which may be substituted with one or more hetero groups selected from N, O, S, S(O), and S(02) which may be saturated or unsaturated.
R is -CH=CH-R2, - C≡C-R2, -C(R2)=C¾, -C(R2)=C(R3), -CH=NR2, -C(R2)=N-R3, 4-7 membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from R1, R2, or R3. Preferably, these R, R1, R2, or R3 do not include -(C2-4 alkenylJ-COi-Ci-g alkyl, -(C2-4 alkenyl)-C02-Ci.8 alkyl-phenyl, and-(CM alkenyl)-C02-C e alk l-O-Ci-4 alkyl.
R1 is H, -R, -N02, -CN, -halo, -N3, -C w alkyl, -(CH2)nC02R2, -C2-8 alkenyl-C02R2, -0(CH2)nC02R2, -C(0)NR2R3, -P(0)(OR2)2, alkyl substituted tetrazol-5-yl, -(CH2)„0(CH2)n aryl, - R2R3, -(CH2)„ OR2, -(CH2)n SR2, -N(R2)C(0)R3, -S(02)NR2R3, -N(R2)S(02)R3, -(CHR2)n NR2R3, -C(0)R3, (CH2)n N(R3)C(0)R3, -N(R2)CR2R3 substituted or unsubstituted (CH2)n-cycloalkyl, substituted or unsubstituted (CH2)n-phenyl, or substituted or unsubstituted (CH2)n-heterocycle which may be saturated or unsaturated. m is 1 except that when El is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring. For instance if the ring is 6 atoms, m can be 1 or 2.
R2 is H, -halo, -alkyl, -haloalkyl, -(CH2)n -phenyl, -(CH2)j.3-biphenyl, -(CH2)M-Ph-N(S02-Ci.2-alkyl)2, -COCCHR^-OR1, -(CHRVheterocycle, -(CHR^n-NH-CO-R1, -(CHRVNH-SC^R1, -(CHR^n-Ph-NiSOz-d^-alky z, -(CHRl)n-C(0)(Cmx)-NHR -(CHR^n-CCSXCHR^-NH 1, -(CH2)nO(CH2)nCH3, -CF3, -C2.5 acyl, -(CHR^nOH, -(CHR^COjR1, -(CHR^n-O-alkyl, -(CHRl)n-0-(CH2)n-0-alkyl, -(CHR^n-S-alkyl, -(CHRVS(O)-alkyl, -(CHRVS(02)-alkyl, -(CHRl)n-S(02)-NHR3, -(CHR3)n-N3, -(CHR3)„NHR4, 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted-(CHR3)n heterocycle, or substituted or unsubstituted-(CHR3)n cycloalkyl which may be saturated or unsaturated.
When n is more than 1, the substitutions R1 and R3 may be same or different.
R3 is H, -OH, -CN, substituted alkyl, -C2-8 alkenyl, substituted or unsubstituted cycloalkyl, -NfR^R2, or 5-6 membered saturated substituted or unsubstituted hetero ring.
-NR2R3 may form a ring system having 4 to 7 atoms or may be bicyclic ring. The ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted.
W is a direct bond, -CHR2-, -CH=CR2-, -CR2=CH-, -CR2=CR2-, -C≡C-, -O-CHR2-, -CHR2-0-, -N(R2)-C(0)-, -C(0)-N(R2)-, -N(R2)-CH-(R3)-, -CH2-N(R2)-, -CH(Rl)-N(R2)-, -S-CHR2-, -CHR -S-, -S(02)-N(R2)-, -C(0)N(R2)-(CHR )n-, -C R-^ NR2-, -N(R2)-S(02)-, -R2C(0)NR2-, -R2NC(0) R2-, -CONR2CO-, -C(=NR2)NR2-, -NR2C(== R2)NR2-, -NR 0-s -N=NCHR2-, or -C(0) R2S02-.
E2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Ci-g alkyl, C2-8 alkenyl, C2-8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkyltbio, or alkylamino. each X individually is a direct bond, substituted or unsubstituted C methylene chain; O, S, R2 , S(O), S(02), or N(O) containing one or two C substituted or unsubstituted methylene chains. X at different places may be same or different.
B is H, -halo, -CN, - ¾, -(CH2)n-C(=NR )NHR5, -(CH2)„-NHR4, -(CH2)nNHC(=NR ) R1, -(CH2)„-OR4, C w substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated.
B1 is selected from B; B1 and B may be same or different.
There may be more than one similar or different R2 groups present on E2, when E2 is a cyclic system of more than 5 atoms, p is 1 or higher if E2 is a cyclic ring of more than 5 atoms. For example, if the ring is 6 atoms, p can be 1 or 2. n is 0-4 A is selected from R . o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring. For instance, if the ring is 6 atoms, o can be 1 or 2.
Each V and V1 mdividually is selected from R1 and N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; N,N-disubstituted carboxamidyl (~CONRiR2 where i and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or -SO2NR1R2); and methylene- or polymethylene chain-extended variants thereof.
Each R4 and R5 individually is H, -(CH2)„OH, -C(0)OR6, -C(0)SR6, -(CH2)n C(0)NR7R8, -O-C(O)-0-R7, an amino acid or a dipeptide, Each R6 is H, R7, -C(R7)(R8)-(CH2)n-0-C(0)-R9, -(CH2)„-C(R7)(R8)-0-C(0)R9, -(CH2)n-C(R7)(R8)-0-C(0)-0-R9, or -C(R7)(R8)-(CH2)n-0-C(0)-0-R9, Each R7, R8" and R9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH2C02alkyl. substituent groups employed pursuant to the present invention contribute to significantly enhanced activity of the compounds of the present invention.
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term "alkyl" refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. The expression "lower alkyl" refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The terms "alkenyl" and "aikynyl" refer to straight or branched chain unsubstituted hydrocarbon groups typically having 2 to 8 carbon atoms.
The terms "substituted alkyl", "substituted alkenyl" or substituted alkynyl" refer to an alkyl, alkenyl or alkynyl group substituted by, for example, one to four substituents, such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloaU^lamino, heterocycloamino, disubstituted amines in which the 2 arnino substituents are selected from alkyl, aryl or aralkyl, alkanoylarnine, aroylamino, aralkanoylamino, substituted alkanolamino, substituted arylamino, substituted aralkanoylarmno, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CO H2), substiluted carbamyl (e.g. CONH alkyl, CONH aryl, CO H aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guamdino and heterocyclos, such as indolyl, imidazolyl, fiiryl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term *¾alogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
The term, "aralkyl" or "alkylaryl" refers to an aryl group bonded directly through an alkyl group, such as benzyl or phenethyl.
The term "substituted aryl" or "substituted alkylaryl" refers to an aryl group or alkylaryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, azido, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, hydroxyalkyl, aminoalkyl, azidoalkyl, alkenyl, alkynyl, allenyl, cycloalkylarnino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkyltbio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent maybe further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl. "Substituted benzyl" refers to a benzyl group substituted by, for example, any of the groups listed above for substituted aryl.
The term "cycloalkyl" refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring. Exemplary groups include cydopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term "cycloalkenyl" refers to optionally substituted, unsaturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3-7 carbons per ring. Exemplary groups include cyclopentenyl and cyclohexenyl.
The terms "heterocycle", "heterocyclic" and "heterocyclo" refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quatemized. The heterocyclic group may be attached at any heteroatom or carbon atoms.
Exemplary monocyclic heterocyclic groups include pyirolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazoUdinyl, furyl, tetrahy&ofuryl, thienyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrroUdinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, dihydropyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, mo^holinyl, tMomoφholinyl, miomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane and tetrahydro-l, 1-dioxothienyl, dioxanyl, isothiazoUdinyl, thietanyl, thiiranyl, triazinyl and triazolyl and the like.
Exemplary b .cyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoqumolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolapridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3 ,l-b]pyri(-inyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, diyhydroquinazolinyl (such as 3 ,4-dmydro-4-oxo-qumazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzothrasolyl, benzpyrasolyl, d ydroberizofuryl, dmydrobenzothienyl, dmydrobenzothiopyranyl, d ydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, mdolinyL isochromanyl, isoindolinyl, mphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroqumolinyl, meinofuryl, thienopyridyl, thienothienyl, and the like.
Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents.
Within the above-described definitions, certain embodiments are preferred.
Preferred alkyl groups are lower alkyl groups containing 1 to about 8 carbon, and more preferably 1 to about 5 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups.
Examples of suitable alkyl groups include methyl, ethyl and propyl. Examples of branched alkyl groups include isopropyl and t-butyl. An example of a suitable alkylaryl group is phenethyl. Examples of suitable cycloalkyl groups typically contain 3-8 carbon atoms and include oyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phenyl C1-3 alkyl such as benzyl.
The N-heterocyclic rings preferably contain 3-7 atoms in the ring and a heteroatom such as: N, S or O in the ring. Examples of suitable preferred heterocyclic groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2-methylpiperidino and 2-ethylpiperidino. In addition, the above substitutions can include halo such as F, CI, Br, lower alkyl, lower alkoxy and halo substituted lower alkoxy.
Examples of some preferred B groups include ~NHC(=NH)NH2, -C(=NH)NH2, N¾, various N-substituted variants, and assorted prodrug derivatives.
Prodrug forms of the compounds bearing various nitrogen functions (amino, hydroxyamino, hydrazino, guamdino, amidino, amide, etc.) may include the following types of derivatives where each R group individually may be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, or cycloalkenyl groups as defined beginriing on page 7. (a) Carboxamides, -NHC(0)R (b) Carbamates, -NHC(0)OR (c) (Acyloxy)alkyl carbamates, -NHC(0)OROC(0)R (d) Enaimnes, - HCR(==CHCR02R) or -NHCR(==CHCRONR2) Schiff bases, -N=CR2 (f) Mannich bases (from carboximide compounds), RCONHCH2NR2 Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al, J. Med. Chem. 1988, 31, 318; gas-Martin et al, PCT WO pp/41531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the invention.
Prodrug forms of carboxyl-bearing compounds of the invention include esters (-CO2R) where the R group corresponds to any alcohol whose release in the body through enzymatic or hydjolytic processes would be at pharmaceutically acceptable levels.
Another prodrug derived from a carboxylic acid form of the invention may be a quaternary salt type of structure described by Boder et al, J. Med. Chem. 1980, 23, 469.
Examples of some preferred groups for W are -CH2CH2-, -CH=CH-, -C≡C-, -CH2CH2CH2-, -CH2CH=CH-, -CH2OC-, -CONH, -CH2CONH-, -NHCONH-, -CONHCO-, -CONHCH2-, -C(=NH)NH-, -CH2C(= H)NH-, -NHC(= H)NH-, -NHNH-, -NHO-, -CONHSO2-, -SO2NH-, -NHS02CH2-, -S02NHCH2-, -CH20-, -CH2OCH2-, -OCH2CH2-, -CH2 H-, -CH2CH2 H-, -CH2NHCH2-, -CH2S-, -SCH2CH2, -CH2SCH2-, -CH2S02CH2-, -C¾SOCH2-, -CH(C02H)0 and -CH(C02H)OCH2.
Examples of some preferred groups for V and V1 are N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic, and typically containing up to ten carbons; Ν,Ν-disubstituted carboxamidyl (-CO R1R2 where Rj and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or -SO2 R1R2); methylene- or polymethylene chain- extended variants thereof such as -(CH2)nCONHRi, -(CH2)nCONRlR2s -(CH2)nS02NHRi3 -^Η2)„802Μ ^2 (where n = 1-4), -NHC(0)R, N(Ri)C(0)R2, NHS02R, CH2NHR, CH2 RiR2.
Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable, inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulphonic acids.
Salts derived from appropriate bases include alkali such as sodium and ammonia.
It is of course understood that the compounds of the present invention relate to all isomers and stereo-isomers at the various possible atoms of the molecule.
The synthetic routes leading to the conipounds in formula (I) are described following schemes.
Scheme 1 W 0234711 Scheme 2 Scheme 3 Scheme 4 Scheme 5 Conversion of Κ, Ι-1 24ab 25ab Κ, Ι-l ^ 24ac 25ac Κ, Ι-l ^ 24ae 2Sae Κ, Ι-1 24ad 2Saf The reduction of the formyl group of 24ab, 24ac, 24ae, and 24ad was accomplished with NaBH4 to give corresponding alcohols 24ab-i, 24ac-i, 24ae-i, and 24ad-i, respectively. Later, the MEM group was removed under acidic conditions to give 25ab, 25ac, 25ae, and 25af, respectively.
E, H, 1-1 Conversion of 24ad *- 25ad The aldehyde 24ad was oxidized to acid 24ad-i which was protected as benzyl ester to give 24ad-ii. MEM deprotection under acidic conditions produced 25ad.
Conversion of 24an 2Sah The vinyl compound 24ah was oxidized with Os04 to give diol 24ah-i, followed by acidic hydrolysis of the MEM group to produce 25ah.
L, M, K, N, 0, 1-1 Conversion of 24ah 25ai The vinyl compound 24ah on dihydroxylation with Os04 gave diol 24ah-i. Oxidative cleavage of the diol with NaI04 produced aldehyde 24ah-ii. The aldehyde on reduction gave alcohol 24ah-ui, which on further reaction with methane sulfonyl chloride yielded mesylate 24ab-iv. The mesylate on further reaction with sodium azide gave the conesponding azide 24ah-v, which on acidic hydrolysis produced 25ai.
Conversion of 24w 25 w Scheme 6 K, N, 0, 1-1 Conversion of 29g 30g Aldehyde 29g was converted to alcohol 29g-i by reduction with NaB¾, followed by the reaction of methanesulfonyl chloride to give mesylate 29g-ii. The mesyl group was displaced with azide to give 29g-iii and finally, the MEM group was removed under acidic conditions to give 30g. Κ, Ι-1 Conversion of 29h »- 30h K, 1-1 29i *- 30i The reduction of the fonnyl group of 29h and 29i was accomplished with NaB¾ to give corresponding alcohols 29h-i and 29i-i, respectively. Later, the MEM group was removed under acidic conditions to give 30h and 30i, respectively.
Compounds of the type 23 and 28, where X = -Sn(Bu)3, are prepared using the methods AG-1 or AG-2 Scheme 7  33 Scheme 8E 26n— 27aj(R= 32f —G— »»27ak(R=- 26ai 27al(R = "NR.
 Scheme 11 a, 78a, 79a, 80a, R = C=CH. ; R* = CH3 b, 79b, R = OS02CF3; R' = Bn; 80b, R = OH b, 78c, 79c, R = -0-CH2C02C2H5; R' = Bn; 80c, = -O-CI^COjH c, 78d, 79d, 80d, R = -0-CH2CONH2; R' =Bn n 7i, 78k, 79k, R = OCH2-CH2-OAc; R' = Bn; 80k, R = -0-CH2-CH2-OH Scheme 12 Scheme 13 Scheme 1 Scheme IS Ill 112 PCTUSO 1/32582 — C(CH3)3 Scheme 16a Scheme 17 133, 134, R = (continued) Scheme 17a Scheme 18 Scheme 19 Scheme 19a Scheme 20 Ol32582 Scheme 21  Scheme 23 Scheme 24 3f, 184b, 185b, 186b, 187b, 188b, R=CH2CF3 3i, 184c, I85c, 186c, 187c, 188c, R = CHjCH5 Scheme 25 AB-4, 1-2 184a ^'3» 189b— 2—^ 189c 189a,X=H,Y = OCH3 189b,X = OCH2C6H5,Y = H l89c,X=OH,Y = H Scheme 27 Scheme 28 Scheme 29 a, R = H b -211b, R = Scheme 30 Scheme 31 Scheme 32 a, 232a, 233a, 234a, 235a, R b, R = C02CH3 b, 233b, 234b, R = C02H Scheme 33 Scheme 34 P TU Ol/32582 Scheme 36 General Methods of Preparation The following abbreviations have been used: THF: Tetrahydrofuran; DMF: Dimethylformamide DME: 1,2-Dimethoxyethane; DMAP: 4-(Bimemylammo)pvridine Boc anhydride: Di-tert-butyl dicarbonate; TIPS: Triisopropylsilyl MEM: Methoxyethoxymethyl; Bn: Phenylmethyl or Benzyl The organic extracts were dried over sodium sulfate or magnesium sulfate.
The general methods for the preparation of the compounds of formula (I) are given below: A-l: Conversion of acid to amide To derivative (1 mmol), was added thionyl chloride (12.6 mmol) and a few drops of DMF. The reaclion mixture was refluxed for 2 h and concentrated in vacuo to obtain an oily residue. Hie residue was dissolved in dichloromethane (3 mL); cooled with ice water and amine (5 mmol) was added. The reaction mixture was stirred at room temperature overnight, washed with IN 'HQ, saturated sodium hydrogen carbonate, water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-2: Conversion off acid to amide To a solution of acid derivative (1 mmol) in dichloromethane (10 mL) at 0 °C was added triethylamine (3 mmol) and ethyl chloroformate (3 mmol). The reaction mixture was stirred at the same temperature for 30 min and the corresponding amine (6 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with IN HC1. The organic layer was separated, washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-3: Conversion of acid to amide To a solution of acid (1 mmol) in dichloromethane (5 mL) was added 2 oxalyl chloride in dichloromethane (2.5 mmol), followed by a drop of DMF. The reaction mixture was stirred for 2h at room temperature and concentrated in vacuo. The residue was co-evaporated once with dichloromethane (5 mL) and then dried in vacuo. To the residue in dichloromethane (10 mL) were further added triethylarnine (3 mmol) and the corresponding amine (1.2 mmol). The reaction mixture was stirred for 16 h and washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-4: Conversion of acid to amide To a solution of acid (1 mmol) in dichloromethane or THF (10 mL) cooled with an ice bath was added triemylamine (1.2 mmol) and ethyl chloroformate or isobutyl chloroformate (1.2 mmol). The reaction mixture was stirred at 0°C for 30 min and the corresponding amine (2.5 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with IN HC1. The organic layer was separated, washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-5: Conversion of acid to amide A mixture of carboxylic acid (1 mmol), amine (1.1 mmol), 1-hydroxybenzotriazole (1 mmol) and l-(3-dimemylamijiopropyl)-3-ethylcarbodiirnide methiodide (1.1 mmol) in pyridine (10 mL) was stirred overnight at room temperature and was concentrated in vacuo to dryness. The residue obtained was purified by column chromatography or used as such for the next step.
A-6: Reduction of acid to alcohol To a solution of acid (1 mmol) in dichloromethane or THF (10 mL) at 0 °C was added triethylamine (1.2 mmol) and ethyl chloroformate or isobutyl chloroformate (1.2 mmol). The reaction mixture was stirred at 0 °C for 30 min and sodium borohydride (1.25 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with IN HC1. The reaction mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried and concentrated in vacuo to furnish the desired alcohol. This can be purified further, if needed, by crystallization or column chromatography.
A-7: Conversion of acid to amide A mixture of carboxylic acid (1 mmol), amine (1 mmol), and 4-diuriemylarninopyridie (0.12 mmol) in xylene (10 mL) was stirred at 80 °C for 10 min. Phosphorus trichloride (1 mmol) was added and the reaction mixture was heated with stirring at 150 °C for 2 hr. After cooling, the product was extracted with EtOAc. The organic layers were combined, washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by flash column chromatography to furnish the desired amide.
B-l : Conversion of phenolic hydroxyl to inflate To a phenol (1 nimol) in dichloromethane (2.5 mL) was added pyridine (5 mmol) under a nitrogen atmosphere and cooled to -10 C. To the cold reaction mixture was added dropwise triflic anhydride (2 mmol) in dichloromethane (2.5 mL) over a period of 10 mins and allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and the organic layer was separated. The organic layer was washed with IN HCl, saturated sodium hydrogen carbonate, water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired inflate.
B-2: Conversion of phenolic hydroxyl to triflate To a solution of substituted phenol (1 mmol) in DMF (10 mL) was added N-phenylbis(trifluoromethanesulphonimide) (1.1 mmol), and triemylamine (2 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with ice water and extracted twice with ether. The organic layers were combined, washed with brine, dried and concentrated in vacuo to furnish the desired triflate.
C: Conversion of acid to MEM ester To a solution of acid derivative (1 mmol) in DMF (10 mL) was added sodium bicarbonate (1.05 mmol), and MEM-C1 (1.05 mmol) and was stirred at room temperature for 24 h. The reaction mixture was quenched with ice water and extracted twice with ether. The organic layers were combined, washed with brine, dried and concentrated in vacuo to furnish crude product. Purification by flash column chromatography or crystallization gave the desired MEM ester.
P T Ol/32582 D-l: Coupling of boronic acid with triflate A mixture of triflate (1 mmol), aryl boronic acid (1.5 mmol), potassium phosphate (3 mmol), potassium bromide (2.4 mmol) and tetrakis(triphenylphosphine)palladium (0.05 mmol) in dioxane (10 mL) was heated at reflux overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water and was extracted with ethyl acetate. The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-2: Coupling of boronic acid with triflate A mixture of triflate (1 mmol), aryl boronic acid (2 mmol), sodium hydrogen carbonate (3 mmol) and tetrakis(triphenylphosphine)palladium (0.05 mmol) or bis(triphenylphosplime)paUadium(n)chloride (0.05 mmol) in DME/water (9:1, 10 mL) was heated at reflux overnight. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product D-3: Coupling of tiributyltin derivative with triflate A mixture of triflate (1 mmol), tributyltin derivative (3 mmol), tetraethylammonium chloride (6 mmol), and bis(triphenylphosphine)palladium(II)-chloride (0.05 mmol) in DMF (10 mL) was heated at 70 °C overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-4: Coupling of trimethyltin derivative with triflate A mixture of triflate (1 mmol), trimethyltin derivative (3 mmol), and bis(triphenylphosphme)palladium(IT)chloride (0.05 mmol) in THF (10 mL) was heated at 70 °C overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-5: Coupling of alkyne with triflate A mixture of triflate (1 mmol), triemylarnine (4.5 mmol), substituted alkyne (3.5 mmol), and bis(triphenylphospIune)paUadium(n)chloride (0.05 mmol) in DMF (10 mL) was heated at 70 °C overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product D-6: Coupling of boronate ester with aryl bromides A mixture of boronate ester (2 mmol)," aryl bromide (1 mmol), potassium phosphate (3 mmol) and bis(diphenylphosplnnoferrocene)palladium(II)chloride (0.05 mmol) in DMF (10 mL) was heated at 100 °C for overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the desired product.
D-7: Coupling of boronate ester with aryl bromides A mixture of boronate ester (2 mmol), aryl bromide (1 mmol), sodium hydrogen carbonate (3 mmol) and bis(diphenylphosprnnofeirocene)palladium(II)chloride (0.05 mmol) in DME/water (9:1, 10 mL) was heated at 50-70 °C for overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and was extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-8: Coupling of phenol with boronic acid A mixture of phenol (1 mmol), aryl boronic acid (3 mmol), molecular sieves (4A°), pyridine (5 mmol), copper(II)acetate (1 mmol) and bis(triphenylphosphine)-palladium(n)chloride (0.05 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was cooled, filtered through a pad of Celite and concentrated in vacuo. Purification of the crude by flash column chromatography gave the coupled aryl ether.
D-9: Coupling of trimetbyltin derivative with inflate To a solution of triflate (1 mmol), LiCl (4 mmol), PPh3 (0.15 mmol), CuBr (0.2 mmol), andbis( phenylphosphme)palladium(lI)chloride (0.07 g) i DMF (10 mL) under an atmosphere of argon was added trimethylstannyl compound (0.8 mmol) and a crystal of 2,6-di-i-butyI-4-methylphenol. After the mixture was stirred at 90 °C for 3 h, a second portion of aryl-trimethylstannyl compound (0.5 mmol) was added. The reaction mixture was stirred at 90 °C overnight. Water was added and extracted with ethyl acetate. The organic layer was dried (MgS04), concentrated and purified by flash column chromatography or ciystallization to furnish the desired coupled product.
D-10: Coupling of amine with triflate A mixture of triflate (0.75 mmol), amine (0.9 mmol), potassium phosphate (1.1 mmol), 2-(di-t-burylphosphino)biphenyl (0.015 mmol) and tris(dibenzyiideneacetone) dipalladium(0) (10 mg) in DME (10 mL) was heated at reflux overnight under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography to furnish the desired coupled product.
D-l 1 : Conversion of triflate to cyano compound To a solution of triflate (0.84 mmol), zinc cyanide (0.54 mmol), Palladium acetate (0.016 mmol), 2-(di-ieri-butylphospliine)biphenyl ( 0.016 mmol) and N-methyl pyrrolidine (10 mL) was heated under argon at 1 0 °C for 48 h. The reaction mixture was cooled to room temperature and quenched with water (50 mL). The reaction mixture was extracted with ethyl acetate (2 X 25 mL). The organic layers were combined, dried, filtered and concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired cyano compound.
D-12: Coupling of tetravinyltin with triflate or halide To a solution of aryl triflate or bromide (1 mmol) in DMF (5 mL) were added LiCl (5 mmol), tetravinyltin (2 mol), and Q^cUorbis(1riphenylphosphine)palladium (Π) (0.01 mmol). The reaction mixture was stirred at 70 °C under nitrogen for 5 h and then diluted with ethyl acetate and filtered. The organic layer was washed with water and brine and dried MgSO^. After evaporating the solvent in vacuo, the compound was purified by flash-column chromatography to give the desired product.
E: Oxidation of aryl aldehyde to acid A mixture of aldehyde (1 mmol), tert-butanol (5 mL), water (2 mL) and acetonitrile (1 mL, additional amount may be added until the reaction mixture was homogenous) was stirred at room temperature. The solution was cooled in ice-bath and 2-methyl-2-butene (1 mL), sodium chlorite (6 mmol) and sodium dihydrogenphosphate (1.6 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. If the solid separated out, the mixture was filtered to collect the solid, the desired product. If no solid separated out, then the reaction mixture was concentrated in vacuo to remove acetonitrile, diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, washed with water, brine, dried and concentrated in vacuo to furnish crude acid. Purification was achieved, if needed, by crystallization or using flash column chromatography to obtain pure acid.
E-2: Oxidation of vinyl compound to acid To a solution of vinyl compound (1 mmol) in acetone (5 mL) was added M11O4 (4 mmol). The reaction mixture was stirred for 3 h (the reaction is exothermic, and refluxed on its own during the addition of Mn04). The reaction mixture was diluted with methanol and water and filtered. The organic solvents were evaporated in vacuo and the aqueous layer was acidified to pH 1 and extracted several times with ethyl acetate/DME. The combined organic layers were dried (MgSO- to furnish the desired acid.
F: Conversion of aromatic acid to MEM ester To a solution of aromatic acid (1 mmol) in THF (10 mL) was added dusopropylethylainine (2 mmol) and 2-methoxyethoxymethylchloride (1.1 mmol). The reaction mixture was stirred a room temperature for 3 h and diluted with ether (25 mL).
The reaction mixture was washed with water (10 mL), brine (10 mL), dried and concentrated in vacuo to obtain product as colorless oil. The product was purified by flash column chromatography to furnish desired product.
G: Conversion of aromatic benzyl ether to aromatic phenol, benzyl ester to acid, benzyl carbamate to amine, alkene to alkane, azide to amine, nitro to amine, and oxime to amine To a solution of appropriate substrate (1 mmol) in ethanol (10 mL) was added 10% palladium on carbon (10-wt%). The reaction mixture was hydrogenated at 50 psi for 2 to 24 h (until all starting material disappeared as confirmed by MS and TLC analysis). The catalyst was removed by filtration through a pad of Celite under nitrogen. The filtrate was concentrated in vacuo to furnish the product, which was purified by flash column chromatography or crystallization.
H: Conversion of aromatic acid to benzyl ester To a solution of aromatic acid (1 mmol) in DMF (10 mL) was added sodium bicarbonate (1.05 mmol), and benzyl bromide (1.05 mmol) and stirred at room temperature for 24 h. The reaction mixture was quenched with ice water and extracted twice with ethyl acetate. The organic layers were combined, washed with water and brine, dried and concentrated in vacuo to furnish crude product. Purification by crystallization or flash column chromatography gave the desired ester. 1-1 : Hydrolysis of MEM ester to acid To a solution of MEM ester (1 mmol) in DME (8 mL) was added 6 N HC1 (2 mL) and stirred at room temperature overnight. The reaction mixture was neutralized with solid sodium hydrogen carbonate (18 mmol) and concentrated in vacuo. The reaction mixture was acidified with 0.5 N HC1 (20 mL) and extracted with ethyl acetate (2 X 20 mL). The organic layers were combined, washed with brine (20 mL), dried and concentrated in vacuo to furnish crude product. Purification of the crude by flash column chromatography gave the product. Alternatively the crude reaction mixture was diluted with water (10 mL) and concentrated in vacuo to remove DME. The solid obtained was collected by filtration and dried in vacuo to furnish pure acid. 1-2: Hydrolysis of ester to acid To a solution of ester (1 mmol) in MeOH (10 mL) was added 1 N NaOH (10 mmol). The reaction mixture was stirred at room temperature for 2-3 h, filtered through a plug of cotton, and concentrated in vacuo to remove MeOH. The pH of the aqueous layer was adjusted to below 7. The solid that separated, was collected by filtration, washed with water and diied in vacuo to furnish the desired acid.
J: Coupling of acid with amino compounds To a solution of acid (1 mmol) in DMF (5 mL) was added corresponding amine (1.1 mmol) and stirred at room temperature until homogenous. Pyridine (5 mL) was added to the reaction mixture followed by 1,3-dicyclohexylcarbodiimide (1.2 mmol) and stirred overnight at room temperature. The mixture was quenched with 6 N HC1 (10 mL), diluted with ice cold water (10 mL) and extracted with chloroform (2 X 10 mL). The organic layers were combined washed with brine (10 mL), dried and filtered. Purification of the crude by flash column chromatography gave the product as a solid. If the product was soluble in water, then the reaction mixture was concentrated in vacuo to remove pyridine and DMF and purified by flash column chromatography.
K: Reduction of aldehyde to alcohol To a solution of aldehyde (1 mmol) in THF (10 mL) was added sodium borohydride (0.4 mmol). The reaction mixture was stirred for 30 mins and quenched with glacial acetic acid (0.3 mL). The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL).. The organic layers were combined and washed with brine (1.0 mL), dried, filtered and concentrated in vacuo to obtain crude product which was purified by flash column chromatography.
L: Conversion of vinyl group to diol To a solution of vinyl compound (1 mmol) in THF/terf-butanol (1:1, 10 mL) and water (2 mL) was added 4-methylmorpholine N-oxide (2.5 mmol) and osmium tetraoxide (1 mL, 2.5 wt% in tert-butanol, 0.1 mmol). The reaction mixture was stirred at room temperature for 2 h and quenched with saturated aqueous solution of sodium sulfite (5 mL). The reaction was stirred at room temperature for 30 mins and diluted with brine (10 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL). The organic layers were combined and washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to furnish the desired diol.
M: Conversion of diol to aldehyde To a solution of diol (1 mmol) in DME/water (9:1, 10 mL) was added sodium metaperiodate (3 mmol) and stirred at room temperature for 30 min. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined and washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to furnish the desired aldehyde.
N: Conversion of alcohol to mesylate To a solution of alcohol (1 mmol) in DME (10 mL) was added dimetnylaminopyridine (0.1 mmol), methane sulfonyl chloride (3 mmol) and diisopropylethylamine or triemylamine (5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo. The residue obtained, was purified by column chromatography to furnish the desired mesylate.
O: Conversion of mesylate to azide To a solution of mesylate (1 mmol) in DMSO (10 mL) was added sodium azide (25 mmol) and heated at 100 °C overnight. The reaction mixture was cooled and diluted with cold water (25 mL). The reaction mixture was extracted with ethyl acetate (2 X 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried, filtered and concentrated in vacuo The residue obtained was purified by column chromatography to fttrnish the desired azido compound.
P: Protection of amine as benzyl carbamate A mixture of amino compound (1 mmol), benzyl chloroformate (2 mmol) and triemylamine (10 mL) in pyridine (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to remove organic solvents and diluted with 0.1 N HC1 (10 mL). The product was extracted with chloroform (2 X 10 mL), dried, filtered and concentrated in vacuo. The residue obtained was purified by column chromatography to furnish the desired carbamate.
Q: Conversion of silyl protected amine to amine A mixture of silyl protected amine (1 mmol), tetrabutylammonium fluoride (1.0 M in THF, 2 mmol) in THF (10 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated in vacuo and purified by column chromatography to obtain the desired product R: Protection of amine as tert-butyl carbamate To a solution of amino compound (1 mmol) in acetonitrile (5 mL) was added triemylarnine (2 mmol) and BOC anhydride (1.2 mmol). The reaction mrxture was stirred for 2 h and concentrated in vacuo. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSC ), and the solvent was evaporated in vacuo to furnish tert-butyl carbamate. If needed, the product was purified by crystallization or column chromatography.
S: Conversion of tert-butyl carbamate to amine To a solution of tert-butyl carbamate (1 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 4 h and concentrated in vacuo. The residue was purified by column chromatography or crystallization to give the desired amine.
S-2: Conversion of tert-butyl carbamate to amine To a solution of tert-butyl carbamate (1 mmol) in methanol (13 mL) was added 6 N HC1 (8.75 mL, 52 mmol) and water (4.25 mL). The reaction mixture was stirred at room temperature for 2 days. The pH was adjusted to 7 using cone, ammonium hydroxide and the solid that separated out, was collected by filtration, washed with ether, dried in vacuo to fAirnish the desired product. If no solid separated out, the product was isolated by extraction with chloroform and evaporating the organic layer.
T: Protection of aldehyde as acetal To a solution of aldehyde (1 mmol) in ethanol (5 mL) was added triethyl orthoformate (1.4 mmol), ammonium nitrate (0.2 mmol) and stirred at room temperature overnight (if reaction was not complete by TLC and NMR analysis of an aliquot, the reaction mixture was heated at 50 °C until complete). After completion of the reaction, the mixture was quenched with Iriethylamine (0.2 mmol) and concentrated in vacuo to remove ethanol. The residue was dissolved in ether, filtered to remove any insoluble inorganic impurities, and evaporated to dryness. The product obtained was used as such without further purification.
U-l: Conversion of bromide to boronic acid To a mixture of bromo compound (1 mmol) in ether (10 mL), cooled to -78 °C, n-butyl lithium (1.2 mmol) was added dropwise and the reaction mixture was stirred for 30 rnins after the addition was completed. Tributyl borate (1.3 mmol) in ether (10 mL) was added to the reaction and stirred at -78 °C for 2 h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCl (10 mL). The reaction mixture was stirred at • room temperature for lh and cooled with ice. The aqueous layer was separated and the organic layer was extracted twice with IN NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 N HCl and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid product is obtained then the basic layer was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
U-2: Synthesis of boronic acid by ortho lithiation of aryl aldehyde To a solution of Ν,Ν,Ν'-liimemylemylenediamine (1 mmol) in THF/ether (10 mL, 1:1) cooled to -20 °C was added dropwise, over a period of 15 mins, n-butyl lithium (1 mmol) and stirred at -20 °C for 15 mins. Aldehyde (1 mmol) at -20 °C was added dropwise over a period of 10 mins to this mixture. The reaction mixture was further stirred for 15 mins at -20 °C followed by the addition of n-butyl lithium (2.8 mmol) dropwise over a period of 15 mins and stirred at 4 °C overnight. The reaction mixture was cooled to -40 °C and tributyl borate (5.6 mmol) in ether (20 mL) was added to the reaction and stirred at 4 °C for 12 h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HC1 (3 mmol) and heated at reflux for 2 h and added to ice water (25 mL). The aqueous layer was separated and the organic layer extracted twice with IN NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 3 using 6 N HC1 and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid product was obtained, then the basic layer was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
U-3: Synthesis of boronic acid by ortho lithiation of aryl acetal To a solution of aryl acetal compound (1 mmol) in ether (10 mL) at -78 °C, tert-butyl lithium (1.1 mmol) was added dropwise and the reaction mixture was stirred for 3 h at -20 °C after the addition was completed. Tributyl borate (1.2 mmol) in ether (10 mL) was added to the reaction and stirred at -20 °C for 1 h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HC1 (10 mL). The reaction mixture was stirred at room temperature for lh. The aqueous layer was separated and the organic layer was extracted twice with IN NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 N HC1 and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid' product was obtained then the mixture was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
V-l: Demethylation of aryl methyl ether to phenol In a round bottom flask (50 mL), pyridine hydrochloride (lOg) was heated in an oil bath at 180 °C. After the entire solid had melted, the corresponding aryl methyl ether (1 mmol) was added in small portions over a period of 20 min. The reaction mixture was heated at 180 °C for 4 h, cooled and quenched with water (100 mL). The reaction mixture was extracted with ethyl acetate (3 X lOmL). The combined organic layers were washed with brine, dried over MgS04, concentrated to give phenol. This can be further purified if needed by crystallization or column chromatography.
V-2: Demethylation of aryl methyl ether to phenol To a solution of aryl ether (1 mmol) in dichloromethane (10 mL) cooled to -78 °C was added boron tribromide (3 mmol). The reaction mixture was allowed to warm to room temperature overnight and quenched with water (10 mL). The solid obtained was collected by filtration to give the desired product. More product was obtained after evaporation of the organic layer and washing the residue with water. Alternatively, if a homogenous biphasic mixture was obtained on addition of water, the organic layer was separated, washed with brine, dried over MgS04, and concentrated to give the desired phenol. This can be further purified if needed by crystallization or column chromatography.
V-3: Demethylation of aryl methyl ether to phenol To a solution of aryl methyl ether (1 mmol) in dichloromethane (5 mL) was added AlC-3 (8.5 mmol). The reaction mixture was heated to reflux for 12 h under nitrogen. To this mixture was added 12 mL of 1 N HC1 slowly and the organic layer was separated. The aqueous layer was re-extracted several times with ethyl acetate DME. The combined organic layers were washed with brine, dried (MgSO.j), and evaporated in vacuo to furnish the desired phenol, which was purified by column chromatography.
V-4: Demethylation of aryl methyl ether to phenol To a stirred slurry of NaH (2 mmol) in anhydrous toluene (5 mL) under nitrogen atmosphere was added para-thiocresol (2 mmol) dissolved in toluene (40 mL). The mixture was stirred at room temperature for 30 min and hexamethylphosphoric triamide (2 mmol) in toluene (5 mL) was added dropwise over a period of 30 min. A solution of aryl ether (1 mmol) in toluene (5 mL) was added in one portion. The reaction mixture was stirred at reflux: for 9.5 h, cooled to room temperature and diluted with ethyl acetate (40 mL). The organic layer was extracted with 1 N aqueous NaOH solution (2 X 20 mL). The basic layer was acidified to pH 5 and extracted with ethyl acetate (2 X 20 mL). The organic layers were combined, washed with water, dried ( gS0 ) and concentrated in vacuo. The residue obtained was purified by flash column chromatography to afford the desired phenol compound.
: Conversion of acid to methyl ester A mixture of acid (1 mmol), cone. ¾S04 or cone HC1 (0.5 mL) and methanol (10 ml.) was heated at reflux for 16 h. The mixture was concentrated to half of its volume and the residue pour ed into a saturated sodium bicarbonate solution. The precipitate was collected by filtration, washed with water and dried to give the desired ester. If the ester did not come as solid, it was extracted with ethyl acetate. The organic layer was dried, filtered and concentrated to give the desired ester.
W-2: Conversion of acid to ester A solution of methanolic HCl or ethanolic HCl was prepared by the addition of acetyl chloride (1 mL) to methanol/ethanol (9 mL) at 0 °C and stirred for 30 mins. To the solution of anhydrous methanolic HCl was added acid (1 mmol) and stirred at room temperature (or reflux if needed) overnight. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by column chromatography or crystallization to furnish the desired ester.
X: Conversion of phenol to alkyl aryl ethers or alkylation of amines To a solution phenol or amine (1 mmol) in DMF (10 mL) was added cesium carbonate (1.25 mmol) and corresponding bromide (1.1 mmol). The reaction mixture was stirred at room temperature overnight and quenched with water (25 mL). The product was extracted with ether (2 X 25 mL), the organic layers were combined and washed with water (25 mL), brine (25 mL), dried and concentrated in vacuo to furnish crude product. The crude was purified by crystallization or flash column chromatography.
Y: Conversion of nitrile to hydroxycarbamimidoyl To a solution of nitrile compound (1 mmol) in ethyl alcohol (10 mL) was added hydroxylamine (50% aqueous solution, 5 mmol). The mixture was stirred at reflux for 2-5 h. The reaction mixture was concentrated in vacuo to furnish the desired hydroxycarbamimidoyl compound.
Z: Opening of aromatic methylene dioxy compound with alcohol A solution of potassium tert-butoxide (2.25 mmol) in DMSO (1.25 mL) was heated at 50 °C for 30 min. Methanol (1.25 mL) was added to it and continued heating at 50 °C for 30 min. To the reaction mixture was added 1,2-methylenedioxy aromatic compound (1 mmol) and continued heating at 50 °C for 30 min. The reaction mixture was cooled to room temperature and quenched with water (10 mL) and 1 N sodium hydroxide (16 mL), The reaction m mixture was washed with ether (2 X 10 mL) and acidified to pH 4 using cone HCl. The solid obtained was collected by filtration to furnish the desired product.
Z-l: Opening of aromatic methylene dioxy compound with alcohol To a mixture of methylene dioxy compound (1 mmol) in HMPA (2.5 mL) were added sodium methoxide (2.5 mmol) and heated with stirring at 150 °C for 12 min. The mixture was cooled and poured into ice water (20 mL), NaOH (30 mg) and stirred for 10 min. It was then extracted with ether and the aqueous layer was acidified to pH 4 with HCl and extracted with ether. The later ethereal extracts were combined, dried and concentrated. The residue was purified by crystallization or column chromatography.
AA: Conversion of amine to amide in the presence of a phenol To a solution of amino compound (1 mmol) in pyridine (5 mL) was added, dropwise, acid chloride (2 mmol) at 0 °C under N2. The rnixture was stirred for 45 rnin and was then poured into ice water and acidified with 1 N HCl. The precipitated solid was collected by filtration, washed with IN HCl, hexane, and then dried in vacuo to give crude product. The crude product was added to freshly prepared sodium methoxide solution (0.1 M, 10 mL) and stirred for 30 min at room temperature. The reaction mixture was quenched with acetic acid (1 mmol) and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The water layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO- and evaporated to yield a solid. The solid was washed with hexane and dried.m vacuo to furnish the desired amide.
AB-1: Conversion of amino of amidine to amino carbamate To amidine compound (1 mmol) was added 0.1N NaOH (10 mL) and stirred at room temperature for 5 min. The reaction mixture was concentrated in vacuo and to the residue was added alkyl or aryl 4-nitrophenyl carbonate (2 mmol) in 20 mL of hexamethylphosphoramide and stirred at 45 °C for 24 h. The reaction was quenched with water (100 mL) and. extracted with ethyl acetate (2 X 100 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired product.
AB-2: Conversion of amino of amidine to amino carbamate To a solution of amidine compound (1 mmol) in acetonitrile (25 mL) was added triemylamine (5 mL) and aryl/alkyl chloroformate (2 mmol) or dialkyl/aryl carbonate. The reaction mixtme was stirred at room temperature for 16 h and quenched with water (100 mL). The reaction mixture was extracted with ethyl acetate (2 X 100 mL). The combined extracts were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and. concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired product.
AC: Conversion of aldehyde to oxime To a stirred s olution of aldehyde (1 mmol) in ethanol (10 mL) was added pyridine (10 mL) and hydroxylamine hydrochloride (1.25 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen and then concentrated in vacuo to one third of its origin al volume. Water (10 mL) was added and the precipitated solid was collected by filtration and dried in vacuo. The product was used as such for next step without further purification.
AD: Debenzylation in the presence of aldehyde To a solution of phenyl methoxyaryl aldehyde (1 mmol) in dichloromethane (10 mL) cooled to -78 °C was added dropwise under a nitrogen atmosphere boron tnbromide (1M solution in dichloromethane, 1.2 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with chloroform (10 mL). The organic layers were combined, washed with brine (10 mL), dried, filtered and concentrated in vacuo to furnish crude product. Purification of the crude by flash column chromatography furnished the desired phenolic aldehyde AE-1: Reductive animation of aldehyde To a stirred solution of aldehyde (1 mmol) in methanol (40 mL) was added arnine (3.3 mmol) followed by the addition of glacial acetic acid (0.3 mL). The reaction mixture was stirred for 30 min under nitrogen at room temperature, and then sodium cyanoborohydride (1.5 mmol) was added. After stirring for 20 min, the solvent was evaporated in vacuo, and the residue was taken in ethyl acetate. The orgamc layer was washed with water, and the insoluble material was removed from the organic layer by filtration. The pH of the aqueous phase was adjusted to 7 with IN NaOH and was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO^. The solvent was evaporated in vacuo to furnish crude product. The crude product was purified by crystallization or flash column chromatography.
AE-2: Reductive amination of aldehyde To a mixture of animoarylamidine (1.2 mmol), 4A° molecular sieves, and sodium hydroxide (1 N solution in anhydrous methanol, 1.2 mL, 1.2 mmol) in methanol (10 mL) was added a solution of aldehyde (1 mmol) in THF (10 mL). The reaction mixture was heated for 15 mins at reflux temperature and was cooled to room temperature. Acetic acid (1 %) and sodium cyanoborohydnde (1 M solution in THF, 5 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with 1 N NaOH (30 mmol) and stirred for additional 2 h and concentrated in vacuo to remove methanol. The mixture was diluted with water (15 mL) and washed with ether (2 10 mL). The aqueous layer was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration, washed with ether, dried in vacuo to furnish product, which was purified by flash column chromatography, if needed.
AE-3: Reductive amination of aldehyde A mixture of ammoarylamidine (2 mmol), 4A° molecular sieves, pyridine (6 mL) in methanol (9 mL) was heated at 50 °C for one hour. A solution of aldehyde (1 mmol) in methanol (7.5 mL) containing acetic acid (1 %) was added and continued heating for 4 h to 12 h. The reaction mixture was cooled and sodium cyanoborohydride (1 M solution in THF, 5 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with 5 N NaOH (30 mmol) and stirred for additional 2 h. The reaction mixture was filtered through Celite (to remove molecular sieves) and concentrated to remove methanol. The mixture was diluted with water (15 mL) and washed with ether (2 X 10 mL). The aqueous layer was filtered and solid obtained was kept aside (mainly product). The aqueous layer was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration. The combined solid materials were purified, if needed, by flash column chromatography.
AE-4: Reductive amination of aldehyde To a mixture of aldehyde (1 mmol) and ammoarylamidine (1.1 mmol) in MeOH at room temperature was added triethyl arnine (2.75 mmol), sodium cyanoborohydride (0.83 mmol) and zinc chloride (0.9 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to remove methanol. The reaction rnixture was quenched with 1 N NaOH (10 mL), diluted with water (10 mL), and extracted with EtOAc (5 X 20 mL). The combined organic extracts were washed with brine (15 mL), dried (MgS04), filtered through Celite and concentrated to give the product. Purification of the crude by flash column chromatography gave the desired product.
AE-5: Reductive amination of aldehyde To a solution of amine (1.2 mmol) in MeOH (10 mL) was added aldehyde (1 mmol) in THF (10 mL) containing acetic acid (0.1 mL) drop-wise. The mixture was stirred at 50 °C for 4-12 h and then cooled to room temperature. Sodium cyanoborohydride (1.5 mmol) was added to the reaction mixture and stirred at room temperature overnight. Water was added and pH of the solution was adjusted to 7. The solution was extracted with ethyl acetate. The organic layer was dried (MgS04) and evaporated in vacuo. The residue was purifeid by flash column chromatography to furnish the desired amine.
AF-1: Synthesis of amidine from nitrite Acetyl chloride (5 mL) was added to methanol (5 mL) at 0 °C drop-wise and stirred at room temperature for 15 mins. To this solution of methanolic HCI was added nitrile compound (1 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and dried. The residue obtained of the resulting methyl irnidate was dissolved in methanol (10 mL). Dry ammonia gas was bubbled into the reaction mixture at reflux temperature for 5 h. The reaction mixture was concentrated to furnish the required amidine.
AG: Addition of Grignard reagent to aryl aldehyde To a solution of aryl aldehyde (1 mmol) in THF (15 mL) cooled to -78 °C was added drop wise under a nitrogen atmosphere, vinyl magnesium bromide (1 M solution in THF, 5 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 48 h. The reaction was quenched carefully with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, washed with brine (10 mL), dried and concentrated in vacuo. The residue obtained was purified by flash column chromatography to obtain the desired addition product.
AG-1: Synthesis of tributylvinyltin compounds from vinyl bromide containing hydroxyl To a solution of vinyl bromide with hydroxyl (1 mmol) in dichloromethane (20 mL) was added tert-butyldimelhylsilyl chloride (1.5 mmol) and DMAP (1.5 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with water (20 mL) and the aqueous layer separated. The organic layer was washed with 0.1 N aqueous HCI (10 mL), brine (20 mL), dried and concentrated in vacuo to furnish corresponding ter^butyldimemylsilyloxy compound as an oil which was used as such for the next step.
To a solution of the above oily residue (1 mmol) in diethyl ether (20 mL) cooled to -78 °C was added dropwise ieri-butyllithium (1.7 M in pentane, 2 mmol) over a period of 15 mins. The reaction mixture was stirred at -78 °C for 3 h and quenched at -78 °C with 2 N aqueous sulfuric acid (2 mL) and water (18 mL). The reaction mixture was neutralized using 2 N NaOH and the organic layer was separated. The organic layer was washed with water (20 mL), brine (20 mL), dried and concentrated in vacuo. Purification of the crude residue obtained by flash column chromatography furnished the desired tributyltin compound.
AG-2: Synthesis of tributylmethyltin compounds from arylmethyl bromides or allyl bromides To lithium clippings (10 mmol) in THF (10 mL) cooled to -40 °C was added dropwise tributyltin chloride (0.27 mL, 1 mmol) in THF (5 mL) over a period of 15 min. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was filtered through glass wool to remove insoluble impurities and cooled to -40 °C. A. freshly prepared solution of arylmethyl bromide or allyl bromide (1 mmol) was added dropwise over a period of 10 mins and stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ether (2 X 10 mL). The organic layers were combined, washed with brine (10 mL), dried, filtered and concentrated in vacuo to furnish desired tributyltinalkyl and was used as such without further purification.
AG-3: 4-Bromo-5-formyl-benzo[l,3]dioxoIe-2-carboxyIic acid methyl ester To a mixture of 2-bromo-3,4-dihydroxy-benzaldehyde (2.17 g, 10.0 mmol) and K2CO3 (5.56 g, 40.2 mmol) in n-propanol (25 mL) was added dibromoacetic acid (2.18, 10.0 mmol) and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature, another portion of dibromoacetic acid (1.75 g, 8.0 mmol) was added. The mixture was stirred at reflux for 46 h. w-Propanol was evaporated and water (30 mL) was added. The resulting aqueous solution was acidified to pH 2 by adding 1 N HCl and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were dried (MgSO/ and evaporated in vacuo to afford crude 4-bromo-5-formyl-benzo[l,3]dioxole-2-carboxylic acid (1.34 g) as a brownish solid. This crude product was dissolved in anhydrous methanol (50 mL) and cone. H2SO4 (5 mL) was added drop by drop. The resulting mixture was refluxed overnight and cooled to room temperature. Water (50 mL) was added and the resulting aqueous solution was extracted with ethyl acetate (100 mL X 3). The combined organic layers were dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (ethyl acetate:hexane = 5:95) to furnish 4-bromo-5-formyl-benzo[l,3]dioxole-2-carboxylic acid methyl ester as a white solid.
AH: Synthesis of tert-butyl ester of phenol To a solution of phenol (1 mmol) in pyridine (10 mL) was added 2,2-dimethyl-propionyl chloride (1.2 mmol) dropwise. The mixture was stirred at room temperature for overnight and diluted with water (100 mL). The reaction mixture was extracted with ethyl acetate (3 X 50 mL). The organic layers were combined and washed with aqueous 0.5 N HCl (100 mL), water, brine, dried (MgSCu) and concentrated in vacuo. The crude residue was purified by flash column chromatography to furnish the desired ester.
AI: Preparation of 2-bromo-5-hydroxy benzaldehyde To a solution 3-hydroxybenzaldehyde (Aldrich, 101.39 g, 805 mmol) in chloroform (1000 mL), was added bromine (45 mL, 845 mmol) in chloroform (200 mL) drop wise over a period of 2 h at room temperature. The reaction mixture was stirred at room temperature overnight and filtered to collect crude 2-bromo-5-hydroxy benzaldehyde (32 g) as a dark brown solid. The filtrate was concentrated to 200 mL, filtered through a. pad of Celite and silica gel (40 g) and washed with ether (1000 mL). The filtrate was concentrated in vacuo to give a second crop of the crude desired aldehyde (60 g) as a dark brown solid. The above solids were combined and dissolved in glacial acetic acid (360 mL) by heating. Water (840 mL) was added and the solution was filtered hot. The solution was allowed to attain room temperature and kept in a refrigerator overnight. The crystals obtained were collected by filtration and washed with water, dried overnight in vacuo to furnish (60 g, 37%) of the desired product as a purplish brown crystalline solid, mp: 135 °C.
AJ-1: Amidine from nitrite A mixture of nitrile (1 mmol) and hydroxylamine (aqueous 50%, 1.8 mL) in EtOH (15 mL) was refluxed for 3 h and concentrated in vacuo. To the residue obtained was added EtOH (20 mL), acetic acid (2 mL) and a small amount of Raney nickel. The reaction mixture was hydrogenated (50 psi) for 14-24 h, filtered and concentrated in vacuo. The residue obtained, was purified by flash column chromatography to obtain the corresponding amidine.
AJ-2: Amidine from nitrile A mixture of nitrile (1 mmol) and saturated methanolic HC1 solution (freshly prepared by bubbling HC1 gas or prepared in-situ by premixing methanol and acetyl chloride at ice cold temperature) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to furnish methyl imidate. To the residue of methyl imidate was added MeOH (40 mL) and ammonia gas was bubbled at reflux temperature for 16 h or till the reaction was complete. The reaction rnixture was concentrated in vacuo and dried to furnish the desired amidine. Alternatively, the methyl imidate was dissolved in methanol and ammonium acetate (10 mrnol) was added. The reaction mixture was concentrated in vacuo and purified by flash column chromatography to obtain the corresponding amidine.
AJ-3: Amidine from nitrile To a solution of nitrile (1 mmol) dissolved in methanol (5 mL) was added N-acetyl cystein (0.1 or 1 mmol) and ammonium acetate (5 mmol) and heated at reflux till the reaction was complete. The reaction mixture was concentrated in vacuo and purified by flash column chromatography to obtain the corresponding amidine.
A : Conversion of aryl inflates or halides to boronate ester To dic oro[l, -bis(diphenylphosphino)ferrocene]palladium (Π) dichloro-methane adduct (0.75 mmol) under argon in dioxane (100 mL) was added aryl triflate (25 mmol), pinacolborane (31.5 mmol) and triemylamine (75 mmol). The reaction mixture was heated under argon at 100 °C for 3h or until complete as evidenced from TLC analysis. The reaction mixture was concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired boronate ester. Alternatively, the following method can be used.
To dichloro[l, -bis(Q phenylphosphino)ferrocene3palladium (Π) dichloro-methane adduct (0.03 mmol), l, -bis(diphenylphosphmo)ferrocene (0.03 mmol) under argon in dioxane (100 mL) was added aryl triflate (1 mmol), bis(pinacolata)diboron (1.1 mmol) and potassium acetate (3 mmol). The reaction mixture was heated under argon at 100 °C for 3h or until complete as evidenced from TLC analysis. The reaction mixture was concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired boronate ester.
The examples of the compounds prepared are given in the following tables. The tables describe the compounds, their method of preparation, the starting material, and the analytical data. In some cases, where analytical data have not been given, those compounds were characterized at the later step in the synthesis.
Ill 1X2 1ϋ2 16X \ n X87 224 The following non-limiting examples are presented to further illustrate the present invention. 2'-[( {4-[Ammo(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylaniino)carbonyl]-4,-t en-2-yl-14'-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-ttiien-3-yl- 1 , 1 '-biphenyl-2-carboxylic acid 2'-[({4-[Arruno(imino)methyl]phenyl}amino)carbonyl]-4-[(isobutylamino)carbonyl]- 1 , 1 ':4', 1 "-terphenyl-2-carboxylic acid 2'-[( {4-[Armno{imino)methyl]phenyl} ammo)carbonyl]-4'-(3-furyl)- -[(isobu1ylarnino)carbonyl]-l,r-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(irnino)methyl]phenyl} arnino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-pyridm-4-yl-l,r-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-(lH-pyrrol-2-yl)- 1 , 1 '-biphenyl-2-carboxylic acid 2'-[({4-[Ammo(iimno)me l^ 3-yl]-4-[(isobutylamino)carbonyl]- 1 , 1 '-biphenyl-2-carboxylic acid 2 ({4-[Arnko(im o)methyl]phen 2-yl]-4-[(isobutylamino)carbonyl]- 1 , 1 '-biphenyl-2-carboxylic acid 2'-[( {4-[Arnino(irriino)methyl]phenyl} amino)carbonyl]-4-[(isoburylarnino)carbonyl]-4'-vinyl-l,r-biphenyl-2-carboxylic acid 4'-AUyl-2'-[( {4-[amino(imino)methyl]p enyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]- 1 , 1 '-biphenyl-2-carboxylate 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-(l ,3-thiazol-2-yl)-l , 1 '-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)rnetliyl]phenyl} amino)carbonyl]-4'-[3-(hydroxymethyl)-2-fiuyl]-4-[(isobutylamino)carbonyl]-l,l'-biphenyl-2-carboxylic acid 2'-[( {4-[Aii-ino(imino)methyl]phenyl} amino)carbonyl]-4-[(isob tyIaniino)carbonyl]-4'-prop-l-ynyl-l, -biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-(3-hydroxy-3-methylbut-1 -ynyl)-4-[(isobutylamiao)carbonyl]- 1 , 1 '-biphenyl-2-carboxylic acid 2'-[({4-[Ainiao(imino)methyl]phenyl}amino)carbonylj-4-[(3-methylbutanoyl)amino]-4'-vinyl-l, -bipb.enyl-2-carboxylic acid 2'-[( {4-[Ainuio(imino)methyl]phenyl} amino)carbonyl]-4'-(4-hydroxybut-l-ynyl)-4-[(isobutylamino)carbonyl]-l , 1 '-biphenyl-2-carboxylic acid 2'-[({4-[Ainkio(imino)methyl]phenyl}amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-[(lE)-3-methylbuta- 1 ,3-dienyl]-l , 1 '-biphenyl-2-carboxylic acid 2'-[( {4-[Ainino(-mino)methyl]phenyl} amino)carbonyl]-4'-(3 -hydroxyprop- 1 -ynyl)-4-[(isobulylaniino)carbonyl]-l,ll-biphenyl-2-carboxylic acid 2'-[( {4-[Ammo(imino)methyl]phenyl} amino)carbonyl]-4'-(2-furyl)-4-[(propylainino)carbonyl]-l, -biphenyl-2-carboxylic acid 2H({4-[Amino(imino)meth^^ butylamino)c8irbonyl]-4'-(2-furyl)- 1 , 1 '-biphenyl-2-carboxylic acid 2'-[( {4-[Aniino(imino)methyl]phenyl} amino)carbonyl]-4'-(2-furyl)-4- {[(2,2,2-trifluoroethyl)imiino]carbonyl}-l,r-biphenyl-2-carboxylic acid 2'-[( {4-[Aminc)(imino)methyl]phenyl} amino)carbonyl]-4'-(2-furyl)-4- {[(4-hydroxybutyl)amino] carbonyl} -1 , 1 '-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)methyl]phenyl}amin (2-fiiryl)- 1 , 1 '-biphenyl-2-carboxylic acid 2'-[( {4-[An-ino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylammo)carbonyl]-5'-methoxy-4'-vinyl-l, -biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylairdno)carbonyl]-4'-(thien-2-ylmethyl)- 1 , 1 '-biphenyl-2-carboxylic acid 2- {3-[({4-[Amino(imino)methyl]phenyl} amino)carbonyl]pyridin-4-yl} -5-[(isobutylamino)carbonyl]benzoic acid 2'-[( {4-[Amino(iinino)methyl]phenyl} amino)carbonyl]-4-[(cyclopentylamino)carbonyl]-4'-vinyl- 1 , 1 '-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-5'-ethoxy-4-[(isobutylamino)carbonyl]-4'- vinyl- 1 , 1 '-biphenyl-2-carboxylic acid Methyl 2'-[( {4-[( {[(acetyloxy)methoxy]carbonyl} aniino)(imino)methyl]phenyl} ainino)carbonyI]-4-[(isobutylamino)carbonyl]-4'- vinyl- 1 , 1 '-biphenyl-2-carboxylate Methyl 2'-[({4-[{[(benzyloxy)carbonyl]anu¾o}(immo)methyl]phenyl}aniino) carbonyl]-4-[(isobutylamino)carbonyl]-4'-vinyl- 1 , 1 '-biphenyl-2-carboxylate N1 - {4-[Amino(imino)methyl]phenyl} -N8-isobutyl-6-oxo-6H-benzo[c]chromene-1 ,8-dicarboxamide 2'-[({4-[Amirio(immo)methyl]phenyl}aniko)methyl]-4-[(i 4-vinyl- 1 , -biphenyl-2-carboxylic acid 2'-( {[4-(4,5-Dihydro- 1 H-imidazol-2-yl)phenyl]amino} carbonyl)-4-[(isobutylamino)carbonyl]-l , -biphenyl-2-carboxylic acid 2-[( {4-[Amin.o(imino)methyl]phenyl} amino)carbonyl]-4-[(isobulylamnio)catbonyl]-5'-thien-2-yl- 1 , 1 '-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-5'-(2-amino-2-o [(isobutylamino)carbonyl]- 1 , 1 '-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-ethoxy-4-[(isobutylamino)carbonyl]- 1 , 1 '-biphenyl-2-carboxylic acid 27S 2- {5-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]- 1 ,3-benzodioxol-4-yl} -5-[(isobutylan ino)carbonyl]benzoic acid 2'-[l-({4-[Ammo(immo)methyl]pheny 1 , 1 '-biphenyl-2-carboxylic acid 3- [2-[( {4-[Ainino(iinino)methyl]phenyl} ainino)carbonyl]-4-(benzyloxy)phenyl]-6-[(isobutylamko)carbonyl]pyridine-2-carboxylic acid 3-[2-(4-Carbaminiidoyl-phenylcarbamoyl)-4-vinyl-phenyl]-6-isobutylcarbam pyridine-2-carboxylic acid 2'-[(5-Carbamimidoyl-pyridin-2^ biphenyl-2-carboxylic acid 2*-{[4-(N-Hydroxycarbainimidoyl)-phenylamino]-methyl}-4-i vinyl-biphenyl-2-carboxylic acid 2'- {[4-(N-Hydroxycarbamimidoyl)-phenylamino]-methyl} -4-isobutylcarbamoyl-4'-vinyl-biphenyl-2-carboxylic acid methyl ester 3- {2-[(4-Carbamiimdoyl-phenylammo)-rnetliyl]-4-vinyl-phenyl} -6-isobulylcarbamoyl-pyridine-2-carboxylic acid Biological Assay Methods In Vitro Assay for Inhibition of TF/FVIIa To assess the inhibition of the test compounds against the target enzyme, TF/FVIIa, an amidolytic assay based upon the absorbance of p-Nitroanalide (pNA) at OD405 was utilized. The IC50 of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Vmax values.
TF/FVIIa assay reactions were performed in a 200 μΤ, mixture containing 4 nM FVTia, 10 nM lipidated tissue factor, in an assay buffer containing 100 mM Tris, pH 7.2, 150 mM NaCl, 5 mM calcium chloride, 0.1 % bovine serum albumin (BSA), and 10% dimethyl sulfoxide (DMSO). TF and FVIIa were allowed to equilibrate at room temperature for 15 minutes. Test compounds dissolved in DMSO were incubated at varied concentrations with TF FVIIa for 10 minutes, followed by addition of 500 DM substrate Spectrozyme-FVIIa. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD405 nm for 10 minutes at 21 second intervals with a Powerwave χ (Bio-Tek Instruments) microplate reader.
In Vitro Assay for Human Thrombin This colorimetric assay was used to assess the ability of the test compounds to inhibit the human thrombin enzyme. IC50 of the test compounds was determined by using C4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Vmax values.
Thrombin assay reactions were performed in a 200 uL mixture containing human thrombin at (1 U/mL) in an assay buffer containing 100 mM HEPES, 10 mM calcium chloride, and 10 % DMSO, pH 7.5. Test compounds dissolved in DMSO were added to thrombin enzyme reactions at varied concentrations, followed by the addition of substrate Na-Benzoyl-Phe-Val-Arg p-Nitroanilide at a final concentration of 1 mM. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD405 nm for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
In Vitro Assay for Human Trypsin This enzymatic assay was employed to evaluate the ability of the test compounds to inhibit human pancreatic trypsin. IC50 of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Vmax values.
Trypsin assay reactions were performed in a 200 μΐ, mixture containing human pancreatic trypsin at 1 μg/mL in an assay buffer containing 200 mM triemanolamine (TEA), 10 mM calcium chloride, 10 % DMSO, pH 7.8. Test compounds dissolved in DMSO were added to trypsin enzyme reactions at varied concentrations, followed by the addition of substrate N -Benzoyl-LrArginine p-Nitroanilide (L-BAPNA) at a final concentration of (0.25 mg/mL). Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD405 nm for 10 minutes at 21 second intervals with a Powerwave χ (Bio-Tek Instruments) microplate reader.
Biological Data ICso Values of Some Selected Compounds on Different Serine Protease Enzymes + means >1 μΜ; ++ means >100 nM; +++ means <100 nM A comparison of Examples with R group and without R group illustrates the greatly -enhanced activity achieved pursuant to the present invention.
Compounds of the present invention are useful as inhibitors of trypsin-like serine protease enzymes such as thrombin, factor Vila, TF/FVIIa, and trypsin.
These compounds may be employed to inhibit me coagulation cascade and prevent or limit coagulation.
These compounds may be used to inhibit the formation of emboli or thromboli in blood vessels.
These compounds may be used to treat thrombolymphangitis, thrombosinusitis, thromboendocarditis, thromboangitis, and thromboarteritis.
These compounds may be used to inhibit thrombus formation following angioplasty. These may be used in combination with other antithrombolytic agents such as tissue plasminogen activators and their derivatives, streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial occlusion following thrombolytic therapy.
These compounds may also be used in matastatic diseases, or for any disease where inhibition of coagulation is indicated.
These compounds may be used as diagnostic reagents in vitro for inhibiting clotting of blood in the tubes.
These compounds may be used alone or in combination with other compounds such as heparin, aspirin, or warfarin and any other anticoagulant agents.
These compounds may be used as anti-inflammatory agents.
According to a further aspect of the invention, compounds may be employed in preventing ex vivo coagulation such as that encountered in the extracorporeal perfusion of blood through for example artificial valves, prothesis, stents or catheters. According to this aspect of the invention the extracorporeal device may be coated with the compositions of the invention resulting in a lower risk of clot formation due to extrinsic pathway activation.
Dosage and Formulation The compounds of this invention can be administered by any means that produces contact of Hie active agent's site of action with factor Vila and other serine proteases in the body of a human, mammal, bird, or other animal. They can be administered by any conventional means, such as oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. Parenteral infusion includes intramuscular, intravenous, and intraarterial. They can be administered alone, but generally administered with a pharmaceutical carrier elected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage administered will, or course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms, the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.0001 to 1000 milligram (mg) per kilogram (kg) of body weight, with the preferred dose being 0.1 to about 30 mg kg.
Dosage forms (compositions suitable for administration) contain from about mg to about 500 mg of compound per unit. In these pharmaceutical compositions, the compound of the present invention will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
The daily dose of the compounds of the invention that is to be administered can be a single daily dose or can be divided into several, for example, two, three or four, part administrations. The pharmaceutical compositions or medicaments of the invention can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
Gelatin capsules contain a compound of the present invention and powdered carriers, such as lactose, starch, cellulose derivatives, biocompatible polymers, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours.
Compressed tablets can be sugar coated to mask by unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. They may also contain buffering agents, surfactants and preservatives. Liquid oral products can be developed to have sustained-release properties. They may also contain cyclodextrin derivatives to enhance the solubility of the active ingredient and to promote its oral uptake.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral adrninistration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffering agents. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company and in the Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association, both standard reference texts in this field.
Useful, pharmaceutical dosage forms for adrninistration of the compounds according to the present invention can be illustrated as follows: Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered 1500 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.
Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The prodrug can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets • A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcystalline cellulose, 11 mg of starch, and 9.98 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The drag is mixed containing ingredient such as sugar, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Moreover, the compounds of the present invention can be administered in the form of nose drops, metered dose nasal or buccal inhalers. The drug is delivered from a nasal solution as a fine mist or from a powder as an aerosol.
In another embodiment of the invention, a compound of the invention can be used in an assay to identify the presence of factor Vila and other serine protease or to isolate , factor Vila and other serine protease in a substantially purified form. For example, the compound of the invention can be labeled with, for example, a radioisotope, and the labeled compound is detected using a routine method useful for detecting the particular label. In addition, έ compound the invention can be used advantageously as a probe to detect the location or amount of factor Vila and other serine protease activity in vivo, in vitro or ex vivo.
Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.
The foregoing disclosure includes all the information deemed essential to enable those skilled in the art to practice the claimed invention. The foregoing description of the invention illustrates and describes the present invention. Additionally, the disclosure shows and describes only the preferred embodiments of the invention but, as mentioned above, it is to be understood that the invention is capable of use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the inventive concept as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described hereinabove are further intended to explain best modes known of practicing the invention and to enable others skilled in the art to utilize the invention in such, or other, embodiments and with the various modifications required by the particular applications or uses of the invention. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended that the appended claims be construed to include alternative embodiments;

Claims (8)

155202/4 is claimed is The compound represented by the structure -OCH3; and R' is selected from the group consisting of -CHO, -C02H, and -C02MEM; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
2. The compound represented by the structure 155202/4 155202/4 and R' is selected from the group consisting of -CHO, -C02H, and -C02MEM; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
3. The compound represented by the structure wherein R is selected from the group consisting of 155202/4 and N3 ; and pharmaceutically acceptable salts thereof.
4. The compound represented by the structure wherein R is selected from the group consisting of 155202/4 155202/4 and R' is selected from the group consisting of pharmaceutically acceptable salts thereof.
The compound represented by the structure 155202/4 wherein R is selected from the group consisting of pharmaceutically acceptable salts thereof.
The compound represented by the structure wherein R is selected from the group consisting of harmaceutically acceptable salts thereof.
The compound represented by the structure wherein R is selected from the group consisting of and R" is selected from the group consisting of and pharmaceutically acceptable salts thereof.
8. The compound represented by the structure 155202/4 wherein R is selected from the group consisting of , -CH=CH2; R is -H or -Boc; and R" is -C02MEM or -C02H; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
9. The compound represented by the structure wherein R is -CH3 and R' is selected from the group consisting of and pharmaceutically acceptable salts thereof.
10. The compound represented by the structure wherein R is and R' is selected from the group consisting of 155202/4 pharmaceutically acceptable salts thereof. The compound represented by the structure wherein R is -CH3 and R' is selected from the group consisting of harmaceutically acceptable salts thereof. The compound represented by the structure wherein at least one R is selected from the group consisting of -OCH3, -OH, -OS02CF3, -CH=CH2-, -OCH2C02C2H5, -OCH2CONH2, selected from the group consisting of 300 155202/4 and R" is selected from the group consisting of -H, -CH3 and -Bn; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
14. The compound represented by the structure wherein at least one R is selected from the group consisting of -CH=CH2, -OS02CF3, -OCH2C02C2H5, -OCH2CONH2, - - , -C02H, -OBn, -OCH3, and -CH(OH)CH3; and R' is selected from the group consisting of -CH3, -CH2C6H5, -Bn, -H; and pharmaceutically acceptable salts thereof. 155202/4
15. The compound represented by the structure wherein at least one R is selected from the group consisting of -CH=CH2, -CH(OH)CH2OH, -CH=0, -CH2OH, -C02H, -OCH3, -CH=CH2; and pharmaceutically acceptable salts thereof.
16. The compound represented by the structure and pharmaceutically acceptable salts thereof.
17. The compound represented by the structure 155202/4 wherein R is selected from the group consisting of R' is selected from the group consisting of -OBn, -OH, -OS02CF3, and -CH=CH2; R" is selected from the group consisting of -C02H, -C02MEM, or -CHO; and R'" is selected from the group consisting of wherein MEM designates a methoxyethoxymethyl group.
18. The compound represented by the structure wherein R is selected from the group consisting of 155202/4 R' is -H or alkyl; and R" is selected from the group consisting of thereof.
19. The compound of claim 18 wherein said alkyl is CH3.
20. The compound represented by the structure wherein R is selected from the group consisting of 155202/4 R' is -H, -CH=CH2; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
21. The compound of claim 20 wherein said alkyl is -CH3.
22. The compound represented by the structure wherein R is selected from the group consisting of , -CH=CH2, and -H; R' is -H or alkyl; and R" is selected from the group consisting of 155202/4
23. The compound of claim 22 wherein said alkyl is -CH3.
24. The compound represented by the structure wherein N is located at position 3 or 4 in the phenyl ring; R is selected from the group consisting of -CHO, -C02H, and R' is -H or alkyl; and pharmaceutically acceptable salts thereof. The compound of claim 24 wherein said alkyl is -CH3. 155202/4
26. The compound represented by the structure wherein R is selected from the group consisting of - and R' is -H or alkyl; and pharmaceutically acceptable salts thereof.
27. The compound of claim 26 wherein alkyl is CH3
28. The compound represented by the structure wherein at least one R is selected from the group consisting of -CH=CH2, -OCH3, -OBn, -OH, and -H; R' is 155202/4 selected from the group consisting of and R " is -H; and pharmaceutically acceptable salts thereof. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -CHO, -C02H, -C02MEM, R' is selected from the group consisting of -OBn, -OH, -0S02CF3, and and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
30. The compound of claim 29 wherein said alkyl is -CH3. 155202/4 wherein R is -H or -C02H; R' is selected from the group consisting of -CHO, -C02H, and and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
32. The compound of claim 31 wherein said alkyl is -CH3.
33. The compound represented by the structure wherein R is selected from the group consisting of -CH(OH)-CH2OH, -CHO, and -CH(OH)-CH=CH2; R' is -Boc or -H; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
34. The compound of claim 33 wherein said alkyl is -CH3. 155202/4
35. The compound represented by the structure
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Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1383731B1 (en) * 2001-04-06 2009-08-05 Biocryst Pharmaceuticals, Inc. Biaryl compounds as serine protease inhibitors
GB0124936D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124933D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124934D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124938D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124941D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124931D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124939D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
JP4472349B2 (en) * 2002-02-12 2010-06-02 スミスクライン ビーチャム コーポレーション Nicotinamide derivatives useful as p38 inhibitors
GB0217757D0 (en) 2002-07-31 2002-09-11 Glaxo Group Ltd Novel compounds
WO2004072101A2 (en) * 2003-02-11 2004-08-26 Bristol-Myers Squibb Company Phenylglycine derivatives useful as serine protease inhibitors
US7144895B2 (en) * 2003-02-11 2006-12-05 Bristol-Myers Squibb Co. Benzene acetamide compounds useful as serine protease inhibitors
GB0308185D0 (en) * 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
EP1626966A1 (en) * 2003-05-20 2006-02-22 Genentech, Inc. Benzofuran inhibitors of factor viia
EP1628954A2 (en) * 2003-05-20 2006-03-01 Genentech, Inc. Acylsulfamide inhibitors of factor viia
GB0402143D0 (en) * 2004-01-30 2004-03-03 Smithkline Beecham Corp Novel compounds
US20080051416A1 (en) * 2004-10-05 2008-02-28 Smithkline Beecham Corporation Novel Compounds
DE602006016566D1 (en) * 2005-01-10 2010-10-14 Bristol Myers Squibb Co PHENYLGLYCINAMIDE DERIVATIVES USED AS ANTICOAGULANTS
HUE054365T2 (en) 2005-02-16 2021-09-28 Anacor Pharmaceuticals Inc Boronophthalides for therapeutic use
ATE473975T1 (en) * 2005-02-16 2010-07-15 Astrazeneca Ab CHEMICAL COMPOUNDS
US7767657B2 (en) 2005-02-16 2010-08-03 Anacor Pharmaceuticals, Inc. Boron-containing small molecules
US20060257337A1 (en) * 2005-04-28 2006-11-16 David Sherris Compositions and methods to treat skin diseases characterized by cellular proliferation and angiogenesis
USRE46558E1 (en) 2005-04-28 2017-09-26 Paloma Pharmaceuticals, Inc. Compositions and methods to treat diseases characterized by cellular proliferation and angiogenesis
GB0512429D0 (en) * 2005-06-17 2005-07-27 Smithkline Beecham Corp Novel compound
ATE455103T1 (en) * 2005-06-24 2010-01-15 Bristol Myers Squibb Co PHENYLGLYCINAMIDE AND PYRIDYLGLYCINAMIDE DERIVATIVES USED AS ANTICOAGULATION AGENTS
WO2007072041A1 (en) * 2005-12-23 2007-06-28 Astex Therapeutics Limited Therapeutic compounds
MX335993B (en) * 2005-12-30 2016-01-07 Anacor Pharmaceuticals Inc Boron-containing small molecules.
US8623871B2 (en) 2006-01-25 2014-01-07 Synta Pharmaceuticals Corp. Substituted biaryl compounds for inflammation and immune-related uses
EP1996021B1 (en) * 2006-02-28 2017-12-13 Paloma Pharmaceuticals, Inc. Compositions and methods to treat diseases characterized by cellular proliferation and angiogenesis
US8084614B2 (en) 2007-04-06 2011-12-27 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
PA8775701A1 (en) 2007-04-06 2009-04-23 Neurocrine Biosciences Inc ANTAGONIST OF THE RECEIVERS OF THE GONADOTROPINE LIBERATING HORMONE AND PROCEDURES RELATED TO THEM
AU2009228303B2 (en) * 2008-03-25 2015-08-13 Paloma Pharmaceuticals, Inc. Methods of treating fibrotic disorders
US9221765B2 (en) * 2009-06-10 2015-12-29 North Carolina State University Inhibition and dispersion of bacterial biofilms with benzimidazole derivatives
WO2012112791A1 (en) 2011-02-16 2012-08-23 Paloma Pharmaceuticals, Inc. Radiation countermeasure agents
US8980823B2 (en) 2012-03-07 2015-03-17 Shaker A. Mousa Formulations of Factor VIIa inhibitors and utility
CA2917298C (en) * 2013-07-05 2021-06-22 Shaker A. Mousa Novel formulations of factor viia inhibitors and utility
WO2016029216A2 (en) 2014-08-22 2016-02-25 Biocryst Pharmaceuticals, Inc. Method for producing amidine derivatives
EP3182962B1 (en) * 2014-08-22 2023-06-07 Biocryst Pharmaceuticals, Inc. Compositions and uses of amidine derivatives
WO2017035263A1 (en) * 2015-08-24 2017-03-02 Biocryst Pharmaceuticals, Inc. Compositions comprising a plasma kallikrein inhibitor
US11447506B2 (en) 2016-05-09 2022-09-20 Anacor Pharmaceuticals, Inc. Crystal forms of crisaborole in free form and preparation method and use thereof
US10759759B2 (en) * 2016-10-31 2020-09-01 Biocryst Pharmaceuticals, Inc. Prodrugs of kallikrein inhibitors
JOP20200001A1 (en) 2017-07-11 2022-10-30 Vertex Pharma Carboxamides as modulators of sodium channels
MX2021003158A (en) 2018-09-18 2021-07-16 Nikang Therapeutics Inc Fused tricyclic ring derivatives as src homology-2 phosphatase inhibitors.
TW202322824A (en) 2020-02-18 2023-06-16 美商基利科學股份有限公司 Antiviral compounds
AU2022256476A1 (en) 2021-04-16 2023-10-12 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100424688B1 (en) * 1997-02-14 2004-07-23 니혼덴신뎅와가부시키가이샤 A waveguide circuit, a method of manufacturing the same, and a waveguide circuit module
FR2770307B1 (en) * 1997-10-27 1999-11-26 Commissariat Energie Atomique PHASE ARRAY OR PHASAR DEVICE AND MANUFACTURING METHOD THEREOF
US5905824A (en) * 1997-12-09 1999-05-18 Delisle; Vincent Temperature compensated insensitive optical multiplexor/demultiplexor
WO1999041231A1 (en) * 1998-02-17 1999-08-19 Ono Pharmaceutical Co., Ltd. Amidino derivatives and drugs containing the same as the active ingredient
JP3434489B2 (en) * 1999-09-24 2003-08-11 古河電気工業株式会社 Array waveguide type diffraction grating
EP1383731B1 (en) * 2001-04-06 2009-08-05 Biocryst Pharmaceuticals, Inc. Biaryl compounds as serine protease inhibitors

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