US20070299073A1 - Imidazolyl derivatives - Google Patents

Imidazolyl derivatives Download PDF

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Publication number
US20070299073A1
US20070299073A1 US11/805,227 US80522707A US2007299073A1 US 20070299073 A1 US20070299073 A1 US 20070299073A1 US 80522707 A US80522707 A US 80522707A US 2007299073 A1 US2007299073 A1 US 2007299073A1
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Prior art keywords
phenyl
alkyl
ome
optionally substituted
compound according
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US11/805,227
Inventor
Christophe Thurieau
Lydie Poitout
Marie-Odile Galcera
Thomas Gordon
Barry Morgan
Christophe Moinet
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Ipsen Pharma SAS
Original Assignee
Thurieau Christophe A
Poitout Lydie F
Marie-Odile Galcera
Gordon Thomas D
Morgan Barry A
Moinet Christophe P
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Application filed by Thurieau Christophe A, Poitout Lydie F, Marie-Odile Galcera, Gordon Thomas D, Morgan Barry A, Moinet Christophe P filed Critical Thurieau Christophe A
Priority to US11/805,227 priority Critical patent/US20070299073A1/en
Publication of US20070299073A1 publication Critical patent/US20070299073A1/en
Assigned to SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES, SAS reassignment SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATIONS SCIENTIFIQUES, SAS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: THURIEAU, CHRISTOPHE, CONTOUR, MARIE-ODILE GALCERA, MOINET, CHRISTOPHE P., POITOUT, LYDIE
Assigned to BIOMEASURE, INCORPORATED reassignment BIOMEASURE, INCORPORATED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GORDON, THOMAS, MORGAN, BARRY A.
Assigned to IPSEN PHARMA S.A.S. reassignment IPSEN PHARMA S.A.S. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIOMEASURE, INCORPORATED
Assigned to IPSEN PHARMA S.A.S. reassignment IPSEN PHARMA S.A.S. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: SOCIETE DE CONSEILS DE RECHERCHES ET D`APPLICATIONS SCIENTIFIQUES, SAS
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    • C07D233/64Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Definitions

  • the present invention is directed to compounds and compositions containing said compounds which bind selectively to somatostatin receptor subtypes and the use of said compounds for treating medical disorders which are mediated by somatostatin receptor subtypes.
  • Somatostatin somatotropin release inhibiting factor, SRIF
  • SRIF somatotropin release inhibiting factor
  • somatostatin The actions of somatostatin are mediated via membrane bound receptors.
  • the heterogeneity of its biological functions has led to studies to identify structure-activity relationships of peptides analogs at the somatostatin receptors which resulted in the discovery of five receptor subtypes (Yamada, et al, Proc. Natl. Acad. Sci. U.S.A, 89, 251-255, 1992; Raynor, K. et al, Mol. Pharmacol., 44, 385-392, 1993).
  • the functional roles of these receptors are under extensive investigation. Binding to the different types of somatostatin subtypes have been associated with the treatment of the following conditions and/or diseases.
  • Activation of types 2 and 5 have been associated with growth hormone suppression and more particularly GH secreting adenomas (Acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 has been associated with treating prolactin secreting adenomas.
  • somatostatin subtypes are restenosis, inhibition of insulin and/or glucagon and more particularly diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; treatment of cancer such as hepatoma; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding.
  • Somatostatin agonists can also be used for decreasing body weight in a patient.
  • the present invention is directed to a family of nonpeptide compounds, which are selective and potent somatostatin receptor ligands.
  • the present invention is directed to a compound of the formula (I), the racemic-diastereomeric mixtures and optical isomers of said compound of formula (I), the pharmaceutically-acceptable salts and prodrugs thereof or a pharmaceutically acceptable salt thereof, wherein
  • a preferred compound of formula I is where R 1 is H; R 2 is H; R 3 is —CH 2 -phenyl;
  • R 1 is H;
  • R 2 is H;
  • R 3 is —CH 2 -phenyl;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl;
  • R 6 is H;
  • R 1 is H;
  • R 2 is H;
  • R 3 is —CH 2 -phenyl;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl;
  • R 6 is H;
  • R 1 is H;
  • R 2 is H;
  • R 3 is —CH 2 -indol-3-yl;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl or t-Bu;
  • R 6 is H;
  • R 1 is H;
  • R 2 is H;
  • R 3 is —CH 2 -indol-3-yl;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl or t-Bu;
  • R 6 is H;
  • R 1 is H;
  • R 2 is H;
  • R 3 is —CH 2 -indol-3-yl;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl or t-Bu;
  • R 6 is H;
  • R 1 is H;
  • R 2 is H;
  • R 3 is —CH 2 -indol-3-yl;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl or t-Bu;
  • R 6 is H;
  • R 1 is H;
  • R 2 is H;
  • R 3 is —CH 2 -indol-3-yl, —(CH 2 ) 4 —NH—CO—O-t-Bu or —(CH 2 ) 4 —NH 2 ;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl, o-methoxyphenyl, p-Br-phenyl, p-nitro-phenyl or p-N,N-diethylamino-phenyl;
  • R 6 is H;
  • R 5 is phenyl and R 3 is —(CH 2 )-indol-3-yl that the stereochemistry at the carbon to which R 3 is attached is in the R-configuration.
  • R 1 is H
  • R 2 is H
  • R 3 is —CH 2 -indol-3-yl, —(CH 2 ) 4 —NH—CO—O-t-Bu or —(CH 2 ) 4 —NH 2
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0
  • R 5 is phenyl, o-methoxyphenyl, p-methoxyphenyl, p-Br-phenyl, p-nitro-phenyl or p-N,N-diethylamino-phenyl
  • R 6 is H
  • R 5 is phenyl or o-OMe-phenyl and R 3 is —(CH 2 )-indol-3-yl; it is preferred that the compounds are the separated enantiomers (R or S configuration) according to the carbon to which R 3 is attached.
  • R 1 is H;
  • R 2 is H;
  • R 3 is —(CH 2 ) 4 —NH—CO—O-t-Bu or —(CH 2 ) 4 —NH 2 ;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl;
  • R 6 is H;
  • R 1 is H;
  • R 2 is H;
  • R 3 is —(CH 2 ) 4 —NH—CO—O-t-Bu or —(CH 2 ) 4 —NH 2 ;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl;
  • R 6 is H;
  • R 1 is H;
  • R 2 is H;
  • R 3 is —(CH 2 ) m -indol-3-yl, —(CH 2 ) 4 —NH—CO—O-t-Bu or —(CH 2 ) 4 —NH 2 ;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl, o-OMe-phenyl or p-OMe-phenyl;
  • R 6 is H;
  • R 1 is H;
  • R 2 is H;
  • R 3 is —(CH 2 ) 4 —NH—CO—O-t-Bu or —(CH 2 ) 4 —NH 2 ;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl;
  • R 6 is H;
  • R 1 is —(CH 2 )—CO-Z 1 ;
  • R 2 is H;
  • R 3 is —(CH 2 ) 4 —NH—CO—O-t-Bu, —(CH 2 ) 4 —NH—CO—O-benzyl, —(CH 2 )-phenyl or —(CH 2 )-indol-3-yl;
  • R 4 is —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl;
  • R 6 is H;
  • R 1 is —(CH 2 )—CO—(CH 2 ) m -Z 1 where m in the definition of R 1 is 0, 1 or 2;
  • R 2 is H;
  • R 3 is —(CH 2 )-indol-3-yl or —(CH 2 ) 4 —NH—CO—O-t-Bu;
  • R 4 is H or —(CH 2 ) m -A 1 where m in the definition of R 4 is 0;
  • R 5 is phenyl, o-OMe-phenyl, p-nitro-phenyl, p-Br-phenyl, t-Bu, —CH(CH 3 ) 2 —CO—NH—(CH 2 ) 2 —CO—O-t-Bu, —CH(CH 3 ) 2 —CO—NH—(CH 2 ) 3 -imidazol-1-yl, —CH(CH 3 ) 2 —CO—NH—(CH 2 ) 2 -pyri
  • Another preferred compound of formula (I) is where R 1 and R 2 are taken together to form a compound of formula (Ib) or (Ic);
  • the present invention is directed to a compound of the formula (II), the racemic-diastereomeric mixtures and optical isomers of said compound of formula (II), the pharmaceutically-acceptable salts or prodrugs thereof or a pharmaceutically acceptable salt of said prodrug, wherein
  • Still another preferred group of compounds of formula (II) have the following formula: wherein X 2 is p-chloro-phenyl, p-methoxy-phenyl, 2,4-difluoro-phenyl or thienyl.
  • Still another preferred group of compounds of formula (II) have the following formula: wherein X 2 is p-chloro-phenyl, p-methoxy-phenyl, phenyl or thienyl.
  • R 7 is m-nitro-phenyl or 2-phenyl-ethyl; or and R 7 is 3,4-dichlorophenyl or and R 7 is 3,4-dichlorophenyl.
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of a compound of formula (I) or formula (II), as defined hereinabove, and a pharmaceutically acceptable carrier.
  • the present invention is directed to a method of eliciting an agonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.
  • the present invention is directed to a method of eliciting an antagonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.
  • the present invention is directed to a method of binding one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.
  • the present invention is directed to a method of treating acromegaly, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux, Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, polycystic ovary disease, cancer, cancer cachexia, hypotension, postprandial hypotension, panic attacks, GH secreting adenomas or TSH secreting adenomas, in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II
  • the present invention is directed to a method of treating diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon, Nephropathy, peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis, gastrointestinal hormone secreting tumors, angiogenesis, inflammatory disorders, chronic allograft rejection, angioplasty, graft vessel bleeding or gastrointestinal bleeding in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.
  • the present invention is directed to a method of inhibiting the proliferation of helicobacter pylori in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, to said subject.
  • the compounds of Formula I or II can be made by processes which include processes known in the chemical arts for the production of compounds. Certain processes for the manufacture of Formula I or II compounds are provided as further features of the invention and are illustrated by the following reaction schemes and examples.
  • alkyl groups are intended to include those alkyl groups of the designated length in either a straight or branched configuration.
  • exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
  • C 0 -alkyl When the definition “C 0 -alkyl” occurs in the definition, it means a single covalent bond.
  • alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration.
  • exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • halogen or halo is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
  • cycloalkyl is intended to include a mono-cycloalkyl group or a bi-cycloalkyl group of the indicated carbon number known to those of skill in the art.
  • aryl is intended to include aromatic rings known in the art, which can be mono-cyclic, bi-cyclic or tri-cyclic, such as phenyl, naphthyl and anthracene.
  • heterocycle includes mono-cyclic, bi-cyclic and tri-cyclic systems having one or more heteroatoms, such as oxygen, nitrogen and/or sulfur.
  • the ring systems may be aromatic, for example pyridine, indole, quinoline, pyrimidine, thiophene (also known as thienyl), furan, benzothiophene, tetrazole, dihydroindole, indazole, N-formylindole, benzimidazole, thiazole, and thiadiazole.
  • the ring systems may be non-aromatic, for example pyrrolidine, piperidine, morpholine and the like.
  • a chemical structure as used herein has an arrow emanating from it, the arrow indicates the point of attachment.
  • the structure is a pentyl group.
  • the arrow indicates that the cyclic moiety can be attached at any of the available bonding points, for example means that the phenyl can be bonded ortho, meta or para to the X group.
  • the arrow indicates that the bi-cyclic or tri-cyclic ring can be attached at any of the available bonding points in any of the rings, for example means that the indole is bonded either through the phenyl portion of the ring or the nitrogen containing ring portion.
  • the compounds of the instant invention have at least one asymmetric center as noted by the asterisk in the structural formula (I), (Ia) and (Ib), above. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers, racemic mixtures or diastereomeric mixtures thereof, be included within the scope of the instant invention.
  • the instant compounds can be generally isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids.
  • acids are hydrochloric, nitric, sulfuric, phosphoric, acetic, propionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methane sulfonic and the like.
  • certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter-ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
  • the pharmaceutically acceptable salts are formed by taking about 1 equivalent of a compound of formula (I) or (II) and contacting it with about 1 equivalent of the appropriate corresponding acid of the salt which is desired. Work-up and isolation of the resulting salt is well-known to those of ordinary skill in the art.
  • agonists and antagonists of somatostatin are useful for treating a variety of medical conditions and diseases, such as inhibition of H. pylori proliferation, acromegaly, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux and in treating endocrinological diseases and/or conditions, such as Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, and polycystic ovary disease; in treating various types of cancer such as thyroid cancer, hepatome, leuk
  • Activation of type 2 but not type 5 subtype receptor has been associated with treating prolactin secreting adenomas.
  • Other indications associated with activation of the somatostatin subtypes are inhibition of insulin and/or glucagon and more particularly diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding.
  • Somatostatin agonists can also be used for decreasing body weight in a patient. Accordingly, the compounds of the instant invention are useful for the foregoing methods.
  • compositions comprising, as an active ingredient, at least one of the compounds of Formula (I) or (II) in association with a pharmaceutically acceptable carrier.
  • the compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant
  • nasal, vaginal, rectal, sublingual or topical routes of administration can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
  • Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.
  • compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
  • a compound of this invention can be administered in a sustained release composition such as those described in the following patents.
  • U.S. Pat. No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester.
  • U.S. Pat. No. 5,595,760 teaches sustained release compositions comprising a bioactive agent-in a gelable form.
  • U.S. application Ser. No. 08/929,363 filed Sep. 9, 1997, teaches polymeric sustained release compositions comprising a bioactive agent and chitosan.
  • U.S. application Ser. No. 08/740,778 filed Nov. 1, 1996 teaches sustained release compositions comprising a bioactive agent and cyclodextrin.
  • U.S. application Ser. No. 09/015,394 filed Jan. 29, 1998 teaches absorbable sustained release compositions of a bioactive agent.
  • the teachings of the foregoing patents and applications are incorporated herein by reference.
  • an effective dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment, all of which are within the realm of knowledge of one of ordinary skill in the art.
  • dosage levels of between 0.0001 to 100 mg/kg of body weight daily are administered to humans and other animals, e.g., mammals.
  • a preferred dosage range is 0.01 to 10.0 mg/kg of body weight daily, which can be administered as a single dose or divided into multiple doses.
  • the affinity of a compound for human somatostatin subtype receptors 1 to 5 is determined by measuring the inhibition of [ 125 I-Tyr 11 ]SRIF-14 binding to CHO—K1 transfected cells.
  • the human sst 1 receptor gene was cloned as a genomic fragment.
  • a 1.5 Kb PstI-XmnI segment containing 100 bp of the 5′-untranslated region, 1.17 Kb of the entire coding region, and 230 bp of the 3′-untranslated region was modified by the Bg1II linker addition.
  • the resulting DNA fragment was subcloned into the BamHI site of a pCMV-81 to produce the mammalian expression plasmid (provided by Dr. Graeme Bell, Univ. Chicago).
  • a clonal cell line stably expressing the sst 1 receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method (1).
  • the plasmid pRSV-neo was included as a selectable marker.
  • Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.
  • the human sst 2 somatostatin receptor gene isolated as a 1.7 Kb BamHI-HindIII genomic DNA fragment and subcloned into the plasmid vector pGEM3Z (Promega), was kindly provided by Dr. G. Bell (Univ. of Chicago).
  • the mammalian cell expression vector is constructed by inserting the 1.7 Kb BamH1-HindII fragment into compatible restriction endonuclease sites in the plasmid pCMV5.
  • a clonal cell line is obtained by transfection into CHO—K1 cells using the calcium phosphate co-precipitation method.
  • the plasmid pRSV-neo is included as a selectable marker.
  • the human sst 3 was isolated at genomic fragment, and the complete coding sequence was contained within a 2.4 Kb BamHI/HindIII fragment.
  • the mammalian expression plasmid, pCMV-h3 was constructed by inserting the a 2.0 Kb NcoI-HindIII fragment into the EcoR1 site of the pCMV vector after modification of the ends and addition of EcoR1 linkers.
  • a clonal cell line stably expressing the sst 3 receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method.
  • the plasmid pRSV-neo (ATCC) was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.
  • the human sst 4 receptor expression plasmid, pCMV-HX was provided by Dr. Graeme Bell (Univ. Chicago).
  • the vector contains the 1.4 Kb NheI-NheI genomic fragment encoding the human sst 4 , 456 bp of the 5′-untranslated region and 200 bp of the 3′-untranslated region, clone into the XbaI/EcoR1 sites of PCMV-HX.
  • a clonal cell line stably expressing the sst 4 receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method.
  • the plasmid pRSV-neo was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.
  • the human sst 5 gene was obtained by PCR using a ⁇ genomic clone as a template, and kindly provided by Dr. Graeme Bell (Univ. Chicago).
  • the resulting 1.2 Kb PCR fragment contained 21 base pairs of the 5′-untranslated region, the full coding region, and 55 bp of the 3′-untranslated region.
  • the clone was inserted into EcoR1 site of the plasmid pBSSK(+). The insert was recovered as a 1.2 Kb HindIII-XbaI fragment for subcloning into pCVM5 mammalian expression vector.
  • a clonal cell line stably expressing the SST 5 receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method.
  • the plasmid pRSV-neo was included as a selectable marker.
  • Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.
  • CHO—K1 cells stablie expressing one of the human sst receptor are grown in RPMI 1640 containing 10% fetal calf serum and 0.4 mg/ml geneticin.
  • Cells are collected with 0.5 mM EDTA, and centrifuged at 500 g for about 5 min. at about 4° C.
  • the pellet is resuspended in 50 mM Tris, pH 7.4 and centrifuged twice at 500 g for about 5 min. at about 4° C.
  • the cells are lysed by sonication and centrifuged at 39000 g for about 10 min. at about 4° C.
  • the pellet is resuspended in the same buffer and centrifuged at 50000 g for about 10 min. at about 4° C. and membranes in resulting pellet are stored at ⁇ 80° C.
  • Bound from free [ 125 I-Tyr 11 ]SRIF-14 is separated by immediate filtration through GF/C glass fiber filter plate (Unifilter, Packard) presoaked with 0.1% polyethylenimine (P.E.I.), using Filtermate 196 (Packard) cell harvester. Filters are washed with 50 mM HEPES at about 0-4° C. for about 4 sec. and assayed for radioactivity using Packard Top Count.
  • Binding data are analyzed by computer-assisted nonlinear regression analysis (MDL) and inhibition constant (Ki) values are determined.
  • CHO—K1 Cells expressing human somatostatin (SRIF-14) subtype receptors are seeded in 24-well tissue culture multidishes in RPMI 1640 media with 10% FCS and 0.4 mg/ml geneticin. The medium is changed the day before the experiment.
  • reaction medium is removed and 200 ml 0.1 N HCl is added.
  • cAMP is measured using radioimmunoassay method (Kit FlashPlate SMP001A, New England Nuclear).
  • a carboxylic acid is first converted into an acyl chloride using oxalyl chloride or thionyl chloride or activated as a mixed anhydride with an alkylchloroformate (isobutylchloroformate (Krantz, A., Copp, L. J., Biochemistry, 1991, 30, 4678-4687) or ethylchloroformate (Podlech, J., Seebach, D., Liebigs Ann., 1995, 1217-1228)) in the presence of a base (triethylamine or N-methyl morpholine).
  • alkylchloroformate isobutylchloroformate (Krantz, A., Copp, L. J., Biochemistry, 1991, 30, 4678-4687) or ethylchloroformate (Podlech, J., Seebach, D., Liebigs Ann., 1995, 1217-1228)
  • a base triethylamine or N
  • the activated carboxyl group is then transformed into a diazoketone using ethereal diazomethane or trimethylsilyldiazomethane (Aoyama, T., Shiori, T., Chem. Pharm. Bull., 1981, 29, 3249-3255) in an aprotic solvent such as diethyl ether, tetrahydrofuran or acetonitrile.
  • aprotic solvent such as diethyl ether, tetrahydrofuran or acetonitrile.
  • the bromination is then carried out using a brominating agent such as HBr in acetic acid, hydrobromic acid in water or in diethyl ether.
  • a brominating agent such as HBr in acetic acid, hydrobromic acid in water or in diethyl ether.
  • a methyl ketone is converted to a bromoketone by using different brominating agents:
  • the 2- ⁇ 2-[(1S)-1-(tertbutoxycarbonylamino)-2-[(1H)-indol-3-yl]ethyl]-1H-imidazol-4-yl ⁇ -2-methyl-propionic acid 2 can be activated preferentially by carbonyldiimidazole in an aprotic solvent such as THF or DMF at about 20-100° C. for about 1-4 hours.
  • an aprotic solvent such as THF or DMF
  • N-Boc-ethylene-diamine (0.43 g, 2.7 mmol) was added and the mixture was shaken for about 1 hour at about 25° C.
  • Carboxylic acids are activated overnight at room temperature with carbonyldiimidazole in an aprotic solvent such as chloroform, THF or THF/DMF before addition of an amino starting material as shown above followed by a further 12-15 hours of stirring.
  • the excess acylating agent is quenched with aminomethylated resin for about 12-15 hours and then purified on silica gel pad with dichloromethane or ethyl acetate as eluent.
  • 2-Furancarboxylic acid (12.6 mg, 0.11 mmol) was activated overnight at about 22° C. with carbonyldiimidazole (0.11 mmol, 0.2M in chloroform).
  • 2- ⁇ (1S)-1-Amino-2-[indol-3-yl]ethyl ⁇ -4-phenyl-1H-imidazole (0.1 mmol, 0.5M in chloroform) was added to the media and the mixture was stirred for about 12 hours at about 22° C.
  • Aminomethylated resin was then added (50-60 mg, 1.2 mmol/g, Novabiochem) in order to quench the excess of acylating agent for about 12 hours.
  • Example 8470 The following compounds were prepared analogously to the procedure described for Example 8470, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein.
  • thioimidates were previously synthesized by condensation of thioamides and iodomethane in acetone at room temperature. The precipitate was collected and then rinsed with acetone. Thioimidates so formed were used without further purification.
  • the resulting N-alkylated compound can be isolated either by aqueous work-up followed by flash chromatography on silica gel, or by addition to the reaction mixture of a nucleophile supported on polymer (to trap the excess of electrophile) such as aminomethyl or thiomethyl polystyrene resin followed by filtration and then rapid purification of the resulting residue on a silica gel pad (using Alltech silica cartridge and Alltech manifold).
  • a nucleophile supported on polymer to trap the excess of electrophile
  • electrophile such as aminomethyl or thiomethyl polystyrene resin
  • Example 12308 The following compounds were prepared analogously to the procedure described for Example 12308, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein.
  • Example 13774 The following compound was prepared analogously to the procedure described for Example 13774 using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein.
  • a compound of formula (f) can react with isocyanates, isothiocyanates, N-succinimidyl carbamates, acyl chlorides or activated carboxylic acids in an aprotic solvent at 20-70° C. for 2-18 hours.
  • the resulting derivative can be isolated by evaporation of the mixture followed by flash chromatography on silica gel or by addition to the mixture of a nucleophile supported on polymer such as aminomethyl or thiomethyl polystyrene resin followed by a filtration.
  • Mass spectra were acquired on a single quadrupole electrospray mass spectrometer (Micromass, Platform model), 0.8 Da resolution. A monthly calibration, between 80 and 1000 Da, is performed with sodium and rubidium iodide solution isopropanol/water (1/1 Vol.).
  • HPLC retention times were acquired on an HPLC system: HP1100 (Hewlett-Packard) equipped with a photodiode array UV detector.
  • HPLC conditions are as follows and the conditions used for each of the following tables of compounds are noted below, the wavelength of the UV detector is noted in parenthesis after the formula number.

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Abstract

The present invention is directed to imidazolyl derivatives of formula (I) where the substituents are defined in the specification, which are useful as agonist or antagonists of somatostatin receptors.

Description

    BACKGROUND OF THE INVENTION
  • The present invention is directed to compounds and compositions containing said compounds which bind selectively to somatostatin receptor subtypes and the use of said compounds for treating medical disorders which are mediated by somatostatin receptor subtypes. Somatostatin (somatotropin release inhibiting factor, SRIF), a tetradecapeptide hormone, originally isolated from bovine hypothalami (Brazeau, P. et al., Science 179, 77-79, 1973) has been shown to have a wide range of regulatory effects on the release of a variety of hormones such as growth hormone, prolactin, glucagon, insulin, gastrin (Bloom, S. R. and Poldack, J. M., Brit. Med. J. 295, 288-289, 1987). In addition, antiproliferative properties (Reichlin, S., N. Engl. J . Med. 309, 1495-1501, 1983) have been obtained with somatostatin analogs in metastatic prostatic cancer (Parmar, H. et al, Clin. Exp. Metastasis, 10, 3-11, 1992) and in several other neuroendocrine neoplasms in man (Anthony, L. et al, Acta Oncol., 32, 217-223, 1993). Metabolism of somatostatin by aminopeptidases and carboxypeptidases leads to a short duration of action.
  • The actions of somatostatin are mediated via membrane bound receptors. The heterogeneity of its biological functions has led to studies to identify structure-activity relationships of peptides analogs at the somatostatin receptors which resulted in the discovery of five receptor subtypes (Yamada, et al, Proc. Natl. Acad. Sci. U.S.A, 89, 251-255, 1992; Raynor, K. et al, Mol. Pharmacol., 44, 385-392, 1993). The functional roles of these receptors are under extensive investigation. Binding to the different types of somatostatin subtypes have been associated with the treatment of the following conditions and/or diseases. Activation of types 2 and 5 have been associated with growth hormone suppression and more particularly GH secreting adenomas (Acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 has been associated with treating prolactin secreting adenomas. Other indications associated with activation of the somatostatin subtypes are restenosis, inhibition of insulin and/or glucagon and more particularly diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; treatment of cancer such as hepatoma; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding. Somatostatin agonists can also be used for decreasing body weight in a patient.
  • In drug research, it is a key issue to minimize side effects by developing highly potent and selective drug molecules. Recent work on the development of nonpeptide structures (Hirschmann, R. et al, J. Am. Chem. Soc. 115, 12550-12568, 1993; Papageorgiou, C. and Borer, X., Bioorg. Med. Chem. Lett. 6, 267-272, 1996) have described compounds with low somatostatin receptor affinity.
  • The present invention is directed to a family of nonpeptide compounds, which are selective and potent somatostatin receptor ligands.
  • SUMMARY OF THE INVENTION
  • In one aspect the present invention is directed to a compound of the formula (I),
    Figure US20070299073A1-20071227-C00001

    the racemic-diastereomeric mixtures and optical isomers of said compound of formula (I), the pharmaceutically-acceptable salts and prodrugs thereof or a pharmaceutically acceptable salt thereof,
    wherein
    • Figure US20070299073A1-20071227-P00900
      represents an optional bond;
    • R1 is H, —(CH2)m—C(O)—(CH2)m-Z1, —(CH2)m-Z1, —(CH2)m—O-Z1 or —(C0-C6)alkyl-C(O)—NH—(CH2)m-Z3;
      • Z1 is an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazolyl, indolyl,
        Figure US20070299073A1-20071227-C00002
    • R2 is H or (C1-C6)alkyl;
    • or R1 and R2 are taken together with the nitrogen atoms to which they are attached to form a compound of formula (Ia), (Ib) or (Ic),
      Figure US20070299073A1-20071227-C00003
    • R3 is —(CH2)m-E-(CH2)m-Z2;
      • E is O, S,—C(O)—, —C(O)—O—, —NH—C(O)—O— or a bond;
      • Z2 is H, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, (C1-C12)alkylguanidino, or an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl and naphthyl;
    • R4 is H or —(CH2)m-A1;
      • A1 is —C(═Y)—N(X1X2), —C(═Y)—X2, —C(═NH)—X2 or X2;
        • Y is O or S;
        • X1 is H, (C1-C12)alkyl, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m—N-di-(C1-C6)alkyl or —(CH2)m-aryl;
        • X2 is —(CH2)m—Y1—X3 or optionally substituted (C1-C12)alkyl;
          • Y1 is O, S, NH, C═O, (C2-C12)alkenyl having one or more double bonds, —NH—CO—, —CO—NH—, —NH—CO—O—(CH2)m—, —C≡C—, SO2 or a bond;
          • X3 is H, an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)alkoxy, aryloxy, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —CH-di-(C1-C12)alkoxy, pyrrolidinyl, pyridinyl, thiophene, imidazolyl, piperidinyl, piperazinyl, benzothiazolyl, furanyl, indolyl, morpholino, benzo[b]furanyl, quinolinyl, isoquinolinyl, —(CH2)m-phenyl, naphthyl, fluorenyl, phthalamidyl, pyrimidinyl,
            Figure US20070299073A1-20071227-C00004
          • or X1 and X2 are taken together with the nitrogen to which they are attached to form an optionally substituted moiety selected from the group consisting of thiazolyl
            Figure US20070299073A1-20071227-C00005
            • Y2 is CH—X4, N—X4, —C(X4X4), O or S;
            • X4 for each occurrence is independently —(CH2)m—Y3—X5;
            •  Y3 is —C(O)—, —C(O)O— or a bond;
            •  X5 is hydroxy, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, or an optionally substituted moiety selected from the group consisting of aryl, aryl(C1-C4)alkyl, furanyl, pyridinyl, indolyl, —CH(phenyl)2,
              Figure US20070299073A1-20071227-C00006
    • R5 is (C1-C12)alkyl, (C0-C6)alkyl-C(O)—O-Z5, (C0-C6)alkyl-C(O)—NH—(CH2)m-Z3 or optionally substituted aryl;
      • Z3 for each occurrence is independently amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —NH—C(O)—O—(CH2)m-phenyl —NH—C(O)—O—(CH2)m—(C1-C6)alkyl or an optionally substituted moiety selected from the group consisting of imidazolyl, pyridinyl, morpholino, piperidinyl, piperazinyl, pyrazolidinyl, furanyl and thiophene;
    • R6 is H or (C1-C6)alkyl;
    • R7 is (C1-C12)alkyl or —(CH2)m-Z4;
      • Z4 is an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, indolyl, thiophene, benzo[b]furan, benzo[b]thiophene, isoxazolyl,
        Figure US20070299073A1-20071227-C00007
      • Z5 is H, (C1-C12)alkyl, (CH2)m-aryl;
        wherein an optionally substituted moiety is optionally substituted by one or more substituents, each independently selected from the group consisting of Cl, F, Br, I, CF3, CN, N3, NO2, OH, SO2NH2, —OCF3, (C1-C12)alkoxy, —(CH2)m-phenyl-(X6)n, —S-phenyl-(X6)n, —S—(C1-C12)alkyl, —O—(CH2)m-phenyl-(X6)n, —(CH2)m—C(O)—O—(C1-C6)alkyl, —(CH2)m—C(O)—(C1-C6)alkyl,
    • —O—(CH2)m—NH2, —O—(CH2)m—NH—(C1-C6)alkyl, —O—(CH2)m—N-di-((C1-C6)alkyl) and
    • —(C0-C12)alkyl-(X6)n;
      • X6 for each occurrence is independently selected from the group consisting of hydrogen, Cl, F, Br, I, NO2, N3, CN, OH, —CF3, —OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, —(CH2)m—NH2, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m—N-di-((C1-C6)alkyl) and —(CH2)m-phenyl;
    • m for each occurrence is independently 0 or an integer from 1 to 6; and
    • n for each occurrence is independently an integer from 1 to 5;
    • provided that:
    • (a) when R5 is (C1-C12)alkyl, or —C(O)—O-Z5 and Z5 is (C1-C12)alkyl or optionally substituted aryl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl or Z4 and Z4 is thiophene or optionally substituted phenyl, then R3is not —C(O)—O—(CH2)m-Z where m is 0 and Z is H or (C1-C12)alkyl or where m is 1 to 6 and Z is H;
    • (b) when R5 is (C1-C12)alkyl or optionally substituted phenyl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl and R3 is —O—(CH2)-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl, and naphthyl; and
    • (c) when R5 is H or (C1-C12)alkyl; R6 is (C1-C6)alkyl; R7 is (C1-C12)alkyl; and R3 is —O-Z2 or —S-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, thiophene, benzothienyl and indolyl.
  • A preferred compound of formula I is where R1 is H; R2 is H; R3 is —CH2-phenyl;
    • R4is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
      • where A1 is —C(═Y)—N(X1X2);
        • Y is O; X1 is H or methyl;
          • X2 is —(CH2)m—Y1—X3;
            • m in the definition of X2 is 0, 1, 2 or 3; Y1 is a bond or O; and X3 is N-methylpyrrolidin-2-yl, diethylamino, pyridinyl, thiophene, imidazolyl, diethoxymethyl, 1-benzyl-piperidin-4-yl, optionally substituted phenyl or
              Figure US20070299073A1-20071227-C00008
  • Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-phenyl; R4is —(CH2)m-A1 where m in the definition of R4is 0; R5 is phenyl; R6 is H;
      • where A1 is —C(═Y)—N(X1X2);
        • Y is O;
        • X1 is benzyl and X2 is 2-hydroxyethyl;
        • or X1 and X2 are taken together with the nitrogen atom to which they are attached to form
          Figure US20070299073A1-20071227-C00009
          • where Y2 is C—X4 or N—X4;
            • X4 is —(CH2)m—Y3—X5 where m in the definition of X4 is 0 or 1; and
            •  X5 is selected from the group consisting of furanyl, benzyl, phenyl, amino,
              Figure US20070299073A1-20071227-C00010
  • Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-phenyl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
      • where A1 is —C(═Y)—X2;
        • Y is O; X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 0, 1 or 2;
          • Y1 is O, —NH—CO—, —CO—NH—, —NH—CO—O—CH2—, SO2 or a bond; and
          • X3 is methyl, furanyl, pentyl, phenyl, indolyl, p-NO2-phenyl, naphthyl, fluorenyl, —CH(phenyl)2, benzothiazolyl, phthalamidyl, N,N-dimethylamino,
            Figure US20070299073A1-20071227-C00011
  • Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;
      • A1 is —C(═Y)—N(X1X2);
        • Y is O or S; X1 is H; X2 is —(CH2)m—Y1—X3;
          • m in the definition of X2 is 0, 1 or 2;
          • Y1 is a bond; and X3 is phenyl, o-Cl-phenyl, m-Cl-phenyl, p-phenyloxy-phenyl, 2,6-di-isopropylphenyl, m-CF3-phenyl, p-ethoxycarbonyl-phenyl, 2,4-difluorophenyl, m-NO2-phenyl, p-benzyloxyphenyl, o-isopropylphenyl, n-hexyl, 4-morpholino, naphthyl or
            Figure US20070299073A1-20071227-C00012
  • Another compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;
      • where A1 is —C(═Y)—X2;
        • Y is O; X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 0, 1 or 2;
          • Y1 is O, —CO—NH—, —NH—CO—O—CH2-or a bond; and X3 is methyl, 3-pentyl, phenyl, p-NO2-phenyl, phthalamidyl, N,N-dimethylamino, p-aminophenyl, fluorenyl or
            Figure US20070299073A1-20071227-C00013
  • Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;
      • where A1 is —C(═Y)—N(X1X2);
        • Y is O; X1 is hydrogen; X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 0, 1, 2 or 3;
          • Y1 is O, or a bond; and X3 is cyclopentyl, 4-OH-butyl, N,N-diethylamino, N-methyl-pyrrolidin-3-yl, —CH(ethoxy)2, phenyl, p-SO2NH2-phenyl p-OH-phenyl, o-CF3-phenyl, p-Cl-phenyl, —CH(phenyl)2,
            Figure US20070299073A1-20071227-C00014
  • Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;
      • where A1 is —C(═Y)—X2;
        • Y is O; X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 0, 1, 2 or 3;
          • Y1 is —NH—CO, —C═C—, —C—C— or a bond; and X3 is t-butyl, 1-methylcarbonyl-piperidin-4-yl, phenyl, p-Cl-phenyl, m-CF3-phenyl, 4-nitro-naphthyl, p-methoxy-phenyl, m-(phenylethyl)-phenyl, indol-3-yl or p-aminophenyl.
  • Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl, —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl, o-methoxyphenyl, p-Br-phenyl, p-nitro-phenyl or p-N,N-diethylamino-phenyl; R6 is H;
      • where A1 is —C(═Y)—N(X1X2);
        • Y is O; X1 is H; X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 0;
          • Y1 is a bond; and X3 is o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, o-Cl-phenyl, m-Cl-phenyl, p-Cl-phenyl, o-nitro-phenyl, m-nitro-phenyl, p-nitro-phenyl, o-CF3-phenyl, m-CF3-phenyl, p-CF3-phenyl, p-F-phenyl, 2,4-di-F-phenyl, 2,5-di-F-phenyl, 2,5-di-methoxy-phenyl, m-OMe-phenyl, p-OMe-phenyl, 2-CF3-4-Cl-phenyl or 3-nitro-4-F-phenyl.
  • Of the immediately above compounds it is preferred that when R5 is phenyl and R3 is —(CH2)-indol-3-yl that the stereochemistry at the carbon to which R3 is attached is in the R-configuration.
  • Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —CH2-indol-3-yl, —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl, o-methoxyphenyl, p-methoxyphenyl, p-Br-phenyl, p-nitro-phenyl or p-N,N-diethylamino-phenyl; R6 is H;
      • where A1 is —C(═Y)—X2;
        • Y is O; X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 1;
          • Y1 is a bond; and X3 is phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, o-Cl-phenyl, m-Cl-phenyl, p-Cl-phenyl, o-nitro-phenyl, m-nitro-phenyl, p-nitro-phenyl, o-CF3-phenyl, m-CF3-phenyl, p-CF3-phenyl, o-F-phenyl, m-F-phenyl, p-F-phenyl, N,N-di-methylamino-phenyl, o-OMe-phenyl, m-OMe-phenyl, p-OMe-phenyl, 3,4-di-Cl-phenyl, 3,4,5-tri-OMe-phenyl, p-Me-phenyl, p-OH-phenyl or 2,4-di-F-phenyl.
  • Of the immediately foregoing compounds when R5 is phenyl or o-OMe-phenyl and R3 is —(CH2)-indol-3-yl; it is preferred that the compounds are the separated enantiomers (R or S configuration) according to the carbon to which R3 is attached.
  • Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
      • where A1 is —C(═Y)—X2;
        • Y is O; X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 0, 1 or 2;
          • Y1 is S, SO2 or a bond; and X3 is phenyl, 3,4-di-Cl-phenyl, 3,4,5-tri-OMe-phenyl, p-Me-phenyl, p-OH-phenyl, 2,4-di-F-phenyl, 2-furanyl, 2-pyridinyl, 3-pyridinyl, naphthyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 8-quinolinyl, 1-isoquinolinyl, 2-thiophene or 2-pyrimidinyl.
  • Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
      • where A1 is —C(═Y)—X2;
        • Y is O; X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 0, 1, 2 or 3;
          • Y1 is a bond; and X3 is 5-indolyl, 3-indolyl, 4-indolyl, 2-indolyl, 5-OMe-indol-3-yl, 5-OMe-indol-2-yl, 5-OH-indol-2-yl, 5-OH-indol-3-yl, 5-Br-indol-3-yl, 2-Me-indol-3-yl, 2-benzothiophene, 3-benzothiophene or 2-benzofuran.
  • Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —(CH2)m-indol-3-yl, —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl, o-OMe-phenyl or p-OMe-phenyl; R6 is H;
      • where A1 is X2;
        • X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 1, 2 or 3;
          • Y1 is S, O or a bond; and X3 is phenyl, o-OH-phenyl, p-OH-phenyl, o-F-phenyl, m-F-phenyl, p-F-phenyl, o-CF3-phenyl, o-OMe-phenyl, m-OMe-phenyl, o-nitro-phenyl, p-nitro-phenyl, 3,4-di-Cl-phenyl, 2-nitro-3-OMe-phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, 2-thiophene, 3,4,5-tri-OMe-phenyl, p-N,N-dimethylamino-phenyl, p-OCF3-phenyl, p-(3-(N,N-dimethylamino)propoxy)phenyl, 3-F-4-OMe-phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-Cl-quinolin-3-yl, 2-quinolinly, methyl, n-butyl, n-pentyl, n-hexyl, 3,3-dimethyl-butyl, benzyl, cyclohexyl or p-t-Bu-phenyl.
  • Another preferred compound of formula (I) is where R1 is H; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
      • where A1 is X2;
        • X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 1, 2 or 3;
          • Y1 is O or a bond; and X3 is phenyl, o-OH-phenyl, p-OH-phenyl, o-F-phenyl, m-F-phenyl, p-F-phenyl, o-CF3-phenyl, o-OMe-phenyl, m-OMe-phenyl, p-OMe-phenyl, o-nitro-phenyl, p-nitro-phenyl, 3,4-di-Cl-phenyl, 2-nitro-3-OMe-phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, p-phenyl-phenyl, 2-thiophene, 3,4,5-tri-OMe-phenyl, p-N,N-dimethylamino-phenyl, p-benzyloxy-phenyl, p-OCF3-phenyl, p-(3-(N,N-dimethylamino)propoxy)phenyl, 3-F-4-OMe-phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-Cl-quinolin-3-yl, 2-quinolinly, 3-indolyl, 6-methoxycarbonyl-indol-3-yl, 1-methyl-indol-3-yl, 2-methyl-indol-3-yl, methyl, n-butyl, n-pentyl, n-hexyl, 3,3-dimethyl-butyl, benzyl, cyclohexyl or p-t-Bu-phenyl.
  • Another preferred compound of formula (I) is where R1 is —(CH2)—CO-Z1; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu, —(CH2)4—NH—CO—O-benzyl, —(CH2)-phenyl or —(CH2)-indol-3-yl; R4is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
      • where Z1 is ethyl, phenyl, p-OMe-phenyl, p-phenyl-phenyl, p-Cl-phenyl, p-Br-phenyl, p-N3-phenyl, p-F-phenyl, m-nitro-phenyl, p-nitro-phenyl, p-CN-phenyl, 2,5-di-OMe-phenyl, 3,4-di-Cl-phenyl, N,N-dimethylamino-phenyl, 3-methyl-4-Cl-phenyl or naphthyl;
      • A1 is —C(═Y)—X2;
        • Y is O; X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 0;
          • Y1 is O; and X3 is t-Bu.
  • Another preferred compound of formula (I) is where R1 is —(CH2)—CO—(CH2)m-Z1 where m in the definition of R1 is 0, 1 or 2; R2 is H; R3is —(CH2)-indol-3-yl or —(CH2)4—NH—CO—O-t-Bu; R4 is H or —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl, o-OMe-phenyl, p-nitro-phenyl, p-Br-phenyl, t-Bu, —CH(CH3)2—CO—NH—(CH2)2—CO—O-t-Bu, —CH(CH3)2—CO—NH—(CH2)3-imidazol-1-yl, —CH(CH3)2—CO—NH—(CH2)2-pyridin-2-yl, CH(CH3)2—CO—NH—(CH2)3-4-morpholino, —CH(CH3)2—CO—NH—(CH2)-pyridin-4-yl or —CH(CH3)2—CO—NH—(CH2)2-N,N-diethylamino; R6 is H;
      • where Z1 is ethyl, propyl, phenyl, p-OMe-phenyl, p-Cl-phenyl, p-Br-phenyl, p-F-phenyl, p-nitro-phenyl, m-nitro-phenyl, p-CN-phenyl, p-N3-phenyl, p-phenyl-phenyl, 3-Me-4-Cl-phenyl, p-N,N-diethylamino-phenyl, 2,5-di-OMe-phenyl, 3,4-di-Cl-phenyl, 3,4-di-F-phenyl, p-OCF3-phenyl, p-benzyloxy-phenyl, p-pentyl-phenyl, 3,4,5-tri-OMe-phenyl, 3-nitro-4-Cl-phenyl, 3-Cl-4-nitro-phenyl, 3-methyl-5-chloro-benzothiophen-2-yl, 2-benzofuranyl, 3-benzothiophene, 3-phenyl-isoxazol-5-yl, 3-(2,4-di-Cl-phenyl)-isoxazol-5-yl, 3-indolyl, 5-Br-thiophen-2-yl, naphthyl,
        Figure US20070299073A1-20071227-C00015
      • A1 is —C(═Y)—X2;
        • Y is O; X2 is —(CH2)m—Y1—X3;
          • where m in the definition of X2 is 0;
          • Y1 is O; and X3 is t-Bu.
  • Another preferred compound of formula (I) is where R1 and R2 are taken together to form a compound of formula (Ib) or (Ic);
    • R3 is —(CH2)-indol-3-yl, —(CH2)-phenyl, —(CH2)4—NH—CO—O-benzyl or —(CH2)4—NH2;
    • R5 is phenyl, o-OMe-phenyl, p-OMe-phenyl, p-Br-phenyl, p-nitro-phenyl, t-Bu or —CH(CH3)2—CO—NH—(CH2)2—NH2; R6 is H;
      • R7 is ethyl, propyl, phenyl, p-OMe-phenyl, p-Cl-phenyl, p-Br-phenyl, p-F-phenyl, p-nitro-phenyl, m-nitro-phenyl, p-CN-phenyl, p-N3-phenyl, p-phenyl-phenyl, 3-Me-4-Cl-phenyl, p-N,N-diethylamino-phenyl, 2,5-di-OMe-phenyl, 3,4-di-Cl-phenyl, 3,4-di-F-phenyl, p-OCF3-phenyl, p-benzyloxy-phenyl, p-pentyl-phenyl, 3,4,5-tri-OMe-phenyl, 3-nitro-4-Cl-phenyl, 3-Cl-4-nitro-phenyl, 3-methyl-5-chloro-benzothiophen-2-yl, 2-bezofuranyl, 3-benzothiophene, 3-phenyl-isoxazol-5-yl, 3-(2,4-di-Cl-phenyl)-isoxazol-5-yl, 3-indolyl, 5-Br-thiophen-2-yl, naphthyl,
        Figure US20070299073A1-20071227-C00016
  • In another aspect, the present invention is directed to a compound of the formula (II),
    Figure US20070299073A1-20071227-C00017

    the racemic-diastereomeric mixtures and optical isomers of said compound of formula (II), the pharmaceutically-acceptable salts or prodrugs thereof or a pharmaceutically acceptable salt of said prodrug,
    wherein
    • Figure US20070299073A1-20071227-P00900
      represents an optional bond;
    • R1 is H, —(CH2)m—C(O)—(CH2)m-Z1, —(CH2)m-Z1, —(CH2)m—O-Z1 or —(C0-C6)alkyl-C(O)—NH—(CH2)m-Z3;
      • Z1 is an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazolyl, indolyl,
        Figure US20070299073A1-20071227-C00018
    • R2 is H or (C1-C6)alkyl;
    • or R1 and R2 are taken together with the nitrogen atoms to which they are attached to form a compound of formula (IIa), (IIb) or (IIc),
      Figure US20070299073A1-20071227-C00019
    • R3 is —(CH2)m-E-(CH2)m-Z2;
      • E is O, S, —C(O)—, —C(O)—O—, —NH—C(O)—O—, —N(C1-C6)alkyl-C(O)—O— or a bond;
      • Z2 is H, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, (C1-C12)alkylguanidino, or an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl and naphthyl;
    • R4 is H or —(CH2)m-A1;
      • A1 is —C(═Y)—N(X1X2), —C(═Y)—X2, —C(═NH)—X2 or X2;
        • Y is O or S;
        • X1 is H, (C1-C12)alkyl, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m—N-di-(C1-C6)alkyl or —(CH2)m-aryl;
        • X2 is —(CH2)m—Y1—X3 or optionally substituted (C1-C12)alkyl;
          • Y1 is O, S, NH, C═O, (C2-C12)alkenyl having one or more double bonds, —NH—CO—, —CO—NH—, —NH—CO—O—(CH2)m—, —C≡C—, SO2 or a bond;
          • X3 is H, an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)alkoxy, aryloxy, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —CH-di-(C1-C12)alkoxy, pyrrolidinyl, pyridinyl, thiophene, imidazolyl, piperidinyl, piperazinyl, benzothiazolyl, furanyl, indolyl, morpholino, benzo[b]furanyl, quinolinyl, isoquinolinyl, —(CH2)m-phenyl, naphthyl, fluorenyl, phthalamidyl, pyrimidinyl,
            Figure US20070299073A1-20071227-C00020
        • or X1 and X2 are taken together with the nitrogen to which they are attached to form an optionally substituted moiety selected from the group consisting of thiazolyl,
          Figure US20070299073A1-20071227-C00021
            • Y2 is CH—X4, N—X4, —C(X4X4), O or S;
            • X4 for each occurrence is independently H or —(CH2)m—Y3—X5;
            •  Y3 is —C(O)—, —C(O)O— or a bond;
            •  X5 is hydroxy, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, or an optionally substituted moiety selected from the group consisting of aryl, aryl(C1-C4)alkyl, furanyl, pyridinyl, indolyl, piperidinyl, —CH(phenyl)2,
              Figure US20070299073A1-20071227-C00022
    • R5 is (C1-C12)alkyl, (C0-C6)alkyl-C(O)—O-Z5, (C0-C6)alkyl-C(O)—NH—(CH2)m-Z3 or optionally substituted aryl;
      • Z3 for each occurrence is independently amino, (C1-C12)alkylamino, amino(C1-C12)alkyl, (C5-C7)cycloalkylamino, amino(C5-C7)cycloalkyl, N-(C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —NH—C(O)—O—(CH2)m-phenyl, —NH—C(O)—O—(CH2)m—(C1-C6)alkyl,
        Figure US20070299073A1-20071227-C00023
      • or an optionally substituted moiety selected from the group consisting of imidazolyl, pyridinyl, morpholino, piperidinyl, piperazinyl, pyrazolidinyl, furanyl, phenyl, indolyl and thiophene, provided that when m is 0 in the formula for R5 then Z3 is not —NH—C(O)—O—(CH2)m-phenyl or —NH—C(O)—O—(CH2)m-(C1-C6)alkyl;
    • R6 is H or (C1-C6)alkyl;
    • R7 is (C1-C12)alkyl or —(CH2)m-Z4;
      • Z4 is an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, indolyl, thiophene, benzo[b]furan, benzo[b]thiophene, isoxazolyl,
        Figure US20070299073A1-20071227-C00024
      • Z5 is H, (C1-C12)alkyl, or —(CH2)m-aryl;
    • wherein an optionally substituted moiety is optionally substituted by one or more substituents, each independently selected from the group consisting of Cl, F, Br, I, CF3, CN, N3, NO2, OH, SO2NH2, —OCF3, (C1-C12)alkoxy, —(CH2)m-phenyl-(X6)n, —S-phenyl-(X6)n, —S—(C1-C12)alkyl, —O—(CH2)m-phenyl-(X6)n, —(CH2)m—C(O)—O—(C1-C6)alkyl, —(CH2)m—C(O)—(C1-C6)alkyl, —O—(CH2)m—NH2, —O—(CH2)m—NH—(C1-C6)alkyl, —O—(CH2)m—N-di-((C1-C6)alkyl), —(C0-C12)alkyl-(X6)n and —(CH2)m-phenyl-X7;
      • X6 for each occurrence is independently selected from the group consisting of hydrogen, Cl, F, Br, I, NO2, N3, CN, OH, —CF3, —OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, —(CH2)m—NH2, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m—N-di-((C1-C6)alkyl) and —(CH2)m-phenyl;
      • X7 is —NH—C(═NH.HI)—X8, wherein X8 is thiophene, (C1-C6)alkyl or phenyl;
    • m for each occurrence is independently 0 or an integer from 1 to 6; and
    • n for each occurrence is independently an integer from 1 to 5;
    • provided that:
    • (a) when R5 is (C1-C12)alkyl, or —C(O)—O-Z5 and Z5 is (C1-C12)alkyl or optionally substituted aryl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl or Z4 and Z4 is thiophene or optionally substituted phenyl, then R3 is not —C(O)—O—(CH2)m-Z where m is 0 and Z is H or (C1-C12)alkyl or where m is 1 to 6 and Z is H;
    • (b) when R5 is (C1-C12)alkyl or optionally substituted phenyl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl and R3 is —O—(CH2)-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl, and naphthyl; and
    • (c) when R5 is H or (C1-C12)alkyl; R6 is (C1-C6)alkyl; R7 is (C1-C12)alkyl; and R3 is —O-Z2 or —S-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, thiophene, benzothienyl and indolyl.
  • A preferred group of compounds of formula (II) have the following formula:
    Figure US20070299073A1-20071227-C00025

    wherein
    • Z3 is —CH2—NH2, —(CH2)2—NH2, —(CH2)3—NH2 or
      Figure US20070299073A1-20071227-C00026
    • X1 is —(CH2)2—N(CH3)2 and X2 is benzyl; or
    • X1 and X2 are taken together with the nitrogen atom to which they are attached, to form
      Figure US20070299073A1-20071227-C00027
  • Another preferred group of compounds of formula (II) have the following formula:
    Figure US20070299073A1-20071227-C00028
    • X1 is —(CH2)2—N(CH3)2 and X2 is benzyl; or
    • X1 and X2 are taken together with the nitrogen atom to which they are attached, to form
      Figure US20070299073A1-20071227-C00029
  • Yet another preferred group of compounds of formula (II) have the following formula:
    Figure US20070299073A1-20071227-C00030

    wherein X2 is p-chloro-phenyl, p-methoxy-phenyl, 2,4-difluoro-phenyl or thienyl.
  • Still another preferred group of compounds of formula (II) have the following formula:
    Figure US20070299073A1-20071227-C00031

    wherein X2 is p-chloro-phenyl, p-methoxy-phenyl, phenyl or thienyl.
  • Further still a preferred compound of formula (II) has the following formula:
    Figure US20070299073A1-20071227-C00032
  • Further still another preferred compound of formula (II) has the following formula:
    Figure US20070299073A1-20071227-C00033
  • Further still another preferred group of compounds of formula (II) have the following formula:
    Figure US20070299073A1-20071227-C00034

    and R7 is m-nitro-phenyl or 2-phenyl-ethyl; or
    Figure US20070299073A1-20071227-C00035

    and R7 is 3,4-dichlorophenyl or
    Figure US20070299073A1-20071227-C00036

    and R7 is 3,4-dichlorophenyl.
  • In another aspect, this invention is directed to a pharmaceutical composition comprising one or more of a compound of formula (I) or formula (II), as defined hereinabove, and a pharmaceutically acceptable carrier.
  • In another aspect, the present invention is directed to a method of eliciting an agonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.
  • In another aspect, the present invention is directed to a method of eliciting an antagonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.
  • In another aspect, the present invention is directed to a method of binding one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.
  • In another aspect, the present invention is directed to a method of treating acromegaly, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux, Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, polycystic ovary disease, cancer, cancer cachexia, hypotension, postprandial hypotension, panic attacks, GH secreting adenomas or TSH secreting adenomas, in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.
  • In another aspect, the present invention is directed to a method of treating diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon, Nephropathy, peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis, gastrointestinal hormone secreting tumors, angiogenesis, inflammatory disorders, chronic allograft rejection, angioplasty, graft vessel bleeding or gastrointestinal bleeding in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to said subject.
  • In another aspect, the present invention is directed to a method of inhibiting the proliferation of helicobacter pylori in a subject in need thereof, which comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, to said subject.
  • DETAILED DESCRIPTION OF THE INVENTION
  • One of ordinary skill will recognize that certain substituents listed in this invention may have reduced chemical stability when combined with one another or with heteroatoms in the compounds. Such compounds with reduced chemical stability are not preferred.
  • In general, the compounds of Formula I or II can be made by processes which include processes known in the chemical arts for the production of compounds. Certain processes for the manufacture of Formula I or II compounds are provided as further features of the invention and are illustrated by the following reaction schemes and examples.
  • In the above structural formulae and throughout the instant application, the following terms have the indicated meanings unless expressly stated otherwise:
  • The alkyl groups are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
  • When the definition “C0-alkyl” occurs in the definition, it means a single covalent bond.
  • The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • The term halogen or halo is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
  • The term cycloalkyl is intended to include a mono-cycloalkyl group or a bi-cycloalkyl group of the indicated carbon number known to those of skill in the art.
  • The term aryl is intended to include aromatic rings known in the art, which can be mono-cyclic, bi-cyclic or tri-cyclic, such as phenyl, naphthyl and anthracene.
  • The term heterocycle includes mono-cyclic, bi-cyclic and tri-cyclic systems having one or more heteroatoms, such as oxygen, nitrogen and/or sulfur. The ring systems may be aromatic, for example pyridine, indole, quinoline, pyrimidine, thiophene (also known as thienyl), furan, benzothiophene, tetrazole, dihydroindole, indazole, N-formylindole, benzimidazole, thiazole, and thiadiazole. The ring systems may be non-aromatic, for example pyrrolidine, piperidine, morpholine and the like.
  • The chemist of ordinary skill will recognize that certain combinations of heteroatom-containing substituents listed in this invention define compounds which will be less stable under physiological conditions. Accordingly, such compounds are less preferred.
  • When a chemical structure as used herein has an arrow emanating from it, the arrow indicates the point of attachment. For example, the structure
    Figure US20070299073A1-20071227-C00037

    is a pentyl group. When an arrow is drawn through a cyclic moiety, the arrow indicates that the cyclic moiety can be attached at any of the available bonding points, for example
    Figure US20070299073A1-20071227-C00038

    means that the phenyl can be bonded ortho, meta or para to the X group. When an arrow is drawn through a bi-cyclic or a tri-cyclic moiety, the arrow indicates that the bi-cyclic or tri-cyclic ring can be attached at any of the available bonding points in any of the rings, for example
    Figure US20070299073A1-20071227-C00039

    means that the indole is bonded either through the phenyl portion of the ring or the nitrogen containing ring portion.
  • The compounds of the instant invention have at least one asymmetric center as noted by the asterisk in the structural formula (I), (Ia) and (Ib), above. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers, racemic mixtures or diastereomeric mixtures thereof, be included within the scope of the instant invention.
  • The instant compounds can be generally isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, acetic, propionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methane sulfonic and the like. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter-ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
  • The pharmaceutically acceptable salts are formed by taking about 1 equivalent of a compound of formula (I) or (II) and contacting it with about 1 equivalent of the appropriate corresponding acid of the salt which is desired. Work-up and isolation of the resulting salt is well-known to those of ordinary skill in the art.
  • As is known in the art, agonists and antagonists of somatostatin are useful for treating a variety of medical conditions and diseases, such as inhibition of H. pylori proliferation, acromegaly, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux and in treating endocrinological diseases and/or conditions, such as Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, and polycystic ovary disease; in treating various types of cancer such as thyroid cancer, hepatome, leukemia, meningioma and conditions associated with cancer such as cancer cachexia; in the treatment of such conditions as hypotension such as orthostatic hypotension and postprandial hypotension and panic attacks; GH secreting adenomas (Acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 subtype receptor has been associated with treating prolactin secreting adenomas. Other indications associated with activation of the somatostatin subtypes are inhibition of insulin and/or glucagon and more particularly diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding. Somatostatin agonists can also be used for decreasing body weight in a patient. Accordingly, the compounds of the instant invention are useful for the foregoing methods.
  • Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of Formula (I) or (II) in association with a pharmaceutically acceptable carrier.
  • The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.
  • Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
  • Further, a compound of this invention can be administered in a sustained release composition such as those described in the following patents. U.S. Pat. No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester. U.S. Pat. No. 5,595,760 teaches sustained release compositions comprising a bioactive agent-in a gelable form. U.S. application Ser. No. 08/929,363 filed Sep. 9, 1997, teaches polymeric sustained release compositions comprising a bioactive agent and chitosan. U.S. application Ser. No. 08/740,778 filed Nov. 1, 1996, teaches sustained release compositions comprising a bioactive agent and cyclodextrin. U.S. application Ser. No. 09/015,394 filed Jan. 29, 1998, teaches absorbable sustained release compositions of a bioactive agent. The teachings of the foregoing patents and applications are incorporated herein by reference.
  • In general, an effective dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment, all of which are within the realm of knowledge of one of ordinary skill in the art. Generally, dosage levels of between 0.0001 to 100 mg/kg of body weight daily are administered to humans and other animals, e.g., mammals.
  • A preferred dosage range is 0.01 to 10.0 mg/kg of body weight daily, which can be administered as a single dose or divided into multiple doses.
  • Compounds of the instant invention can be and were assessed for its ability to bind to a somatostatin subtype receptor according to the following assays. Human somatostatin subtype receptor binding studies:
  • The affinity of a compound for human somatostatin subtype receptors 1 to 5 (sst1, sst2, sst3, sst4 and sst5, respectively) is determined by measuring the inhibition of [125I-Tyr11]SRIF-14 binding to CHO—K1 transfected cells.
  • The human sst1 receptor gene was cloned as a genomic fragment. A 1.5 Kb PstI-XmnI segment containing 100 bp of the 5′-untranslated region, 1.17 Kb of the entire coding region, and 230 bp of the 3′-untranslated region was modified by the Bg1II linker addition. The resulting DNA fragment was subcloned into the BamHI site of a pCMV-81 to produce the mammalian expression plasmid (provided by Dr. Graeme Bell, Univ. Chicago). A clonal cell line stably expressing the sst1 receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method (1). The plasmid pRSV-neo (ATCC) was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.
  • The human sst2 somatostatin receptor gene, isolated as a 1.7 Kb BamHI-HindIII genomic DNA fragment and subcloned into the plasmid vector pGEM3Z (Promega), was kindly provided by Dr. G. Bell (Univ. of Chicago). The mammalian cell expression vector is constructed by inserting the 1.7 Kb BamH1-HindII fragment into compatible restriction endonuclease sites in the plasmid pCMV5. A clonal cell line is obtained by transfection into CHO—K1 cells using the calcium phosphate co-precipitation method. The plasmid pRSV-neo is included as a selectable marker.
  • The human sst3 was isolated at genomic fragment, and the complete coding sequence was contained within a 2.4 Kb BamHI/HindIII fragment. The mammalian expression plasmid, pCMV-h3 was constructed by inserting the a 2.0 Kb NcoI-HindIII fragment into the EcoR1 site of the pCMV vector after modification of the ends and addition of EcoR1 linkers. A clonal cell line stably expressing the sst3 receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.
  • The human sst4 receptor expression plasmid, pCMV-HX was provided by Dr. Graeme Bell (Univ. Chicago). The vector contains the 1.4 Kb NheI-NheI genomic fragment encoding the human sst4, 456 bp of the 5′-untranslated region and 200 bp of the 3′-untranslated region, clone into the XbaI/EcoR1 sites of PCMV-HX. A clonal cell line stably expressing the sst4 receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture.
  • The human sst5 gene was obtained by PCR using a λ genomic clone as a template, and kindly provided by Dr. Graeme Bell (Univ. Chicago). The resulting 1.2 Kb PCR fragment contained 21 base pairs of the 5′-untranslated region, the full coding region, and 55 bp of the 3′-untranslated region. The clone was inserted into EcoR1 site of the plasmid pBSSK(+). The insert was recovered as a 1.2 Kb HindIII-XbaI fragment for subcloning into pCVM5 mammalian expression vector. A clonal cell line stably expressing the SST5 receptor was obtained by transfection into CHO—K1 cells (ATCC) using the calcium phosphate co-precipitation method. The plasmid pRSV-neo (ATCC) was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 media containing 0.5 mg/ml of G418 (Gibco), ring cloned, and expanded into culture. CHO—K1 cells stablie expressing one of the human sst receptor are grown in RPMI 1640 containing 10% fetal calf serum and 0.4 mg/ml geneticin. Cells are collected with 0.5 mM EDTA, and centrifuged at 500 g for about 5 min. at about 4° C. The pellet is resuspended in 50 mM Tris, pH 7.4 and centrifuged twice at 500 g for about 5 min. at about 4° C. The cells are lysed by sonication and centrifuged at 39000 g for about 10 min. at about 4° C. The pellet is resuspended in the same buffer and centrifuged at 50000 g for about 10 min. at about 4° C. and membranes in resulting pellet are stored at −80° C.
  • Competitive inhibition experiments of [125I-Tyr11]SRIF-14 binding are run in duplicate in polypropylene 96 well plates. Cell membranes (10 μg protein/well) are incubated with [125I-Tyr11]SRIF-14 (0.05 nM) for about 60 min. at about 37° C. in 50 mM HEPES (pH 7.4), 0.2% BSA, 5 mM MgCl2, 200 KIU/ml Trasylol, 0.02 mg/ml bacitracin and 0.02 mg/ml phenylmethylsulphonylfluoride.
  • Bound from free [125I-Tyr11]SRIF-14 is separated by immediate filtration through GF/C glass fiber filter plate (Unifilter, Packard) presoaked with 0.1% polyethylenimine (P.E.I.), using Filtermate 196 (Packard) cell harvester. Filters are washed with 50 mM HEPES at about 0-4° C. for about 4 sec. and assayed for radioactivity using Packard Top Count.
  • Specific binding is obtained by subtracting nonspecific binding (determined in the presence of 0.1 μM SRIF-14) from total binding. Binding data are analyzed by computer-assisted nonlinear regression analysis (MDL) and inhibition constant (Ki) values are determined.
  • The determination of whether a compound of the instant invention is an agonist or an antagonist is determined by the following assay.
  • Functional Assay: Inhibition of cAMP Intracellular Production:
  • CHO—K1 Cells expressing human somatostatin (SRIF-14) subtype receptors are seeded in 24-well tissue culture multidishes in RPMI 1640 media with 10% FCS and 0.4 mg/ml geneticin. The medium is changed the day before the experiment.
  • Cells at 105 cells/well are washed 2 times by 0.5 ml and fresh RPMI with 0.2% BSA supplemented with 0.5 mM (1) 3-isobutyl-1-methylxanthine (IBMX) and incubated for about 5 min at about 37° C.
    • Cyclic AMP production is stimulated by the addition of 1 mM forskolin (FSK) for about 15-30 minutes at about 37° C.
    • The agonist effect of a compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (10−12 M to 10−6 M) and a test compound (10−10 M to 10−5 M).
    • The antagonist effect of a compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (1 to 10 nM) and a test compound (10−10 M to 10−5 M).
  • The reaction medium is removed and 200 ml 0.1 N HCl is added. cAMP is measured using radioimmunoassay method (Kit FlashPlate SMP001A, New England Nuclear).
  • The compounds of the instant invention are synthesized according to the following procedures and examples.
  • Synthesis of Bromoketones
  • General Procedure: Two different methods can be applied: starting either from a carboxylic acid or an arylketone.
  • First method: Starting from a carboxylic acid (Macholan, L.; Skursky, L., Chem listy, 1955, 49, 1385-1388. Bestman, H. J., Seng, F., Chem. Ber., 1963, 96, 465-469).
    Figure US20070299073A1-20071227-C00040
  • A carboxylic acid is first converted into an acyl chloride using oxalyl chloride or thionyl chloride or activated as a mixed anhydride with an alkylchloroformate (isobutylchloroformate (Krantz, A., Copp, L. J., Biochemistry, 1991, 30, 4678-4687) or ethylchloroformate (Podlech, J., Seebach, D., Liebigs Ann., 1995, 1217-1228)) in the presence of a base (triethylamine or N-methyl morpholine).
  • The activated carboxyl group is then transformed into a diazoketone using ethereal diazomethane or trimethylsilyldiazomethane (Aoyama, T., Shiori, T., Chem. Pharm. Bull., 1981, 29, 3249-3255) in an aprotic solvent such as diethyl ether, tetrahydrofuran or acetonitrile.
  • The bromination is then carried out using a brominating agent such as HBr in acetic acid, hydrobromic acid in water or in diethyl ether.
  • Preparation 1 1-Bromo-3-(4-chloro-phenoxy)-3-methyl-butan-2-one
  • Figure US20070299073A1-20071227-C00041
  • To a solution of chloro-4-phenoxy-2-isobutyric acid (2.15 g, 10 mmol) in 10 ml of anhydrous dichloromethane at about 0° C. were added oxalyl chloride (5.5 ml, 11 mmol of a 2M solution in dichloromethane) and DMF (2 drops, catalytic amount) via a septum under nitrogen atmosphere. The solution was stirred and allowed to warm up to room temperature over about 3 hrs. Concentration under reduced pressure afforded the crude acid chloride which was used directly without further purification. The acylchloride was added dropwise at about 0° C. to a solution of TMSCHN2 (11 ml, 22 mmol) in THF-acetonitrile (1:1, 10 ml). The mixture was stirred at about 25° C. for about 1 hour and then evaporated in vacuo.
  • A solution of the diazoketone in dichloromethane (10 ml) was added dropwise during about 10 minutes to a vigorously stirred mixture of concentrated hydrobromic acid (5 ml) in dichloromethane (20 ml). Nitrogen was evolved and a slight temperature rise occurred. After stirring for about a further 10 min., the mixture was diluted and the organic layer was washed with water (3 times 20 ml), dried over magnesium sulfate and evaporated. Flash chromatography of the residue eluting with AcOEt/Heptane (1:4) afforded the desired product with a yield of 79% (2.3 g).
  • 1H-NMR in CDCl3 (100 MHz) δ: 7.05 (m, 4 H, arom. H), 4.41 (s, 2 H, CH2), 1.53 (s, 6H, 2 CH3).
  • Preparations 2-6
  • The following compounds were prepared analogously to the procedure described for Preparation 1:
    Figure US20070299073A1-20071227-C00042
    Prep. # R Yield
    2
    Figure US20070299073A1-20071227-C00043
    78%
    3
    Figure US20070299073A1-20071227-C00044
    60%
    4
    Figure US20070299073A1-20071227-C00045
    10%
    5
    Figure US20070299073A1-20071227-C00046
    79%
    6
    Figure US20070299073A1-20071227-C00047
    41%

    * Compounds already described in literature.

    Second Method: Starting from a Methyl Ketone
    Figure US20070299073A1-20071227-C00048
  • A methyl ketone is converted to a bromoketone by using different brominating agents:
    • CuBr2 (King, L. C., Ostrum, G. K., J. Org. Chem., 1964, 29, 3459-3461) heated in AcOEt or dioxane.
    • N-bromosuccinimide in CCl4.
    • Bromine in glacial acetic acid or sulfuric acid.
    • Phenyltrimethylammonium tribromide (Sanchez, J. P., Parcell, R. P., J. Heterocyclic Chem., 1988, 25, 469-474) at 20-80° C. in an aprotic solvent such as THF.
    • Use of a polymer supported brominating agent such as perbromide on Amberlyst A-26, poly(vinylpyridinium hydrobromide perbromide) resin (Frechet, J. M. J., Farrall, M. J., J. Macromol. Sci. Chem., 1977, 507-514) in a protic solvent such as methanol at about 20-35° C. for about 2-100 h.
    Preparation 7 1-Bromo-2-(3,4,5-trimethoxy-phenyl)-ethanone
  • Figure US20070299073A1-20071227-C00049
  • To a solution of 3,4,5-trimethoxyacetophenone (2.1 g, 10 mmol) in methanol (30 ml) was added pyridine hydrobromide perbromide polymer (1.4 eq). The resulting mixture was shaken at room temperature for about 2 hours and the reaction was stopped by filtration. The polymer was washed with methanol and the filtrate was evaporated in vacuo. The product was then purified by flash chromatography (AcOEt/Heptane, 1:4) affording 1.5 g (53% ) of a white solid.
  • 1H-NMR in CDCl3 (100 MHz) δ: 7.2 (s, 2H, H arom.), 4.4 (s, 2H, CH2), 3.9 (m, 9H, 3 OCH3).
  • Preparations 8-17
  • The following compounds were prepared analogously to the procedure described for Preparation 7:
    Figure US20070299073A1-20071227-C00050
    Reaction
    Prep. # R time (h) Yield
    8
    Figure US20070299073A1-20071227-C00051
    8 78
    9
    Figure US20070299073A1-20071227-C00052
    7 72
    10
    Figure US20070299073A1-20071227-C00053
    85 62
    11
    Figure US20070299073A1-20071227-C00054
    2 62
    12
    Figure US20070299073A1-20071227-C00055
    10 56
    13
    Figure US20070299073A1-20071227-C00056
    2 53
    14
    Figure US20070299073A1-20071227-C00057
    8.5 27
    15
    Figure US20070299073A1-20071227-C00058
    3 43
    16
    Figure US20070299073A1-20071227-C00059
    3 77
    17
    Figure US20070299073A1-20071227-C00060
    3 95

    * Compound already described in literature.
  • Synthesis of Imidazolyl Compounds
  • General Procedure: An amino acid is transformed to its cesium salt using cesium carbonate in a polar solvent such as DMF/H2O (1:1) or EtOH/H2O (1:1). An ester is then obtained using an appropriate bromoketone in a polar aprotic solvent such as dry DMF. The cesium bromide formed is filtered off and ammonium acetate is added in an aprotic solvent having a high boiling point such as xylene or toluene or in a protic acidic solvent such as acetic acid. The mixture is refluxed using a Dean-Stark trap for about 0.5-10 hours. In the scheme immediately below, PG is a protecting group, preferably a carbamate, such as t-Boc or benzyl carbamate.
    Figure US20070299073A1-20071227-C00061
  • EXAMPLE 1 2-{(1S)-1-[tertbutoxycarbonylamino]-2-[(1H)-indol-3-yl]ethyl}-4-(2-methoxyphenyl)-1H-imidazole
  • Figure US20070299073A1-20071227-C00062
  • A solution of Boc-(D,L)-Trp-OH (10 g, 32.8 mmol) and cesium carbonate (0.5 eq., 5.34 g) in EtOH/H2O (1:1, 70 ml) was shaken for about 30 minutes at room temperature, and then concentrated in vacuo at about 40° C.
  • To the resulting salt in 40 mL of dry DMF was added 40 ml of a solution of 2-bromo-2′-methoxyacetophenone (7.66 g, 1 eq.) in dry DMF. The mixture was stirred for about 1 hr at room temperature under argon and then concentrated under reduced pressure. Ethyl acetate was added (100 ml), the mixture filtered, and the CsBr washed with ethyl acetate. The filtrate was then concentrated under reduced pressure.
  • A solution of the foregoing filtrate and ammonium acetate (50.5 g, 20 eq.) in xylene (240 ml) was refluxed for about 3 hours at about 150° C. Excess NH4OAc and H2O were removed using a Dean-Stark trap. The progress of the reaction was monitored by t.l.c. (eluent: CH2Cl2:MeOH, 95:5). The mixture was then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous NaHCO3 solution until basic pH, and with brine until neutral pH. The organic layer was then dried over MgSO4, and concentrated under reduced pressure.
  • Purification of the resulting residue by flash chromatography (eluent: CH2Cl2:MeOH, 95:5) afforded the desired compound (8.7 g, yield: 61%).
  • 1H-NMR (CDCl3, 100 MHz) δ: 8.00 (s, 1H, NH), 7.80 (m, 2H, arom. H), 7.20 (m, 9H, arom. H, NH), 5.40 (m, 1H, NH), 5.10 (m, 1H, CH), 3.80 (s, 3H, OCH3), 3.50 (m, 2H, CH2), 1.50 (s, 9H, 6 CH3). LC/MS: m/z=433.3 (M+H).
  • EXAMPLE 2 N-[2-tertbutoxycarbonylamino ethyl]-2-{2-[(1S)-1-(tertbutoxycarbonylamino)-2-(1H)-indol-3-yl)ethyl]-1H-imidazol-4-yl}-isobutyramide
  • Figure US20070299073A1-20071227-C00063

    A solution of the 2-{2-[(1S)-1-(tertbutoxycarbonylamino)-2-(indol-3-yl)ethyl]-1H-imidazol-4-yl}-2-methyl-propionic acid-methyl ester 1 (2.6 g, 6 mmol), (prepared according to the procedure described in Example 1) and LiOH.H2O (1.7 g, 6.6 eq.) in THF (50 ml) were stirred at about 80° C. for about 3 hours. The progress of the reaction was monitored by t.l.c. (CH2Cl2:MeOH, 95:5). The resulting mixture was then concentrated in vacuo. About 50 ml of water was added to the residue which was then acidified with glacial acetic acid until about pH 5. The product of the reaction was then extracted with ethyl acetate (3×50 ml) and washed with brine until neutral pH. The organic layer was dried with MgSO4, and concentrated under reduced pressure. The resulting intermediate 2 was obtained after crystallization in diethyl ether with a yield of 80% (2 g). 1H-NMR (400 MHz, DMSO) δ: 10.9 (s, 1H, NH), 7.1 (m, 7H, arom. H, NH), 5.00 (m, 1H, CH), 3.3 (m, 2H, CH2), 1.3 (m, 15H, 5 CH3). LC/MS: m/z=525.1 (M+TFA), m/z=413.2 (M+H).
  • The 2-{2-[(1S)-1-(tertbutoxycarbonylamino)-2-[(1H)-indol-3-yl]ethyl]-1H-imidazol-4-yl}-2-methyl-propionic acid 2 can be activated preferentially by carbonyldiimidazole in an aprotic solvent such as THF or DMF at about 20-100° C. for about 1-4 hours.
  • A solution of the acid 2 (1 g, 2.4 mmol) and carbonyldiimidazole (0.39 g, 2.4 mmol) in dry THF (20 ml) was shaken for about 1 hour at room temperature (25° C.).
  • N-Boc-ethylene-diamine (0.43 g, 2.7 mmol) was added and the mixture was shaken for about 1 hour at about 25° C.
  • The mixture was diluted in ethyl acetate (100 ml) and washed with saturated aqueous NaHCO3 solution (2×50 ml) and brine until neutral pH. The organic layer was then dried over MgSO4, and concentrated in vacuo.
  • Purification of the resulting residue by flash-chromatography (in CH2Cl2:MeOH, 95:5) afforded the desired product 3 with a yield of 77% (1 g).
  • 1H-NMR (400 MHz, DMSO) δ: 11.6 (s, 1H, NH), 10.7 (s, 1H, NH), 7.00 (m, 9H, arom. H, NH), 4.8 (m, 1H, CH), 3.00 (m, 6H, 3 CH2), 1.3 (m, 24H, 8 CH3). LC/MS: m/z=667.3 (M+TFA), 555.3 (M+H).
  • EXAMPLES 3-1178
  • The following compounds were prepared analogously to the procedure described for Example 1 or 2 using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (PG (2 substituents)R3 (12 substituents)(R5 (49 substituents))=1176.
    Figure US20070299073A1-20071227-C00064

    PG can also be hydrogen in the foregoing formula,
    Figure US20070299073A1-20071227-C00065
    Figure US20070299073A1-20071227-C00066
    Figure US20070299073A1-20071227-C00067
  • Synthesis of Amides from Imidazoyl Intermediates
  • Figure US20070299073A1-20071227-C00068
  • General procedure: Carboxylic acids are activated overnight at room temperature with carbonyldiimidazole in an aprotic solvent such as chloroform, THF or THF/DMF before addition of an amino starting material as shown above followed by a further 12-15 hours of stirring. The excess acylating agent is quenched with aminomethylated resin for about 12-15 hours and then purified on silica gel pad with dichloromethane or ethyl acetate as eluent.
  • For protected basic derivatives (R3═(CH2)4NHBoc and/or X2 containing NHBoc group), the corresponding deprotected compounds were obtained after treatment under acidic condition (DCM/TFA 10%) to remove the Boc group.
  • EXAMPLE 1179 2-{(1S)-1-[(2-Furanyl)carbonylamino]-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (C24H20N4O2, MW=396.45)
  • Figure US20070299073A1-20071227-C00069
  • 2-Furancarboxylic acid (12.6 mg, 0.11 mmol) was activated overnight at about 22° C. with carbonyldiimidazole (0.11 mmol, 0.2M in chloroform). 2-{(1S)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (0.1 mmol, 0.5M in chloroform) was added to the media and the mixture was stirred for about 12 hours at about 22° C. Aminomethylated resin was then added (50-60 mg, 1.2 mmol/g, Novabiochem) in order to quench the excess of acylating agent for about 12 hours. Purification on silica gel pad (200 mg, Alltech) with ethyl acetate as eluent gave the expected product (37.2 mg, 94%). 1H-NMR (CDCl3, 100 MHz) δ: 8.36 (br s, 1H); 7.67-6.4 (m, 16H); 5.48 (qd, J=7.1 Hz, 1H); 3.6 (ABX system, 2H). LC/MS: m/z=397 (M+H).
  • EXAMPLES 1180-3615
  • The following compounds were prepared analogously to the procedure described for Example 1179 using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 and X2, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (4 substituents))(R5 (7 substituents))(X2 (87 substituents))=2436.
    Figure US20070299073A1-20071227-C00070
    Figure US20070299073A1-20071227-C00071
    Figure US20070299073A1-20071227-C00072
  • Synthesis of Ureas and Thioureas from Imidazoyl Intermediates
  • From Isocyanates and Isothiocyanates
    Figure US20070299073A1-20071227-C00073
  • General procedure: Isocyanates or isothiocyanates are shaken overnight at room temperature with an imidazoyl intermediate in an aprotic solvent like dichloromethane, chloroform or chloroform/DMF. The reaction is quenched by addition of aminomethylated resin for about 12-15 hours and purified on silica gel pad with ethyl acetate as eluent.
  • For protected basic derivatives (R3═(CH2)4NHBoc), the corresponding deprotected compounds were obtained after treatment under acidic condition (DCM/TFA 10%) to remove the Boc group.
  • EXAMPLE 3616 2-{(1R)-1-[(2,4-Difluorophenyl)aminocarbonylamino]-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (C26H21F2N5O, MW=457.49)
  • Figure US20070299073A1-20071227-C00074
  • 2,6-Difluorophenylisocyanate (36 μL, 0.3 mmol) and 2-{(1R)-1-amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (60.4 mg, 0.2 mmol) were stirred overnight in 2 mL of anhydrous dichloromethane. Filtration and purification by flash chromatography on silica gel (ethyl acetate/heptane 1:1 as eluent) afforded the expected product as a white powder (27 mg, 30%). 1H-NMR (DMSO D6, 400 MHz) δ: 12.03 (s, 1H); 10.77 (s, 1H); 8.47 (s, 1H); 8.1 (dd, 1H); 7.8-6.92 (m, 14H); 5.11 (dd, J=7 and 14 Hz, 1H); 3.3 (m, 2H). LC/MS: m/z=458 (M+H).
  • EXAMPLES 3617-4435
  • The following compounds were prepared analogously to the procedure described for Example 3616, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5, and X2 with Y is O or X2 with Y is S, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (3 substituents))(R5 (7 substituents))(X2 (39 substituents))=819.
    Figure US20070299073A1-20071227-C00075
    Figure US20070299073A1-20071227-C00076

    From Carbamate Intermediates and Primary and Secondary Amines:
  • General Procedure: The preparation of carbamate intermediates is described in the literature (Takeda, K. et al., Tetrahedron Letters 1983, 24, 4569-4572; Nimura, N. et al., Anal. Chem. 1986, 58, 2372-2375) from amino derivatives and N,N′-disuccinimidylcarbonate in acetonitrile at room temperature.
    Figure US20070299073A1-20071227-C00077
  • EXAMPLE 4436 2-{(1R)-1-[(2,5-Dioxo-1-pyrrolidinyloxy)carbonylamino]-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (C24H21N5O4, MW=443.46)
  • Figure US20070299073A1-20071227-C00078
  • 302.4 mg (1 mmol) of 2-{(1R)-1-amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole previously dissolved in 20 mL of anhydrous acetonitrile was added dropwise to a solution of N,N′-disuccinimidylcarbonate (528 mg, 2 mmol, DSC) in 20 mL of anhydrous acetonitrile during 1.5 hour. After a further 4 hours of stirring at room temperature, the solvent was evaporated in vacuo and the residue redissolved in 30 mL of chloroform. Excess DSC was then discarded and the organic layer washed with water (4×30 mL), dried over MgSO4 and concentrated to obtain a brown solid (215 mg, 49%). 1H-NMR (CDCl3, 100 MHz) δ: 8.22 (br s, 1H); 8.1-7.08 (m, 12H); 5.9 (br s, 1H); 4.97 (dd, J=3.6 and 9.3 Hz, 1H); 3.75 (dd, J=3.6 and 14.8 Hz, 1H); 3.06 (dd, J=9.7 and 14.6 Hz, 1H); 2.96 (s, 2H); 2.89 (s, 2H). LC/MS: m/z=329 ((M+H)-SuOH.
    Figure US20070299073A1-20071227-C00079
  • General procedure: A primary or secondary amine is stirred for about 2-15 hours at room temperature with a carbamate intermediate in an aprotic solvent like acetonitrile. Tetrahydrofuran and aminomethylated resin are then added and the reaction is then stirred for about 12-15 hours. Ureas are isolated after filtration, rinsed with ethyl acetate and evaporated in vacuo.
  • For protected basic derivatives (R3═(CH2)4NHBoc), the corresponding deprotected compounds were obtained after treatment under acidic condition (DCM/TFA 10%) to remove the Boc group.
  • EXAMPLE 4437 2-{(1R)-1-[(Benzylamino)carbonylamino]-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (C27H25N5O, MW=435.53)
  • Figure US20070299073A1-20071227-C00080
  • Benzylamine (5 μL, 50 mmol) and 2-{(1R)-1-amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (24 mg, 54 mmol) were stirred for about 2 hours at room temperature in anhydrous acetonitrile. Aminomethylated resin (50 mg, 0.75 mmol/g, Novabiochem) was then added and after further stirring overnight, the title product was obtained by filtration on silica gel pad (200 mg) and evaporated in vacuo as a brown powder (20 mg, 92%). 1H-NMR (DMSO D6, 100 MHz) δ: 10.8 (br s, 1H); 7.9-6.88 (m, 17H); 6.53 (m, 2H); 5.12 (dd, J=6 and 14.6 Hz, 1H); 4.28 (m, 2H); 3.25 (m, 2H). LC/MS: m/z=436 (M+H).
  • EXAMPLES 4438-8469
  • The following compounds were prepared analogously to the procedure described for Example 4437, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 and NX1X2, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (3 substituents))(R5 (12 substituents))(NX1X2 (112 substituents))=4032.
    Figure US20070299073A1-20071227-C00081
    Figure US20070299073A1-20071227-C00082
    Figure US20070299073A1-20071227-C00083
    Figure US20070299073A1-20071227-C00084
    Figure US20070299073A1-20071227-C00085
  • Synthesis of Secondary Amines by Reductive Aminations of Imidazolyl Intermediates
  • (Kaldor, S. W., Siegel, M. G.; Fritz, J. E.; Dressman, B. A.; Hahn, P. J. Tetrahedron Letters 1996, 37, 7193-7196)
    Figure US20070299073A1-20071227-C00086
  • General procedure: Condensation of aldehydes with an imidazolyl intermediate in a protic solvent like methanol yields imines which are reduced in presence of AMBERLITE® IRA-400 borohydride. The slurry is then shaken overnight and the excess amino intermediate is quenched by addition of dichloromethane and aldehyde Wang resin. After further overnight stirring, the mixture is filtered, evaporated and purified on silica gel pad with ethyl acetate as eluent.
  • For protected basic derivatives (R3═(CH2)4NHBoc), the corresponding deprotected compounds were obtained after treatment under acidic condition (DCM/TFA 10%) to remove the Boc group.
  • EXAMPLE 8470 2-{(1R)-1-[(4-Methoxybenzyl)amino]-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (C27H26N4O, MW=422.54)
  • Figure US20070299073A1-20071227-C00087
  • 2-{(1R)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (36.3 mg, 0.12 mmol) and p-anisaldehyde (12 μL, 0.1 mmol) in 1 mL of methanol were shaken for about 2 hours at about 22° C. Borohydride resin (76 mg, 2.5 mmol/g, AMBERLITE® IRA-400) was then added and the slury was stirred overnight before addition of dichloromethane (1 mL) and aldehyde Wang resin (31 mg, 3.22 mmol/g, Novabiochem). After about 8 hours of stirring, the slurry was then filtered and evaporated in vacuo to give a yellow solid (32.2 mg, 76%). 1H-NMR (CDCl3, 100 MHz) δ: 8.86 (br s, 1H); 7.73-6.68 (m, 15H); 4.62 (s, 1H); 4.33 (dd, J=4.7 and 8.5 Hz, 1H); 3.81 (s, 2H); 3.74 (s, 3H); 3.27 (ABX system, 2H); 2.26 (s, 1H). LC/MS: m/z=423 (M+H).
  • EXAMPLES 8471-9331
  • The following compounds were prepared analogously to the procedure described for Example 8470, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 and A1, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (3 substituents))(R5 (7 substituents))(X2 (41 substituents))=861.
    Figure US20070299073A1-20071227-C00088
    Figure US20070299073A1-20071227-C00089
  • Synthesis of Amidines by Condensation of an Imidazolyl with Thioimidates
  • Figure US20070299073A1-20071227-C00090
  • A series of thioimidates were previously synthesized by condensation of thioamides and iodomethane in acetone at room temperature. The precipitate was collected and then rinsed with acetone. Thioimidates so formed were used without further purification.
  • General procedure: Thioimidates are stirred overnight at room temperature with an amino intermediate in 2-propanol or 2-propanol/DMF before addition of tetrahydrofuran and aminomethylated resin. Further stirring overnight followed by filtration and washing with ethyl acetate yields an iodohydrate amidine after evaporation in vacuo.
  • For protected basic derivatives (R3═(CH2)4NHBoc), the corresponding deprotected compounds were obtained after treatment under acidic condition (DCM/TFA 10%) to remove the Boc group.
  • EXAMPLE 9332 2-{(1R)-1-[(2-Thienyl(imino)methyl)amino]-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole hydroiodide (C24H21N5S.HI, MW=539.43)
  • Figure US20070299073A1-20071227-C00091
  • 2-{(1R)-1-Amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole (15.1 mg, 0.05 mmol) and S-methyl-2-thiophenethiocarboximide hydroiodide (13 mg, 0.06 mmol) were shaken in 1 mL of 2-propanol for about 16 hours. Aminomethylated resin (50 mg, 1.31 mmol/g, Novabiochem) was then added and after further stirring overnight, a brown solid (19.8 mg, 84%) was isolated by filtration and evaporation in vacuo. 1H-NMR (MeOD, 100 MHz) δ: 8.15 (m, 1H); 7.84-6.96 (m, 13H); 5.3 (m, 1H); 3.61 (m, 2H). LC/MS: m/z=412 (M+H).
  • EXAMPLES 9333-9920
  • The following compounds were prepared analogously to the procedure described for Example 9332, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 and X2, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (7 substituents))(R5 (7 substituents))(X2 (12 substituents))=588.
    Figure US20070299073A1-20071227-C00092
  • Synthesis of Amidines by Condensation of an Aniline with Thioimidates
  • Figure US20070299073A1-20071227-C00093
  • EXAMPLES 9921-9926
  • The following compounds were prepared analogously to the procedure described for Example 9332, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R4 and X7, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R4 (2 substituents))(X7 (3 substituents))=6.
    Figure US20070299073A1-20071227-C00094
  • Imidazole Derivatives N-Alkylation
  • Figure US20070299073A1-20071227-C00095
  • General procedure: A solution of an imidazole intermediate, an alkylating agent such as an α-bromoketone, an α-bromoester, an aryl or alkyl bromide or a sulfonyl chloride, in the presence of an organic or non-organic base which can be or not be supported on a resin such as polystyrene resin, in an aprotic solvent like THF, CH3CN, DMF is heated at 20-80° C. for 2-48 hours. The resulting N-alkylated compound can be isolated either by aqueous work-up followed by flash chromatography on silica gel, or by addition to the reaction mixture of a nucleophile supported on polymer (to trap the excess of electrophile) such as aminomethyl or thiomethyl polystyrene resin followed by filtration and then rapid purification of the resulting residue on a silica gel pad (using Alltech silica cartridge and Alltech manifold).
  • EXAMPLE 9927 2-[1(S)-{1,1-Dimethylethoxy)carbonylamino}-2-phenylethyl]-1-(2-oxo-butyl)-4-phenyl-1H-imidazole
  • Figure US20070299073A1-20071227-C00096
  • To a solution of 2-[1(S)-{(1,1-dimethylethoxy)carbonylamino}-2-phenylethyl]-4-phenyl-1H-imidazole (100 mg, 1 eq) in DMF (2 mL) were successively added morpholinomethyl polystyrene resin (Novabiochem, loading: 3.51 mmol/g, 159 mg, 2 eq) and 1-bromo-2-butanone (28 mL, 2 eq). After about 18 hours of stirring at about 20° C., 2 mL DMF were added to the reaction mixture followed by aminomethylpolystyrene resin (Novabieochem, loading: 1.73 mmol/g, 319 mg). The mixture was stirred overnight at 20° C. and filtered. The filtrate was concentrated under reduced pressure and then purified by a rapid filtration on a silica gel pad (Alltech silica cartridges) with ethylacetate as eluent to yield 107 mg (90% yield) of the title compound. NMR (1H, 400 MHz, CDCl3) δ: 7.80-6.98 (m, 11H, arom. H), 5.45 (d, 1H, NH), 4.80 (m, 1H, CH) 4.40 (AB, J=18 Hz, NCH2CO), 3.33 (m, 2H, CH2Ph), 2.25 (m, 2H, CH2CH3), 1.0 (t, 3H, CH3). LC/MS: calculated MW=433.5, m/z=434.2 (M+H), m/z=432.2 (M−H).
  • EXAMPLES 9928-12307
  • The following compounds were prepared analogously to the procedure described for Example 9927, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3, R5 and R1, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R1 (34 substituents {see definitions of Z1}))(R3 (5 substituents))(R5 (14 substituents))=2380.
    Figure US20070299073A1-20071227-C00097
    Figure US20070299073A1-20071227-C00098
  • Imidazo-Pyrazines
  • Figure US20070299073A1-20071227-C00099
  • General procedure: Intermediate (a) is treated with an acidic solution preferrably TFA in DCM at about 20-30° C. for about 1-4 hours. The mixture is then concentrated under reduced pressure to afford a dihydro-imidazo-pyrazine.
  • EXAMPLE 12308 5,8-Dihydro-8-(3-indolyl)methyl-2,6-diphenyl-imidazo[1,2-a]pyrazine
  • Figure US20070299073A1-20071227-C00100
  • A solution of 2-[1(S)-{1,1-dimethylethoxy)carbonylamino}-2-(3-indolyl)ethyl]-1-(benzoylmethyl)-4-phenyl-1H-imidazole (prepared as described previously) (100 mg) in a mixture of 10% TFA in DCM (1.3 mL) was stirred for about 3 hours at about 20° C. and concentrated under reduced pressure to yield the expected dihydro-imidazo-pyrazine (yield=95%). LC/MS: calculated MW: 402.19, m/z=403.2 (M+H).
  • EXAMPLES 12309-12532
  • The following compounds were prepared analogously to the procedure described for Example 12308, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R5 and R7, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R5 (7 substituents))(R7 (32 substituents))=224.
    Figure US20070299073A1-20071227-C00101
    Figure US20070299073A1-20071227-C00102
  • Imidazo-Pyrazines
  • Figure US20070299073A1-20071227-C00103
  • General procedure: Intermediate (b) is treated with an acidic solution preferrably TFA in DCM at 20-30° C. for 1-4 hours. The mixture is then concentrated under reduced pressure to afford compound (c) which is oxidized to the corresponding fully aromatized imidazopyrazine either by keeping it in solution in methanol or DMSO for 5 hours-3 days at about 20° C. or by using an oxidative reagent such as manganese dioxide in a protic or aprotic solvent such as MeOH, toluene or chloroform at 20-70° C. for 2-10 hours or chromic acid supported or not on a resin in a protic solvent like methanol at 40-70° C. for 3-15 hours.
  • EXAMPLE 12533 2,6-Diphenyl-imidazo[1,2-a]pyrazine-8-butanamine
  • Figure US20070299073A1-20071227-C00104
  • A solution of 2-[1,5-bis{(1,1-dimethylethoxy)carbonylamino}pentyl]-4-phenyl-1H-imidazole (50 mg) in a mixture of TFA/DCM 10% (700 mL) was stirred at about 20° C. for about 3 hours and then concentrated under reduced pressure to yield the intermediate dihydro-imidazo-pyrazine as its trifloroacetate salt. This salt was dissolved in MeOH (1 mL) and manganese dioxide (30 mg) was added. After about 3 hours of stirring at about 20° C., the mixture was filtered on a CELITE® pad and the filtrate concentrated under reduced pressure to afford the fully aromatized imidazo-pyrazine (78% yield). NMR (1H, 400 MHz, CD3OD): 8.75-7.34 (m, 12H, arom. H), 3.32 (m, 4H, CH2), 2.10 (m, 2H, CH2), 1.90 (m, 2H, CH2). LC/MS: calculated MW=342.4, m/z=343.2 (M+H).
  • EXAMPLES 12534-13773
  • The following compounds were prepared analogously to the procedure described for Example 12533, using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein. Each combination of R3 and R7, shown below, were or can be synthesized, therefore, the number of Examples are calculated by multiplying (R3 (5 substituents))(R5 (8 substituents))(R7 (31 substituents))=1240.
    Figure US20070299073A1-20071227-C00105
    Figure US20070299073A1-20071227-C00106
  • Tetrahydro-Imidazo-Pyrazines
  • Figure US20070299073A1-20071227-C00107
  • General procedure: Intermediate (d) is treated with an acidic solution preferrably TFA in DCM at 20-30° C. for 1-4 hours. The mixture is then concentrated under reduced pressure to afford the intermediate dihydro-imidazopyrazine (e). Reduction of (e) to the corresponding tetrahydro-imidazopyrazine is achieved by catalytic hydrogenation or by using any reducing agent such as NaBH4 (which can be supported on a resin), NaBH(OAc)3, NaBH3CN in a protic solvent such as MeOH at pH maintained weakly acidic (around pH 5) by addition of acetic acid or TFA.
  • EXAMPLE 13774 6-Ethyl-5,6,7,8-tetrahydro-2-phenyl-8(S)-phenylmethyl-imidazo[1,2-a]pyrazine
  • Figure US20070299073A1-20071227-C00108
  • 2-[1(S)-{1,1-Dimethylethoxy)carbonylamino}-2-phenylethyl]-1-(2-oxo-butyl)-4-phenyl-1H-imidazole (60 mg) in a mixture of 10% TFA in DCM was stirred at about 20° C. for about 3 hours and then concentrated under reduced pressure. The resulting intermediate dihydro-imidazo-pyrazine was dissolved in methanol and borohydride supported on resin (AMBERLITE® IRA 400, Aldrich, 2.5 mmol BH4 /g; 4 eq) was added. The pH was maintained at about 5 by addition of drops of TFA. After about 2 hours of stirring at about 20° C., the mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate/Heptane 7:3; Rf=0.30). The tetrahydro-imidazo-pyrazine was obtained as a single diastereoisomer in 86% yield (38 mg). NMR (1H, 400 MHz, CDCl3) δ: 7.80-7.10 (m, 11H, arom. H), 4.28 (dd, 1H, 3J=10 Hz, 3J=3 Hz, H8), 3.95 (dd, 1H, 2J=11.5 Hz, 3J=3.6 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=3.0 Hz), 3.60 (t, 1H, 2J=3J=11.5 Hz), 3.85 (dd, 1H, 2J=13.6 Hz, 3J=10. Hz), 2.98 (m, 2H), 1.85 (s, 1H, NH), 1.55 (m, 2H, CH2), 0.95 (t, 3H, CH3). NMR (13C, 100 MHz, CDCl3): 146.3, 140.9, 138.0, 134.4, 129.4, 128.6, 128.5, 126.6, 126.5, 124.8, 113.8, 55.9, 54.4, 50.2, 40.0, 26.6, 10.0.
  • LC/MS: calculated MW=317.43, m/z=318.20 (M+H).
  • EXAMPLE 13775
  • The following compound was prepared analogously to the procedure described for Example 13774 using the appropriate starting materials, which can be obtained from commercial sources or synthesized according to methods known to those skilled in the art or as enabled by the teachings herein.
    Figure US20070299073A1-20071227-C00109
  • N-Substituted Tetrahydro-Imidazo-Pyrazines
  • Figure US20070299073A1-20071227-C00110
  • General procedure: A compound of formula (f) can react with isocyanates, isothiocyanates, N-succinimidyl carbamates, acyl chlorides or activated carboxylic acids in an aprotic solvent at 20-70° C. for 2-18 hours. The resulting derivative can be isolated by evaporation of the mixture followed by flash chromatography on silica gel or by addition to the mixture of a nucleophile supported on polymer such as aminomethyl or thiomethyl polystyrene resin followed by a filtration.
  • EXAMPLE 13776 5,6,7,8-Tetrahydro-7-(methoxymethylcarbonyl)-2,6-diphenyl-8(S)-phenylmethyl-imidazo[1,2-a]pyrazine
  • Figure US20070299073A1-20071227-C00111
  • To a solution of 5,6,7,8-tetrahydro-2,6-diphenyl-8(S)-phenylmethyl-imidazo[1,2-a]pyrazine (29 mg) in chloroform were successively added morpholinomethylpolystyrene resin (Novabiochem, loading=3.51 mmol/g, 50 mg, 2 eq) and methoxyacetylchloride (10 mL, 1.3 eq). After about 3 hours of stirring at about 20° C., chloroform was added to the mixture followed by aminomethylpolystyrene resin (Novabiochem, loading=1.2 mmol/g, 132 mg, 2 eq). The reaction mixture was stirred for another 2 hours and then filtered. The filtrate was concentrated under reduced pressure to afford 23 mg of the title compound (yield=68%). NMR (1H, 100 MHz, CDCl3): 7.9-7.0 (m, 16H, arom. H), 6.6 (m, 1H, H8), 5.3 (m, 1H, H6), 4.6 (dd, 1H, 2J=13 Hz, H5), 4.35 (dd, 1H, 2J=13 Hz, 3J=5 Hz, H5′), 3.7-2.9 (m, 5H, CH2Ph, OCH3).
  • The following tables of compounds illustrate some of the compounds of the present invention that were synthesized and provide the hplc retention time (denoted Rt or Tr) in minutes and mass spectra results of each compound.
  • Mass spectra were acquired on a single quadrupole electrospray mass spectrometer (Micromass, Platform model), 0.8 Da resolution. A monthly calibration, between 80 and 1000 Da, is performed with sodium and rubidium iodide solution isopropanol/water (1/1 Vol.).
  • HPLC retention times were acquired on an HPLC system: HP1100 (Hewlett-Packard) equipped with a photodiode array UV detector.
  • The HPLC conditions are as follows and the conditions used for each of the following tables of compounds are noted below, the wavelength of the UV detector is noted in parenthesis after the formula number.
    Condition A:
    Solvent: A: Water + 0.4% Formic acid
    B: Acetonitrile + 0.4% Formic acid
    T (min) A % B %
     0 90 10
     5 90 10
    16 40 60
    17 10 90
    20 10 90
    Flow rate: 1 ml/min
    Injection volume volume: 20 μL
    Column: Kromasil ODS 5 μm 150 * 4.6 mm i.d.
    Temp.: 40° C.
  • Condition A2:
    Solvent: A: Water + 0.4% Formic acid
    B: Acetonitrile + 0.4% Formic acid
    T (min) A % B %
     0 90 10
     2 90 10
    14 10 90
    20 10 90
    Flow rate: 1 ml/min
    Injection volume: 20 μL
    Column: Kromasil ODS 5 μm 150 * 4.6 mm i.d.
    Temp.: 40° C.
  • Condition A3:
    Solvent: A: Water + 0.4% Formic acid
    B: Acetonitrile + 0.4% Formic acid
    T(min) A % B %
     0 90 10
     5 90 10
    16 46 54
    17.5 10 90
    22 10 90
    Flow rate: 1 ml/min
    Injection volume: 20 μL
    Column: Kromasil ODS 5 μm 150 * 4.6 mm i.d.
    Temp.: 40° C.
  • Condition A4:
    Solvent: A: Water + 0.4% Formic acid
    B: Acetonitrile + 0.4% Formic acid
    T(min) A % B %
     0 90 10
     5 90 10
    20 10 90
    25 10 90
    Flow rate: 1 ml/min
    Injection volume: 20 μL
    Column: Kromasil ODS 5 μm 150 * 4.6 mm i.d.
    Temp.: 40° C.
  • Condition A5:
    Solvent: A: Water + 0.4% Formic acid
    B: Acetonitrile + 0.4% Formic acid
    T(min) A % B %
     0 90 10
     5 90 10
    25 10 90
    30 10 90
    Flow rate: 1 ml/min
    Injection volume: 20 μL
    Column: Kromasil ODS 5 μm 150 * 4.6 mm i.d.
    Temp.: 40° C.
  • Condition B:
    Solvent: A: Water + 0.02% Trifluoroacetic acid
    B: Acetonitrile
    T(min) A % B %
    0 100 0
    1 100 0
    8 30 70
    10  30 70
    Flow rate: 1.1 ml/min
    Injection volume: 5 μL
    Column: Uptisphere ODS 3 μm 33 * 4.6 mm i.d.
    Temp.: 40° C.
  • Condition C:
    Solvent: A: Water + 0.02% Trifluoroacetic acid
    B: Acetonitrile
    T(min) A % B %
     0 100 0
     1 100 0
    10 85 25
    12 85 25
    Flow rate: 1.1 ml/min
    Injection volume: 5 μL
    Column: Uptisphere ODS 3 μm 33 * 4.6 mm i.d
    Temp.: 40° C.
  • Condition D:
    Solvent: A: Water + 0.04% Trifluoroacetic acid
    B: Acetonitrile
    T(min) A % B %
    0 100 0
    1 100 0
    8 30 70
    10  30 70
    Flow rate: 1.1 ml/min
    Injection volume: 5 μL
    Column: Uptisphere ODS 3 μm 33 * 4.6 mm i.d
    Temp.: 40° C.
  • Condition E:
    Solvent: A: Water + 0.04% Trifluoroacetic acid
    B: Acetonitrile
    T(min) A % B %
    0 90 10
    1 90 10
    8 0 100
    10  0 100
    Flow rate: 1.1 ml/min
    Injection volume: 5 μL
    Column: Uptisphere ODS 3 μm 33 * 4.6 mm i.d
    Temp.: 40° C.
  • In the following description Formula numbers are noted in bold and the the wavelength is in parenthesis.
    • Method A=Used for Tables of compounds of Formulas: 17 (250), 18 (250) and 57 (220).
    • Method A4=Used for Tables of compounds of Formulas: 58 (210).
    • Method B=Used for Tables of compounds of Formulas: 7 (220), 8 (220), 9 (220), 10 (220), 11 (220), 12 (250), 19 (220), 20 (260), 21 (250), 25 (240), 26 (220), 27 (220), 28 (220), 29 (220), 37 (220), 38 (220), 39 (220), 40 (240), 44 (220), 45 (220), 46 (220), 47 (220), 48 (220), 49 (250), 55 (260), and 56 (220).
    • Method C=Used for Tables of compounds of Formulas: 1 (220), 2 (220), 3 (220), 4 (260), 5 (220), 6 (220), 13 (220), 14 (220), 16 (260), 23 (250), 24 (250), 30 (220), 31 (254), 32 (250), 33 (250), 34 (250), 35 (250), and 36 (254).
    • Method D=Used for Tables of compounds of Formulas: 15 (220), 51 (220), 52 (220), 53 (220), and 54 (220).
  • Method E=Used for Tables of compounds of Formulas: 22 (250), 41 (220), 42 (250), 43 (220), and 50 (250).
    FORMULA 1
    Figure US20070299073A1-20071227-C00112
    Analysis
    R1 R2 Rt (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00113
    Figure US20070299073A1-20071227-C00114
    7.0 666.5
    2
    Figure US20070299073A1-20071227-C00115
    Figure US20070299073A1-20071227-C00116
    7.1 668.5
    3
    Figure US20070299073A1-20071227-C00117
    Figure US20070299073A1-20071227-C00118
    6.2 712.5
    4
    Figure US20070299073A1-20071227-C00119
    Figure US20070299073A1-20071227-C00120
    6.1 698.5
    5
    Figure US20070299073A1-20071227-C00121
    Figure US20070299073A1-20071227-C00122
    5.0 649.5
    6
    Figure US20070299073A1-20071227-C00123
    Figure US20070299073A1-20071227-C00124
    7.2 656.5
    7
    Figure US20070299073A1-20071227-C00125
    Figure US20070299073A1-20071227-C00126
    6.2 658.5
    8
    Figure US20070299073A1-20071227-C00127
    Figure US20070299073A1-20071227-C00128
    6.4 643.5
    9
    Figure US20070299073A1-20071227-C00129
    Figure US20070299073A1-20071227-C00130
    6.7 661.5
    10
    Figure US20070299073A1-20071227-C00131
    Figure US20070299073A1-20071227-C00132
    7.0 689.5
    11
    Figure US20070299073A1-20071227-C00133
    Figure US20070299073A1-20071227-C00134
    5.8 661.4
    12
    Figure US20070299073A1-20071227-C00135
    Figure US20070299073A1-20071227-C00136
    5.3 657.5
    13
    Figure US20070299073A1-20071227-C00137
    Figure US20070299073A1-20071227-C00138
    5.4 701.5
    14
    Figure US20070299073A1-20071227-C00139
    Figure US20070299073A1-20071227-C00140
    6.2 733.5
    15
    Figure US20070299073A1-20071227-C00141
    Figure US20070299073A1-20071227-C00142
    6.7 653.5
    16
    Figure US20070299073A1-20071227-C00143
    Figure US20070299073A1-20071227-C00144
    5.5 659.5
    17
    Figure US20070299073A1-20071227-C00145
    Figure US20070299073A1-20071227-C00146
    4.8 611.4
    18
    Figure US20070299073A1-20071227-C00147
    Figure US20070299073A1-20071227-C00148
    6.4 681.5
    19
    Figure US20070299073A1-20071227-C00149
    Figure US20070299073A1-20071227-C00150
    6.4 667.5
    20
    Figure US20070299073A1-20071227-C00151
    Figure US20070299073A1-20071227-C00152
    5.4 671.5
    21
    Figure US20070299073A1-20071227-C00153
    Figure US20070299073A1-20071227-C00154
    7.2 680.5
    22
    Figure US20070299073A1-20071227-C00155
    Figure US20070299073A1-20071227-C00156
    7.2 682.5
    23
    Figure US20070299073A1-20071227-C00157
    Figure US20070299073A1-20071227-C00158
    6.4 726.5
    24
    Figure US20070299073A1-20071227-C00159
    Figure US20070299073A1-20071227-C00160
    6.2 712.5
    25
    Figure US20070299073A1-20071227-C00161
    Figure US20070299073A1-20071227-C00162
    5.1 663.5
    26
    Figure US20070299073A1-20071227-C00163
    Figure US20070299073A1-20071227-C00164
    7.2 670.5
    27
    Figure US20070299073A1-20071227-C00165
    Figure US20070299073A1-20071227-C00166
    6.3 672.5
    28
    Figure US20070299073A1-20071227-C00167
    Figure US20070299073A1-20071227-C00168
    6.6 657.5
    29
    Figure US20070299073A1-20071227-C00169
    Figure US20070299073A1-20071227-C00170
    6.8 675.5
    30
    Figure US20070299073A1-20071227-C00171
    Figure US20070299073A1-20071227-C00172
    7.1 703.5
    31
    Figure US20070299073A1-20071227-C00173
    Figure US20070299073A1-20071227-C00174
    5.9 675.5
    32
    Figure US20070299073A1-20071227-C00175
    Figure US20070299073A1-20071227-C00176
    5.4 671.5
    33
    Figure US20070299073A1-20071227-C00177
    Figure US20070299073A1-20071227-C00178
    5.5 715.5
    34
    Figure US20070299073A1-20071227-C00179
    Figure US20070299073A1-20071227-C00180
    6.3 747.5
    35
    Figure US20070299073A1-20071227-C00181
    Figure US20070299073A1-20071227-C00182
    6.8 667.5
    36
    Figure US20070299073A1-20071227-C00183
    Figure US20070299073A1-20071227-C00184
    5.6 673.5
    37
    Figure US20070299073A1-20071227-C00185
    Figure US20070299073A1-20071227-C00186
    4.9 625.5
    38
    Figure US20070299073A1-20071227-C00187
    Figure US20070299073A1-20071227-C00188
    6.5 681.5
    39
    Figure US20070299073A1-20071227-C00189
    Figure US20070299073A1-20071227-C00190
    6.5 695.5
    40
    Figure US20070299073A1-20071227-C00191
    Figure US20070299073A1-20071227-C00192
    5.5 685.5
    41
    Figure US20070299073A1-20071227-C00193
    Figure US20070299073A1-20071227-C00194
    7.2 694.5
    42
    Figure US20070299073A1-20071227-C00195
    Figure US20070299073A1-20071227-C00196
    7.3 696.5
    43
    Figure US20070299073A1-20071227-C00197
    Figure US20070299073A1-20071227-C00198
    6.4 740.5
    44
    Figure US20070299073A1-20071227-C00199
    Figure US20070299073A1-20071227-C00200
    6.3 726.5
    45
    Figure US20070299073A1-20071227-C00201
    Figure US20070299073A1-20071227-C00202
    5.2 677.5
    46
    Figure US20070299073A1-20071227-C00203
    Figure US20070299073A1-20071227-C00204
    7.3 684.5
    47
    Figure US20070299073A1-20071227-C00205
    Figure US20070299073A1-20071227-C00206
    6.4 686.5
    48
    Figure US20070299073A1-20071227-C00207
    Figure US20070299073A1-20071227-C00208
    6.6 671.5
    49
    Figure US20070299073A1-20071227-C00209
    Figure US20070299073A1-20071227-C00210
    6.8 689.5
    50
    Figure US20070299073A1-20071227-C00211
    Figure US20070299073A1-20071227-C00212
    7.1 717.5
    51
    Figure US20070299073A1-20071227-C00213
    Figure US20070299073A1-20071227-C00214
    6.0 689.5
    52
    Figure US20070299073A1-20071227-C00215
    Figure US20070299073A1-20071227-C00216
    5.5 685.5
    53
    Figure US20070299073A1-20071227-C00217
    Figure US20070299073A1-20071227-C00218
    5.5 729.5
    54
    Figure US20070299073A1-20071227-C00219
    Figure US20070299073A1-20071227-C00220
    6.4 761.5
    55
    Figure US20070299073A1-20071227-C00221
    Figure US20070299073A1-20071227-C00222
    6.9 681.4
    56
    Figure US20070299073A1-20071227-C00223
    Figure US20070299073A1-20071227-C00224
    5.6 687.5
    57
    Figure US20070299073A1-20071227-C00225
    Figure US20070299073A1-20071227-C00226
    5.0 639.5
    58
    Figure US20070299073A1-20071227-C00227
    Figure US20070299073A1-20071227-C00228
    6.6 709.5
    59
    Figure US20070299073A1-20071227-C00229
    Figure US20070299073A1-20071227-C00230
    6.6 695.5
    60
    Figure US20070299073A1-20071227-C00231
    Figure US20070299073A1-20071227-C00232
    5.5 699.5
    61
    Figure US20070299073A1-20071227-C00233
    Figure US20070299073A1-20071227-C00234
    7.68 + 7.8 748.5
    62
    Figure US20070299073A1-20071227-C00235
    Figure US20070299073A1-20071227-C00236
    7.7 750.5
    63
    Figure US20070299073A1-20071227-C00237
    Figure US20070299073A1-20071227-C00238
    7.0 794.5
    64
    Figure US20070299073A1-20071227-C00239
    Figure US20070299073A1-20071227-C00240
    6.8 780.5
    65
    Figure US20070299073A1-20071227-C00241
    Figure US20070299073A1-20071227-C00242
    5.8 731.6
    66
    Figure US20070299073A1-20071227-C00243
    Figure US20070299073A1-20071227-C00244
    7.8 738.5
    67
    Figure US20070299073A1-20071227-C00245
    Figure US20070299073A1-20071227-C00246
    6.9 748.5
    68
    Figure US20070299073A1-20071227-C00247
    Figure US20070299073A1-20071227-C00248
    7.2 725.5
    69
    Figure US20070299073A1-20071227-C00249
    Figure US20070299073A1-20071227-C00250
    7.3 743.5
    70
    Figure US20070299073A1-20071227-C00251
    Figure US20070299073A1-20071227-C00252
    7.6 771.5
    71
    Figure US20070299073A1-20071227-C00253
    Figure US20070299073A1-20071227-C00254
    6.5 743.5
    72
    Figure US20070299073A1-20071227-C00255
    Figure US20070299073A1-20071227-C00256
    6.0 739.5
    73
    Figure US20070299073A1-20071227-C00257
    Figure US20070299073A1-20071227-C00258
    6.0 783.5
    74
    Figure US20070299073A1-20071227-C00259
    Figure US20070299073A1-20071227-C00260
    6.8 815.6
    75
    Figure US20070299073A1-20071227-C00261
    Figure US20070299073A1-20071227-C00262
    7.4 735.5
    76
    Figure US20070299073A1-20071227-C00263
    Figure US20070299073A1-20071227-C00264
    6.1 741.5
    77
    Figure US20070299073A1-20071227-C00265
    Figure US20070299073A1-20071227-C00266
    5.6 693.5
    78
    Figure US20070299073A1-20071227-C00267
    Figure US20070299073A1-20071227-C00268
    7.1 + 7.2 749.5
    79
    Figure US20070299073A1-20071227-C00269
    Figure US20070299073A1-20071227-C00270
    7.1 + 7.2 753.5
    80
    Figure US20070299073A1-20071227-C00271
    Figure US20070299073A1-20071227-C00272
    6.0 753.5
  • FORMULA 2
    Figure US20070299073A1-20071227-C00273
    R1 R3 Rt (min.) [M + H]+
    1
    Figure US20070299073A1-20071227-C00274
    Figure US20070299073A1-20071227-C00275
    5.5 566.3
    2
    Figure US20070299073A1-20071227-C00276
    Figure US20070299073A1-20071227-C00277
    5.6 568.3
    3
    Figure US20070299073A1-20071227-C00278
    Figure US20070299073A1-20071227-C00279
    4.9 612.3
    4
    Figure US20070299073A1-20071227-C00280
    Figure US20070299073A1-20071227-C00281
    4.8 598.3
    5
    Figure US20070299073A1-20071227-C00282
    Figure US20070299073A1-20071227-C00283
    3.8 549.4
    6
    Figure US20070299073A1-20071227-C00284
    Figure US20070299073A1-20071227-C00285
    5.6 556.3
    7
    Figure US20070299073A1-20071227-C00286
    Figure US20070299073A1-20071227-C00287
    5.3 540.3
    8
    Figure US20070299073A1-20071227-C00288
    Figure US20070299073A1-20071227-C00289
    4.9 543.3
    9
    Figure US20070299073A1-20071227-C00290
    Figure US20070299073A1-20071227-C00291
    5.1 561.3
    10
    Figure US20070299073A1-20071227-C00292
    Figure US20070299073A1-20071227-C00293
    5.4 589.3
    11
    Figure US20070299073A1-20071227-C00294
    Figure US20070299073A1-20071227-C00295
    4.3 561.3
    12
    Figure US20070299073A1-20071227-C00296
    Figure US20070299073A1-20071227-C00297
    4.1 557.3
    13
    Figure US20070299073A1-20071227-C00298
    Figure US20070299073A1-20071227-C00299
    4.1 601.3
    14
    Figure US20070299073A1-20071227-C00300
    Figure US20070299073A1-20071227-C00301
    4.9 633.4
    15
    Figure US20070299073A1-20071227-C00302
    Figure US20070299073A1-20071227-C00303
    5.3 533.3
    16
    Figure US20070299073A1-20071227-C00304
    Figure US20070299073A1-20071227-C00305
    4.2 559.3
    17
    Figure US20070299073A1-20071227-C00306
    Figure US20070299073A1-20071227-C00307
    3.5 511.3
    18
    Figure US20070299073A1-20071227-C00308
    Figure US20070299073A1-20071227-C00309
    3.5 481.3
    19
    Figure US20070299073A1-20071227-C00310
    Figure US20070299073A1-20071227-C00311
    3.5 467.3
    20
    Figure US20070299073A1-20071227-C00312
    Figure US20070299073A1-20071227-C00313
    4.1 571.3
    21
    Figure US20070299073A1-20071227-C00314
    Figure US20070299073A1-20071227-C00315
    5.6 580.4
    22
    Figure US20070299073A1-20071227-C00316
    Figure US20070299073A1-20071227-C00317
    5.6 582.4
    23
    Figure US20070299073A1-20071227-C00318
    Figure US20070299073A1-20071227-C00319
    4.9 626.4
    24
    Figure US20070299073A1-20071227-C00320
    Figure US20070299073A1-20071227-C00321
    4.8 612.4
    25
    Figure US20070299073A1-20071227-C00322
    Figure US20070299073A1-20071227-C00323
    3.8 563.4
    26
    Figure US20070299073A1-20071227-C00324
    Figure US20070299073A1-20071227-C00325
    5.6 570.4
    27
    Figure US20070299073A1-20071227-C00326
    Figure US20070299073A1-20071227-C00327
    5.4 554.3
    28
    Figure US20070299073A1-20071227-C00328
    Figure US20070299073A1-20071227-C00329
    4.9 557.3
    29
    Figure US20070299073A1-20071227-C00330
    Figure US20070299073A1-20071227-C00331
    5.1 575.3
    30
    Figure US20070299073A1-20071227-C00332
    Figure US20070299073A1-20071227-C00333
    5.4 603.3
    31
    Figure US20070299073A1-20071227-C00334
    Figure US20070299073A1-20071227-C00335
    4.4 575.3
    32
    Figure US20070299073A1-20071227-C00336
    Figure US20070299073A1-20071227-C00337
    4.1 571.3
    33
    Figure US20070299073A1-20071227-C00338
    Figure US20070299073A1-20071227-C00339
    4.1 615.4
    34
    Figure US20070299073A1-20071227-C00340
    Figure US20070299073A1-20071227-C00341
    4.9 647.4
    35
    Figure US20070299073A1-20071227-C00342
    Figure US20070299073A1-20071227-C00343
    5.3 567.3
    36
    Figure US20070299073A1-20071227-C00344
    Figure US20070299073A1-20071227-C00345
    4.2 573.3
    37
    Figure US20070299073A1-20071227-C00346
    Figure US20070299073A1-20071227-C00347
    3.5 525.3
    38
    Figure US20070299073A1-20071227-C00348
    Figure US20070299073A1-20071227-C00349
    3.5 495.3
    39
    Figure US20070299073A1-20071227-C00350
    Figure US20070299073A1-20071227-C00351
    3.5 481.3
    40
    Figure US20070299073A1-20071227-C00352
    Figure US20070299073A1-20071227-C00353
    4.1 585.4
    41
    Figure US20070299073A1-20071227-C00354
    Figure US20070299073A1-20071227-C00355
    5.6 594.4
    42
    Figure US20070299073A1-20071227-C00356
    Figure US20070299073A1-20071227-C00357
    5.6 596.4
    43
    Figure US20070299073A1-20071227-C00358
    Figure US20070299073A1-20071227-C00359
    5.0 640.4
    44
    Figure US20070299073A1-20071227-C00360
    Figure US20070299073A1-20071227-C00361
    4.8 626.4
    45
    Figure US20070299073A1-20071227-C00362
    Figure US20070299073A1-20071227-C00363
    5.6 584.4
    46
    Figure US20070299073A1-20071227-C00364
    Figure US20070299073A1-20071227-C00365
    5.7 568.3
    47
    Figure US20070299073A1-20071227-C00366
    Figure US20070299073A1-20071227-C00367
    5 571.3
    48
    Figure US20070299073A1-20071227-C00368
    Figure US20070299073A1-20071227-C00369
    5.1 589.4
    49
    Figure US20070299073A1-20071227-C00370
    Figure US20070299073A1-20071227-C00371
    5.5 617.4
    50
    Figure US20070299073A1-20071227-C00372
    Figure US20070299073A1-20071227-C00373
    4.4 589.3
    51
    Figure US20070299073A1-20071227-C00374
    Figure US20070299073A1-20071227-C00375
    4.1 585.4
    52
    Figure US20070299073A1-20071227-C00376
    Figure US20070299073A1-20071227-C00377
    4.2 629.4
    53
    Figure US20070299073A1-20071227-C00378
    Figure US20070299073A1-20071227-C00379
    4.9 661.5
    54
    Figure US20070299073A1-20071227-C00380
    Figure US20070299073A1-20071227-C00381
    4.3 587.4
    55
    Figure US20070299073A1-20071227-C00382
    Figure US20070299073A1-20071227-C00383
    3.6 539.4
    56
    Figure US20070299073A1-20071227-C00384
    Figure US20070299073A1-20071227-C00385
    3.6 509.4
    57
    Figure US20070299073A1-20071227-C00386
    Figure US20070299073A1-20071227-C00387
    3.5 495.3
    58
    Figure US20070299073A1-20071227-C00388
    Figure US20070299073A1-20071227-C00389
    4.1 599.3
    59
    Figure US20070299073A1-20071227-C00390
    Figure US20070299073A1-20071227-C00391
    5.8 648.5
    60
    Figure US20070299073A1-20071227-C00392
    Figure US20070299073A1-20071227-C00393
    5.9 650.5
    61
    Figure US20070299073A1-20071227-C00394
    Figure US20070299073A1-20071227-C00395
    5.2 694.5
    62
    Figure US20070299073A1-20071227-C00396
    Figure US20070299073A1-20071227-C00397
    5 680.5
    63
    Figure US20070299073A1-20071227-C00398
    Figure US20070299073A1-20071227-C00399
    5.9 638.5
    64
    Figure US20070299073A1-20071227-C00400
    Figure US20070299073A1-20071227-C00401
    5.2 625.5
    65
    Figure US20070299073A1-20071227-C00402
    Figure US20070299073A1-20071227-C00403
    5.4 643.5
    66
    Figure US20070299073A1-20071227-C00404
    Figure US20070299073A1-20071227-C00405
    5.7 671.4
    67
    Figure US20070299073A1-20071227-C00406
    Figure US20070299073A1-20071227-C00407
    4.6 643.4
    68
    Figure US20070299073A1-20071227-C00408
    Figure US20070299073A1-20071227-C00409
    4.4 639.5
    69
    Figure US20070299073A1-20071227-C00410
    Figure US20070299073A1-20071227-C00411
    4.4 689.5
    70
    Figure US20070299073A1-20071227-C00412
    Figure US20070299073A1-20071227-C00413
    5.2 715.5
    71
    Figure US20070299073A1-20071227-C00414
    Figure US20070299073A1-20071227-C00415
    4.5 641.5
    72
    Figure US20070299073A1-20071227-C00416
    Figure US20070299073A1-20071227-C00417
    3.9 593.4
  • FORMULA 3
    Figure US20070299073A1-20071227-C00418
    Analysis
    Structure Rt (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00419
    9.1 842.5
    2
    Figure US20070299073A1-20071227-C00420
    9.2 844.5
    3
    Figure US20070299073A1-20071227-C00421
    8.3 888.5
    4
    Figure US20070299073A1-20071227-C00422
    8.1 874.5
    5
    Figure US20070299073A1-20071227-C00423
    6.9 825.5
    6
    Figure US20070299073A1-20071227-C00424
    9.2 832.5
    7
    Figure US20070299073A1-20071227-C00425
    8.2 834.5
    8
    Figure US20070299073A1-20071227-C00426
    8.6 819.4
    9
    Figure US20070299073A1-20071227-C00427
    8.7 837.5
    10
    Figure US20070299073A1-20071227-C00428
    9 865.5
    11
    Figure US20070299073A1-20071227-C00429
    7.8 837.4
    12
    Figure US20070299073A1-20071227-C00430
    7.1 833.5
    13
    Figure US20070299073A1-20071227-C00431
    7.1 877.5
    14
    Figure US20070299073A1-20071227-C00432
    8.1 909.5
    15
    Figure US20070299073A1-20071227-C00433
    8.7 829.5
    16
    Figure US20070299073A1-20071227-C00434
    7.2 835.5
    17
    Figure US20070299073A1-20071227-C00435
    6.7 787.4
    18
    Figure US20070299073A1-20071227-C00436
    8.5 843.5
    19
    Figure US20070299073A1-20071227-C00437
    8.5 857.5
    20
    Figure US20070299073A1-20071227-C00438
    7.1 847.5
    21
    Figure US20070299073A1-20071227-C00439
    4.5 710.5
    22
    Figure US20070299073A1-20071227-C00440
    4.1 754.5
    23
    Figure US20070299073A1-20071227-C00441
    4 740.5
    24
    Figure US20070299073A1-20071227-C00442
    3.1 691.6
    25
    Figure US20070299073A1-20071227-C00443
    4.5 698.5
    26
    Figure US20070299073A1-20071227-C00444
    3.9 700.5
    27
    Figure US20070299073A1-20071227-C00445
    4.1 685.5
    28
    Figure US20070299073A1-20071227-C00446
    4.2 703.5
    29
    Figure US20070299073A1-20071227-C00447
    3.1 721.4
    30
    Figure US20070299073A1-20071227-C00448
    3.3 743.5
    31
    Figure US20070299073A1-20071227-C00449
    4.2 695.5
    32
    Figure US20070299073A1-20071227-C00450
    3.4 701.5
    33
    Figure US20070299073A1-20071227-C00451
    3 653.4
    34
    Figure US20070299073A1-20071227-C00452
    4.1 709.5
    35
    Figure US20070299073A1-20071227-C00453
    4 723.5
    36
    Figure US20070299073A1-20071227-C00454
    3.2 623.4
  • FORMULA 4
    Figure US20070299073A1-20071227-C00455
    Tr
    R1 R2 (min) (M + H)+
    1
    Figure US20070299073A1-20071227-C00456
    Figure US20070299073A1-20071227-C00457
    4.53 454.24
    2
    Figure US20070299073A1-20071227-C00458
    Figure US20070299073A1-20071227-C00459
    4.87 488.21
    3
    Figure US20070299073A1-20071227-C00460
    Figure US20070299073A1-20071227-C00461
    4.79 465.24
    4
    Figure US20070299073A1-20071227-C00462
    Figure US20070299073A1-20071227-C00463
    4.53 454.25
  • FORMULA 5
    Figure US20070299073A1-20071227-C00464
    R1 R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00465
    Figure US20070299073A1-20071227-C00466
    8.0 732.2
    2
    Figure US20070299073A1-20071227-C00467
    Figure US20070299073A1-20071227-C00468
    7.7 706.2
    3
    Figure US20070299073A1-20071227-C00469
    Figure US20070299073A1-20071227-C00470
    6.4 755.2
    4
    Figure US20070299073A1-20071227-C00471
    Figure US20070299073A1-20071227-C00472
    7.3 697.3
    5
    Figure US20070299073A1-20071227-C00473
    Figure US20070299073A1-20071227-C00474
    7.6 731.2
    6
    Figure US20070299073A1-20071227-C00475
    Figure US20070299073A1-20071227-C00476
    7.6 760.3
    7
    Figure US20070299073A1-20071227-C00477
    Figure US20070299073A1-20071227-C00478
    7.9 794.3
    8
    Figure US20070299073A1-20071227-C00479
    Figure US20070299073A1-20071227-C00480
    7.8 743.4
    9
    Figure US20070299073A1-20071227-C00481
    Figure US20070299073A1-20071227-C00482
    7.5 774.4
    10
    Figure US20070299073A1-20071227-C00483
    Figure US20070299073A1-20071227-C00484
    7.8 808.3
    11
    Figure US20070299073A1-20071227-C00485
    Figure US20070299073A1-20071227-C00486
    7.8 757.4
    12
    Figure US20070299073A1-20071227-C00487
    Figure US20070299073A1-20071227-C00488
    7.6 743.4
    13
    Figure US20070299073A1-20071227-C00489
    Figure US20070299073A1-20071227-C00490
    7.8 785.4
    14
    Figure US20070299073A1-20071227-C00491
    Figure US20070299073A1-20071227-C00492
    7.6 774.4
    15
    Figure US20070299073A1-20071227-C00493
    Figure US20070299073A1-20071227-C00494
    7.8 763.4
    16
    Figure US20070299073A1-20071227-C00495
    Figure US20070299073A1-20071227-C00496
    8.5 783.3
    17
    Figure US20070299073A1-20071227-C00497
    Figure US20070299073A1-20071227-C00498
    8.9 817.3
  • FORMULA 6
    Figure US20070299073A1-20071227-C00499
    R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00500
    4.7 525.3
    2
    Figure US20070299073A1-20071227-C00501
    6.0 534.3
    3
    Figure US20070299073A1-20071227-C00502
    6.4 536.3
    4
    Figure US20070299073A1-20071227-C00503
    6.5 597.3
    5
    Figure US20070299073A1-20071227-C00504
    6.1 510.4
    6
    Figure US20070299073A1-20071227-C00505
    4.9 559.3
    7
    Figure US20070299073A1-20071227-C00506
    6.4 611.4
    8
    Figure US20070299073A1-20071227-C00507
    7.1 620.4
  • FORMULA 7
    Figure US20070299073A1-20071227-C00508
    R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00509
    4.6 469.4
    2
    Figure US20070299073A1-20071227-C00510
    5.0 533.3
    3
    Figure US20070299073A1-20071227-C00511
    4.6 485.4
    4
    Figure US20070299073A1-20071227-C00512
    4.9 489.4
    5
    Figure US20070299073A1-20071227-C00513
    5.3 523.3
  • FORMULA 8
    Figure US20070299073A1-20071227-C00514
    R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00515
    7.0 687.5
    2
    Figure US20070299073A1-20071227-C00516
    7.3 751.3
    3
    Figure US20070299073A1-20071227-C00517
    6.9 703.4
    4
    Figure US20070299073A1-20071227-C00518
    7.2 707.4
    5
    Figure US20070299073A1-20071227-C00519
    7.5 741.3
  • FORMULA 9
    Figure US20070299073A1-20071227-C00520
    R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00521
    3.8; 3.4 420.3
    2
    Figure US20070299073A1-20071227-C00522
    3.8; 3.6 417.3
    3
    Figure US20070299073A1-20071227-C00523
    3.8; 3.5 439.3
    4
    Figure US20070299073A1-20071227-C00524
    3.7; 3.4 403.3
    5
    Figure US20070299073A1-20071227-C00525
    3.9; 3.6 411.4
  • FORMULA 10
    Figure US20070299073A1-20071227-C00526
    R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00527
    4.4 520.2
    2
    Figure US20070299073A1-20071227-C00528
    4.5 517.2
    3
    Figure US20070299073A1-20071227-C00529
    4.4 539.3
    4
    Figure US20070299073A1-20071227-C00530
    4.4 503.2
    5
    Figure US20070299073A1-20071227-C00531
    4.5 511.3
    6
    Figure US20070299073A1-20071227-C00532
    5.1 523.3
    7
    Figure US20070299073A1-20071227-C00533
    5.5 559.3
  • FORMULA 11
    Figure US20070299073A1-20071227-C00534
    Analyses
    * = (M + TFA − H)−
    R2 Tr (min) (M + H)+
    1
    Figure US20070299073A1-20071227-C00535
    4.6 455.2
    2
    Figure US20070299073A1-20071227-C00536
    4.9 515.2
    3
    Figure US20070299073A1-20071227-C00537
    4.8 473.2
    4
    Figure US20070299073A1-20071227-C00538
    4.9 612.2*
    5
    Figure US20070299073A1-20071227-C00539
    4.8 500.2
    6
    Figure US20070299073A1-20071227-C00540
    4.2 526.3
    7
    Figure US20070299073A1-20071227-C00541
    5.4 539.2
    8
    Figure US20070299073A1-20071227-C00542
    5.1 539.1
    9
    Figure US20070299073A1-20071227-C00543
    5.1 483.3
    10
    Figure US20070299073A1-20071227-C00544
    5.0 495.2
    11
    Figure US20070299073A1-20071227-C00545
    4.1 519.2*
    12
    Figure US20070299073A1-20071227-C00546
    4.4 524.3
  • FORMULA 12
    Figure US20070299073A1-20071227-C00547
    Analyses
    R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00548
    6.9 673.3
    2
    Figure US20070299073A1-20071227-C00549
    7.0 733.3
    3
    Figure US20070299073A1-20071227-C00550
    7.0 691.3
    4
    Figure US20070299073A1-20071227-C00551
    7.1 718.3
    5
    Figure US20070299073A1-20071227-C00552
    7.0 718.3
    6
    Figure US20070299073A1-20071227-C00553
    7.4 744.4
    7
    Figure US20070299073A1-20071227-C00554
    7.6 757.3
    8
    Figure US20070299073A1-20071227-C00555
    7.3 757.2
    9
    Figure US20070299073A1-20071227-C00556
    7.3 701.3
    10
    Figure US20070299073A1-20071227-C00557
    7.2 713.3
    11
    Figure US20070299073A1-20071227-C00558
    6.5 625.3
    12
    Figure US20070299073A1-20071227-C00559
    6.3 742.3
  • FORMULA 13
    Figure US20070299073A1-20071227-C00560
    Analyses
    R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00561
    3.8 425.3
    2
    Figure US20070299073A1-20071227-C00562
    4.2 485.4
    3
    Figure US20070299073A1-20071227-C00563
    4.0 438.4
    4
    Figure US20070299073A1-20071227-C00564
    4.0 403.3
    5
    Figure US20070299073A1-20071227-C00565
    3.9 425.4
    6
    Figure US20070299073A1-20071227-C00566
    3.6 452.4
    7
    Figure US20070299073A1-20071227-C00567
    3.8 403.3
    8
    Figure US20070299073A1-20071227-C00568
    5.1 438.3
    9
    Figure US20070299073A1-20071227-C00569
    4.6 432.3
    10
    Figure US20070299073A1-20071227-C00570
    6.2 506.4
    11
    Figure US20070299073A1-20071227-C00571
    3.8 409.3
  • FORMULA 14
    Figure US20070299073A1-20071227-C00572
    Analysis
    R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00573
    4.6 525.3
    2
    Figure US20070299073A1-20071227-C00574
    5.0 585.3
    3
    Figure US20070299073A1-20071227-C00575
    4.8 538.3
    4
    Figure US20070299073A1-20071227-C00576
    4.9 503.3
    5
    Figure US20070299073A1-20071227-C00577
    4.6 525.4
    6
    Figure US20070299073A1-20071227-C00578
    4.3 552.3
    7
    Figure US20070299073A1-20071227-C00579
    4.6 503.3
  • FORMULA 15
    Figure US20070299073A1-20071227-C00580
    Analysis
    Tr [M +
    R1 R2 (min) H]+
    1
    Figure US20070299073A1-20071227-C00581
    Figure US20070299073A1-20071227-C00582
    5.9 623.4
    2
    Figure US20070299073A1-20071227-C00583
    Figure US20070299073A1-20071227-C00584
    7.6 699.4
    3
    Figure US20070299073A1-20071227-C00585
    Figure US20070299073A1-20071227-C00586
    7.9 733.3
    4
    Figure US20070299073A1-20071227-C00587
    Figure US20070299073A1-20071227-C00588
    7.9 682.4
    5
    Figure US20070299073A1-20071227-C00589
    Figure US20070299073A1-20071227-C00590
    7.7 668.4
    6
    Figure US20070299073A1-20071227-C00591
    Figure US20070299073A1-20071227-C00592
    7.9 710.3
    7
    Figure US20070299073A1-20071227-C00593
    Figure US20070299073A1-20071227-C00594
    7.7 699.4
    8
    Figure US20070299073A1-20071227-C00595
    Figure US20070299073A1-20071227-C00596
    7.9 688.3
    9
    Figure US20070299073A1-20071227-C00597
    Figure US20070299073A1-20071227-C00598
    8.2 722.3
    10
    Figure US20070299073A1-20071227-C00599
    Figure US20070299073A1-20071227-C00600
    7.5 712.4
    11
    Figure US20070299073A1-20071227-C00601
    Figure US20070299073A1-20071227-C00602
    7.6 634.4
    12
    Figure US20070299073A1-20071227-C00603
    Figure US20070299073A1-20071227-C00604
    7.3 673.3
    13
    Figure US20070299073A1-20071227-C00605
    Figure US20070299073A1-20071227-C00606
    7.6 707.3
    14
    Figure US20070299073A1-20071227-C00607
    Figure US20070299073A1-20071227-C00608
    7.6 656.4
    15
    Figure US20070299073A1-20071227-C00609
    Figure US20070299073A1-20071227-C00610
    7.4 642.4
    16
    Figure US20070299073A1-20071227-C00611
    Figure US20070299073A1-20071227-C00612
    7.6 684.3
    17
    Figure US20070299073A1-20071227-C00613
    Figure US20070299073A1-20071227-C00614
    7.4 673.3
    18
    Figure US20070299073A1-20071227-C00615
    Figure US20070299073A1-20071227-C00616
    7.6 662.3
    19
    Figure US20070299073A1-20071227-C00617
    Figure US20070299073A1-20071227-C00618
    7.9 696.3
    20
    Figure US20070299073A1-20071227-C00619
    Figure US20070299073A1-20071227-C00620
    7.2 686.4
    21
    Figure US20070299073A1-20071227-C00621
    Figure US20070299073A1-20071227-C00622
    7.3 608.4
    22
    Figure US20070299073A1-20071227-C00623
    Figure US20070299073A1-20071227-C00624
    6.0 722.3
    23
    Figure US20070299073A1-20071227-C00625
    Figure US20070299073A1-20071227-C00626
    6.4 756.3
    24
    Figure US20070299073A1-20071227-C00627
    Figure US20070299073A1-20071227-C00628
    6.3 705.4
    25
    Figure US20070299073A1-20071227-C00629
    Figure US20070299073A1-20071227-C00630
    6.1 691.4
    26
    Figure US20070299073A1-20071227-C00631
    Figure US20070299073A1-20071227-C00632
    6.4 733.3
    27
    Figure US20070299073A1-20071227-C00633
    Figure US20070299073A1-20071227-C00634
    6.1 722.3
    28
    Figure US20070299073A1-20071227-C00635
    Figure US20070299073A1-20071227-C00636
    6.3 711.3
    29
    Figure US20070299073A1-20071227-C00637
    Figure US20070299073A1-20071227-C00638
    6.7 745.2
    30
    Figure US20070299073A1-20071227-C00639
    Figure US20070299073A1-20071227-C00640
    5.9 735.3
    31
    Figure US20070299073A1-20071227-C00641
    Figure US20070299073A1-20071227-C00642
    6.0 657.4
  • FORMULA 16
    Figure US20070299073A1-20071227-C00643
    Analysis
    R1 R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00644
    Figure US20070299073A1-20071227-C00645
    5.7 477.2
    2
    Figure US20070299073A1-20071227-C00646
    Figure US20070299073A1-20071227-C00647
    6.0 511.1
    3
    Figure US20070299073A1-20071227-C00648
    Figure US20070299073A1-20071227-C00649
    6.1 540.2
    4
    Figure US20070299073A1-20071227-C00650
    Figure US20070299073A1-20071227-C00651
    6.3 574.1
    5
    Figure US20070299073A1-20071227-C00652
    Figure US20070299073A1-20071227-C00653
    6.0 523.3
    6
    Figure US20070299073A1-20071227-C00654
    Figure US20070299073A1-20071227-C00655
    4.4 437.3
    7
    Figure US20070299073A1-20071227-C00656
    Figure US20070299073A1-20071227-C00657
    4.2 423.3
    8
    Figure US20070299073A1-20071227-C00658
    Figure US20070299073A1-20071227-C00659
    4.8 443.3
    9
    Figure US20070299073A1-20071227-C00660
    Figure US20070299073A1-20071227-C00661
    6.8 563.2
    10
    Figure US20070299073A1-20071227-C00662
    Figure US20070299073A1-20071227-C00663
    7.0 597.2
    11
    Figure US20070299073A1-20071227-C00664
    Figure US20070299073A1-20071227-C00665
    6.1 479.3
    12
    Figure US20070299073A1-20071227-C00666
    Figure US20070299073A1-20071227-C00667
    6.5 513.2
    13
    Figure US20070299073A1-20071227-C00668
    Figure US20070299073A1-20071227-C00669
    6.0 462.3
    14
    Figure US20070299073A1-20071227-C00670
    Figure US20070299073A1-20071227-C00671
    5.8/5.9 448.3
    15
    Figure US20070299073A1-20071227-C00672
    Figure US20070299073A1-20071227-C00673
    6.4 490.2
    16
    Figure US20070299073A1-20071227-C00674
    Figure US20070299073A1-20071227-C00675
    6.1 479.3
    17
    Figure US20070299073A1-20071227-C00676
    Figure US20070299073A1-20071227-C00677
    6.4 468.2
    18
    Figure US20070299073A1-20071227-C00678
    Figure US20070299073A1-20071227-C00679
    6.8 502.2
    19
    Figure US20070299073A1-20071227-C00680
    Figure US20070299073A1-20071227-C00681
    6.0 492.3
    20
    Figure US20070299073A1-20071227-C00682
    Figure US20070299073A1-20071227-C00683
    6.5 512.2
    21
    Figure US20070299073A1-20071227-C00684
    Figure US20070299073A1-20071227-C00685
    5.9 453.3
    22
    Figure US20070299073A1-20071227-C00686
    Figure US20070299073A1-20071227-C00687
    6.2 487.2
    23
    Figure US20070299073A1-20071227-C00688
    Figure US20070299073A1-20071227-C00689
    5.7 436.3
    24
    Figure US20070299073A1-20071227-C00690
    Figure US20070299073A1-20071227-C00691
    5.5/5.6 422.3
    25
    Figure US20070299073A1-20071227-C00692
    Figure US20070299073A1-20071227-C00693
    6.2 464.2
    26
    Figure US20070299073A1-20071227-C00694
    Figure US20070299073A1-20071227-C00695
    5.9/6.0 453.3
    27
    Figure US20070299073A1-20071227-C00696
    Figure US20070299073A1-20071227-C00697
    6.1 442.2
    28
    Figure US20070299073A1-20071227-C00698
    Figure US20070299073A1-20071227-C00699
    6.5 476.2
    29
    Figure US20070299073A1-20071227-C00700
    Figure US20070299073A1-20071227-C00701
    5.7 466.3
    30
    Figure US20070299073A1-20071227-C00702
    Figure US20070299073A1-20071227-C00703
    6.2 486.2
    31
    Figure US20070299073A1-20071227-C00704
    Figure US20070299073A1-20071227-C00705
    4.7 502.2
    32
    Figure US20070299073A1-20071227-C00706
    Figure US20070299073A1-20071227-C00707
    5.0 536.2
    33
    Figure US20070299073A1-20071227-C00708
    Figure US20070299073A1-20071227-C00709
    4.6 485.3
    34
    Figure US20070299073A1-20071227-C00710
    Figure US20070299073A1-20071227-C00711
    4.5 471.3
    35
    Figure US20070299073A1-20071227-C00712
    Figure US20070299073A1-20071227-C00713
    5.0 513.2
    36
    Figure US20070299073A1-20071227-C00714
    Figure US20070299073A1-20071227-C00715
    4.7 502.2
    37
    Figure US20070299073A1-20071227-C00716
    Figure US20070299073A1-20071227-C00717
    4.9 491.2
    38
    Figure US20070299073A1-20071227-C00718
    Figure US20070299073A1-20071227-C00719
    5.3 525.2
    39
    Figure US20070299073A1-20071227-C00720
    Figure US20070299073A1-20071227-C00721
    4.6 515.2
    40
    Figure US20070299073A1-20071227-C00722
    Figure US20070299073A1-20071227-C00723
    5.0 535.1
  • FORMULA 17
    Figure US20070299073A1-20071227-C00724
    Analyses
    R1 R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00725
    Figure US20070299073A1-20071227-C00726
    14.3 403.2
    2
    Figure US20070299073A1-20071227-C00727
    Figure US20070299073A1-20071227-C00728
    15.0 479.2
    3
    Figure US20070299073A1-20071227-C00729
    Figure US20070299073A1-20071227-C00730
    14.8 453.2
    4
    Figure US20070299073A1-20071227-C00731
    Figure US20070299073A1-20071227-C00732
    14.4 463.2
    5
    Figure US20070299073A1-20071227-C00733
    Figure US20070299073A1-20071227-C00734
    14.6 437.1
    6
    Figure US20070299073A1-20071227-C00735
    Figure US20070299073A1-20071227-C00736
    15.0 471.1
    7
    Figure US20070299073A1-20071227-C00737
    Figure US20070299073A1-20071227-C00738
    14.8 451.1
    8
    Figure US20070299073A1-20071227-C00739
    Figure US20070299073A1-20071227-C00740
    14.8 481.0
    9
    Figure US20070299073A1-20071227-C00741
    Figure US20070299073A1-20071227-C00742
    14.5 421.2
    10
    Figure US20070299073A1-20071227-C00743
    Figure US20070299073A1-20071227-C00744
    14.3 428.1
    11
    Figure US20070299073A1-20071227-C00745
    Figure US20070299073A1-20071227-C00746
    14.6 444.2
    12
    Figure US20070299073A1-20071227-C00747
    Figure US20070299073A1-20071227-C00748
    14.5 448.1
    13
    Figure US20070299073A1-20071227-C00749
    Figure US20070299073A1-20071227-C00750
    14.5 448.1
    14
    Figure US20070299073A1-20071227-C00751
    Figure US20070299073A1-20071227-C00752
    14.0 355.2
    15
    Figure US20070299073A1-20071227-C00753
    Figure US20070299073A1-20071227-C00754
    14.3 403.2
    16
    Figure US20070299073A1-20071227-C00755
    Figure US20070299073A1-20071227-C00756
    15.2 479.2
    17
    Figure US20070299073A1-20071227-C00757
    Figure US20070299073A1-20071227-C00758
    14.9 453.2
    18
    Figure US20070299073A1-20071227-C00759
    Figure US20070299073A1-20071227-C00760
    14.4 433.2
    19
    Figure US20070299073A1-20071227-C00761
    Figure US20070299073A1-20071227-C00762
    14.5 463.2
    20
    Figure US20070299073A1-20071227-C00763
    Figure US20070299073A1-20071227-C00764
    14.8 437.1
    21
    Figure US20070299073A1-20071227-C00765
    Figure US20070299073A1-20071227-C00766
    15.1 474.1
    22
    Figure US20070299073A1-20071227-C00767
    Figure US20070299073A1-20071227-C00768
    15.0 451.1
    23
    Figure US20070299073A1-20071227-C00769
    Figure US20070299073A1-20071227-C00770
    14.8 481.0
    24
    Figure US20070299073A1-20071227-C00771
    Figure US20070299073A1-20071227-C00772
    14.5 421.2
    25
    Figure US20070299073A1-20071227-C00773
    Figure US20070299073A1-20071227-C00774
    14.4 428.1
    26
    Figure US20070299073A1-20071227-C00775
    Figure US20070299073A1-20071227-C00776
    14.7 444.1
    27
    Figure US20070299073A1-20071227-C00777
    Figure US20070299073A1-20071227-C00778
    14.6 448.1
    28
    Figure US20070299073A1-20071227-C00779
    Figure US20070299073A1-20071227-C00780
    14.5 448.1
    29
    Figure US20070299073A1-20071227-C00781
    Figure US20070299073A1-20071227-C00782
    13.9 355.2
    30
    Figure US20070299073A1-20071227-C00783
    Figure US20070299073A1-20071227-C00784
    15.2 364.2
    31
    Figure US20070299073A1-20071227-C00785
    Figure US20070299073A1-20071227-C00786
    16.3 440.2
    32
    Figure US20070299073A1-20071227-C00787
    Figure US20070299073A1-20071227-C00788
    15.9 414.2
    33
    Figure US20070299073A1-20071227-C00789
    Figure US20070299073A1-20071227-C00790
    15.1 394.2
    34
    Figure US20070299073A1-20071227-C00791
    Figure US20070299073A1-20071227-C00792
    15.1 424.2
    35
    Figure US20070299073A1-20071227-C00793
    Figure US20070299073A1-20071227-C00794
    15.1 435.2
    36
    Figure US20070299073A1-20071227-C00795
    Figure US20070299073A1-20071227-C00796
    15.8 398.1
    37
    Figure US20070299073A1-20071227-C00797
    Figure US20070299073A1-20071227-C00798
    16.8 432.1
    38
    Figure US20070299073A1-20071227-C00799
    Figure US20070299073A1-20071227-C00800
    16.3 412.1
    39
    Figure US20070299073A1-20071227-C00801
    Figure US20070299073A1-20071227-C00802
    16.1 442.0
    40
    Figure US20070299073A1-20071227-C00803
    Figure US20070299073A1-20071227-C00804
    15.6 409.1
    41
    Figure US20070299073A1-20071227-C00805
    Figure US20070299073A1-20071227-C00806
    15.6 409.1
    42
    Figure US20070299073A1-20071227-C00807
    Figure US20070299073A1-20071227-C00808
    14.4 316.2
    43
    Figure US20070299073A1-20071227-C00809
    Figure US20070299073A1-20071227-C00810
    15.1 479.2
    44
    Figure US20070299073A1-20071227-C00811
    Figure US20070299073A1-20071227-C00812
    15.6 529.2
    45
    Figure US20070299073A1-20071227-C00813
    Figure US20070299073A1-20071227-C00814
    15.0 509.2
    46
    Figure US20070299073A1-20071227-C00815
    Figure US20070299073A1-20071227-C00816
    15.2 539.2
    47
    Figure US20070299073A1-20071227-C00817
    Figure US20070299073A1-20071227-C00818
    15.2 550.2
    48
    Figure US20070299073A1-20071227-C00819
    Figure US20070299073A1-20071227-C00820
    15.6 513.1
    49
    Figure US20070299073A1-20071227-C00821
    Figure US20070299073A1-20071227-C00822
    16.0 547.1
    50
    Figure US20070299073A1-20071227-C00823
    Figure US20070299073A1-20071227-C00824
    15.8 527.2
    51
    Figure US20070299073A1-20071227-C00825
    Figure US20070299073A1-20071227-C00826
    15.6 557.0
    52
    Figure US20070299073A1-20071227-C00827
    Figure US20070299073A1-20071227-C00828
    15.2 497.2
    53
    Figure US20070299073A1-20071227-C00829
    Figure US20070299073A1-20071227-C00830
    15.7 520.2
    54
    Figure US20070299073A1-20071227-C00831
    Figure US20070299073A1-20071227-C00832
    15.4 524.2
    55
    Figure US20070299073A1-20071227-C00833
    Figure US20070299073A1-20071227-C00834
    14.5 431.2
  • FORMULA 18
    Figure US20070299073A1-20071227-C00835
    Analyses
    R1 R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C00836
    Figure US20070299073A1-20071227-C00837
    15.4 521.2
    2
    Figure US20070299073A1-20071227-C00838
    Figure US20070299073A1-20071227-C00839
    16.5 597.1
    3
    Figure US20070299073A1-20071227-C00840
    Figure US20070299073A1-20071227-C00841
    16.1 571.2
    4
    Figure US20070299073A1-20071227-C00842
    Figure US20070299073A1-20071227-C00843
    15.3 551.2
    5
    Figure US20070299073A1-20071227-C00844
    Figure US20070299073A1-20071227-C00845
    15.3 581.2
    6
    Figure US20070299073A1-20071227-C00846
    Figure US20070299073A1-20071227-C00847
    15.8 592.2
    7
    Figure US20070299073A1-20071227-C00848
    Figure US20070299073A1-20071227-C00849
    16.1 555.1
    8
    Figure US20070299073A1-20071227-C00850
    Figure US20070299073A1-20071227-C00851
    16.7 589.0
    9
    Figure US20070299073A1-20071227-C00852
    Figure US20070299073A1-20071227-C00853
    16.4 569.1
    10
    Figure US20070299073A1-20071227-C00854
    Figure US20070299073A1-20071227-C00855
    16.1 599.0
    11
    Figure US20070299073A1-20071227-C00856
    Figure US20070299073A1-20071227-C00857
    15.6 539.1
    12
    Figure US20070299073A1-20071227-C00858
    Figure US20070299073A1-20071227-C00859
    15.4 546.2
    13
    Figure US20070299073A1-20071227-C00860
    Figure US20070299073A1-20071227-C00861
    15.8 562.1
    14
    Figure US20070299073A1-20071227-C00862
    Figure US20070299073A1-20071227-C00863
    15.8 566.1
    15
    Figure US20070299073A1-20071227-C00864
    Figure US20070299073A1-20071227-C00865
    15.7 566.1
    16
    Figure US20070299073A1-20071227-C00866
    Figure US20070299073A1-20071227-C00867
    14.8 473.2
    17
    Figure US20070299073A1-20071227-C00868
    Figure US20070299073A1-20071227-C00869
    15.5 521.2
    18
    Figure US20070299073A1-20071227-C00870
    Figure US20070299073A1-20071227-C00871
    16.5 597.1
    19
    Figure US20070299073A1-20071227-C00872
    Figure US20070299073A1-20071227-C00873
    16.1 571.1
    20
    Figure US20070299073A1-20071227-C00874
    Figure US20070299073A1-20071227-C00875
    15.4 551.2
    21
    Figure US20070299073A1-20071227-C00876
    Figure US20070299073A1-20071227-C00877
    15.4 581.1
    22
    Figure US20070299073A1-20071227-C00878
    Figure US20070299073A1-20071227-C00879
    15.9 592.2
    23
    Figure US20070299073A1-20071227-C00880
    Figure US20070299073A1-20071227-C00881
    16.3 555.1
    24
    Figure US20070299073A1-20071227-C00882
    Figure US20070299073A1-20071227-C00883
    16.8 589.0
    25
    Figure US20070299073A1-20071227-C00884
    Figure US20070299073A1-20071227-C00885
    16.7 569.1
    26
    Figure US20070299073A1-20071227-C00886
    Figure US20070299073A1-20071227-C00887
    16.4 599.0
    27
    Figure US20070299073A1-20071227-C00888
    Figure US20070299073A1-20071227-C00889
    15.8 539.1
    28
    Figure US20070299073A1-20071227-C00890
    Figure US20070299073A1-20071227-C00891
    15.6 546.1
    29
    Figure US20070299073A1-20071227-C00892
    Figure US20070299073A1-20071227-C00893
    16.0 562.1
    30
    Figure US20070299073A1-20071227-C00894
    Figure US20070299073A1-20071227-C00895
    15.9 566.1
    31
    Figure US20070299073A1-20071227-C00896
    Figure US20070299073A1-20071227-C00897
    15.8 566.1
    32
    Figure US20070299073A1-20071227-C00898
    Figure US20070299073A1-20071227-C00899
    15.0 473.2
    33
    Figure US20070299073A1-20071227-C00900
    Figure US20070299073A1-20071227-C00901
    16.7 482.2
    34
    Figure US20070299073A1-20071227-C00902
    Figure US20070299073A1-20071227-C00903
    18.0 558.2
    35
    Figure US20070299073A1-20071227-C00904
    Figure US20070299073A1-20071227-C00905
    16.4 512.2
    36
    Figure US20070299073A1-20071227-C00906
    Figure US20070299073A1-20071227-C00907
    16.5 542.2
    37
    Figure US20070299073A1-20071227-C00908
    Figure US20070299073A1-20071227-C00909
    17.0 553.2
    38
    Figure US20070299073A1-20071227-C00910
    Figure US20070299073A1-20071227-C00911
    17.6 516.1
    39
    Figure US20070299073A1-20071227-C00912
    Figure US20070299073A1-20071227-C00913
    18.2 550.1
    40
    Figure US20070299073A1-20071227-C00914
    Figure US20070299073A1-20071227-C00915
    18.0 530.1
    41
    Figure US20070299073A1-20071227-C00916
    Figure US20070299073A1-20071227-C00917
    17.7 560.0
    42
    Figure US20070299073A1-20071227-C00918
    Figure US20070299073A1-20071227-C00919
    16.9 500.2
    43
    Figure US20070299073A1-20071227-C00920
    Figure US20070299073A1-20071227-C00921
    16.7 507.2
    44
    Figure US20070299073A1-20071227-C00922
    Figure US20070299073A1-20071227-C00923
    17.2 523.2
    45
    Figure US20070299073A1-20071227-C00924
    Figure US20070299073A1-20071227-C00925
    16.9 527.2
    46
    Figure US20070299073A1-20071227-C00926
    Figure US20070299073A1-20071227-C00927
    16.8 527.2
    47
    Figure US20070299073A1-20071227-C00928
    Figure US20070299073A1-20071227-C00929
    15.8 434.2
    48
    Figure US20070299073A1-20071227-C00930
    Figure US20070299073A1-20071227-C00931
    15.8 597.2
    49
    Figure US20070299073A1-20071227-C00932
    Figure US20070299073A1-20071227-C00933
    16.8 673.2
    50
    Figure US20070299073A1-20071227-C00934
    Figure US20070299073A1-20071227-C00935
    16.5 647.2
    51
    Figure US20070299073A1-20071227-C00936
    Figure US20070299073A1-20071227-C00937
    15.8 627.2
    52
    Figure US20070299073A1-20071227-C00938
    Figure US20070299073A1-20071227-C00939
    15.8 657.2
    53
    Figure US20070299073A1-20071227-C00940
    Figure US20070299073A1-20071227-C00941
    16.5 631.1
    54
    Figure US20070299073A1-20071227-C00942
    Figure US20070299073A1-20071227-C00943
    17.2 665.1
    55
    Figure US20070299073A1-20071227-C00944
    Figure US20070299073A1-20071227-C00945
    16.7 645.1
    56
    Figure US20070299073A1-20071227-C00946
    Figure US20070299073A1-20071227-C00947
    16.5 675.1
    57
    Figure US20070299073A1-20071227-C00948
    Figure US20070299073A1-20071227-C00949
    16.0 615.1
    58
    Figure US20070299073A1-20071227-C00950
    Figure US20070299073A1-20071227-C00951
    15.9 622.1
    59
    Figure US20070299073A1-20071227-C00952
    Figure US20070299073A1-20071227-C00953
    16.1 638.2
    60
    Figure US20070299073A1-20071227-C00954
    Figure US20070299073A1-20071227-C00955
    16.1 642.1
    61
    Figure US20070299073A1-20071227-C00956
    Figure US20070299073A1-20071227-C00957
    16.2 642.1
    62
    Figure US20070299073A1-20071227-C00958
    Figure US20070299073A1-20071227-C00959
    15.4 549.2
    63
    Figure US20070299073A1-20071227-C00960
    Figure US20070299073A1-20071227-C00961
    15.9 563.2
    64
    Figure US20070299073A1-20071227-C00962
    Figure US20070299073A1-20071227-C00963
    17.0 639.2
    65
    Figure US20070299073A1-20071227-C00964
    Figure US20070299073A1-20071227-C00965
    16.5 613.2
    66
    Figure US20070299073A1-20071227-C00966
    Figure US20070299073A1-20071227-C00967
    15.7 593.2
    67
    Figure US20070299073A1-20071227-C00968
    Figure US20070299073A1-20071227-C00969
    15.8 623.2
    68
    Figure US20070299073A1-20071227-C00970
    Figure US20070299073A1-20071227-C00971
    16.2 634.2
    69
    Figure US20070299073A1-20071227-C00972
    Figure US20070299073A1-20071227-C00973
    16.6 597.1
    70
    Figure US20070299073A1-20071227-C00974
    Figure US20070299073A1-20071227-C00975
    17.4 631.1
    71
    Figure US20070299073A1-20071227-C00976
    Figure US20070299073A1-20071227-C00977
    17.0 611.1
    72
    Figure US20070299073A1-20071227-C00978
    Figure US20070299073A1-20071227-C00979
    16.7 641.1
    73
    Figure US20070299073A1-20071227-C00980
    Figure US20070299073A1-20071227-C00981
    16.1 581.2
    74
    Figure US20070299073A1-20071227-C00982
    Figure US20070299073A1-20071227-C00983
    15.9 588.2
    75
    Figure US20070299073A1-20071227-C00984
    Figure US20070299073A1-20071227-C00985
    16.2 604.2
    76
    Figure US20070299073A1-20071227-C00986
    Figure US20070299073A1-20071227-C00987
    16.2 608.2
    77
    Figure US20070299073A1-20071227-C00988
    Figure US20070299073A1-20071227-C00989
    16.1 608.2
    78
    Figure US20070299073A1-20071227-C00990
    Figure US20070299073A1-20071227-C00991
    15.3 515.3
  • FORMULA 19
    Figure US20070299073A1-20071227-C00992
    Analyses
    * = [M +
    TFA − H]−
    R1 R2 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C00993
    Figure US20070299073A1-20071227-C00994
    6.2 433.2
    2
    Figure US20070299073A1-20071227-C00995
    Figure US20070299073A1-20071227-C00996
    7.0 509.2
    3
    Figure US20070299073A1-20071227-C00997
    Figure US20070299073A1-20071227-C00998
    6.8 483.2
    4
    Figure US20070299073A1-20071227-C00999
    Figure US20070299073A1-20071227-C01000
    6.2 463.2
    5
    Figure US20070299073A1-20071227-C01001
    Figure US20070299073A1-20071227-C01002
    6.5 493.2
    6
    Figure US20070299073A1-20071227-C01003
    Figure US20070299073A1-20071227-C01004
    5.4 504.3
    7
    Figure US20070299073A1-20071227-C01005
    Figure US20070299073A1-20071227-C01006
    6.5 467.2
    8
    Figure US20070299073A1-20071227-C01007
    Figure US20070299073A1-20071227-C01008
    6.9 501.1
    9
    Figure US20070299073A1-20071227-C01009
    Figure US20070299073A1-20071227-C01010
    6.8 481.2
    10
    Figure US20070299073A1-20071227-C01011
    Figure US20070299073A1-20071227-C01012
    6.6 511.1
    11
    Figure US20070299073A1-20071227-C01013
    Figure US20070299073A1-20071227-C01014
    6.3 451.2
    12
    Figure US20070299073A1-20071227-C01015
    Figure US20070299073A1-20071227-C01016
    6.2 458.2
    13
    Figure US20070299073A1-20071227-C01017
    Figure US20070299073A1-20071227-C01018
    6.5 474.2
    14
    Figure US20070299073A1-20071227-C01019
    Figure US20070299073A1-20071227-C01020
    6.3 478.2
    15
    Figure US20070299073A1-20071227-C01021
    Figure US20070299073A1-20071227-C01022
    6.3 478.2
    16
    Figure US20070299073A1-20071227-C01023
    Figure US20070299073A1-20071227-C01024
    5.7 385.2
    17
    Figure US20070299073A1-20071227-C01025
    Figure US20070299073A1-20071227-C01026
    6.9 433.2
    18
    Figure US20070299073A1-20071227-C01027
    Figure US20070299073A1-20071227-C01028
    7.0 509.2
    19
    Figure US20070299073A1-20071227-C01029
    Figure US20070299073A1-20071227-C01030
    6.7 483.2
    20
    Figure US20070299073A1-20071227-C01031
    Figure US20070299073A1-20071227-C01032
    6.2 463.2
    21
    Figure US20070299073A1-20071227-C01033
    Figure US20070299073A1-20071227-C01034
    6.3 493.2
    22
    Figure US20070299073A1-20071227-C01035
    Figure US20070299073A1-20071227-C01036
    5.3 504.3
    23
    Figure US20070299073A1-20071227-C01037
    Figure US20070299073A1-20071227-C01038
    6.5 467.2
    24
    Figure US20070299073A1-20071227-C01039
    Figure US20070299073A1-20071227-C01040
    6.8 501.1
    25
    Figure US20070299073A1-20071227-C01041
    Figure US20070299073A1-20071227-C01042
    6.7 481.2
    26
    Figure US20070299073A1-20071227-C01043
    Figure US20070299073A1-20071227-C01044
    6.5 511.1
    27
    Figure US20070299073A1-20071227-C01045
    Figure US20070299073A1-20071227-C01046
    6.2 451.2
    28
    Figure US20070299073A1-20071227-C01047
    Figure US20070299073A1-20071227-C01048
    6.1 458.2
    29
    Figure US20070299073A1-20071227-C01049
    Figure US20070299073A1-20071227-C01050
    6.4 474.2
    30
    Figure US20070299073A1-20071227-C01051
    Figure US20070299073A1-20071227-C01052
    6.3 478.2
    31
    Figure US20070299073A1-20071227-C01053
    Figure US20070299073A1-20071227-C01054
    6.3 478.2
    32
    Figure US20070299073A1-20071227-C01055
    Figure US20070299073A1-20071227-C01056
    5.6 385.2
    33
    Figure US20070299073A1-20071227-C01057
    Figure US20070299073A1-20071227-C01058
    6.5 481.1
    34
    Figure US20070299073A1-20071227-C01059
    Figure US20070299073A1-20071227-C01060
    7.4 557.1
    35
    Figure US20070299073A1-20071227-C01061
    Figure US20070299073A1-20071227-C01062
    7.1 531.1
    36
    Figure US20070299073A1-20071227-C01063
    Figure US20070299073A1-20071227-C01064
    6.6 511.1
    37
    Figure US20070299073A1-20071227-C01065
    Figure US20070299073A1-20071227-C01066
    6.8 541.1
    38
    Figure US20070299073A1-20071227-C01067
    Figure US20070299073A1-20071227-C01068
    5.7 552.2
    39
    Figure US20070299073A1-20071227-C01069
    Figure US20070299073A1-20071227-C01070
    6.9 515.0
    40
    Figure US20070299073A1-20071227-C01071
    Figure US20070299073A1-20071227-C01072
    7.3 549.0
    41
    Figure US20070299073A1-20071227-C01073
    Figure US20070299073A1-20071227-C01074
    7.1 529.1
    42
    Figure US20070299073A1-20071227-C01075
    Figure US20070299073A1-20071227-C01076
    7.0  670.1*
    43
    Figure US20070299073A1-20071227-C01077
    Figure US20070299073A1-20071227-C01078
    6.6 499.1
    44
    Figure US20070299073A1-20071227-C01079
    Figure US20070299073A1-20071227-C01080
    6.6 506.1
    45
    Figure US20070299073A1-20071227-C01081
    Figure US20070299073A1-20071227-C01082
    6.8 522.1
    46
    Figure US20070299073A1-20071227-C01083
    Figure US20070299073A1-20071227-C01084
    6.8 526.1
    47
    Figure US20070299073A1-20071227-C01085
    Figure US20070299073A1-20071227-C01086
    6.7 526.1
    48
    Figure US20070299073A1-20071227-C01087
    Figure US20070299073A1-20071227-C01088
    6.0 433.1
    49
    Figure US20070299073A1-20071227-C01089
    Figure US20070299073A1-20071227-C01090
    6.6 448.2
    50
    Figure US20070299073A1-20071227-C01091
    Figure US20070299073A1-20071227-C01092
    7.7 524.2
    51
    Figure US20070299073A1-20071227-C01093
    Figure US20070299073A1-20071227-C01094
    7.4 498.2
    52
    Figure US20070299073A1-20071227-C01095
    Figure US20070299073A1-20071227-C01096
    6.6 478.2
    53
    Figure US20070299073A1-20071227-C01097
    Figure US20070299073A1-20071227-C01098
    6.7 508.2
    54
    Figure US20070299073A1-20071227-C01099
    Figure US20070299073A1-20071227-C01100
    5.8 519.2
    55
    Figure US20070299073A1-20071227-C01101
    Figure US20070299073A1-20071227-C01102
    7.2 482.1
    56
    Figure US20070299073A1-20071227-C01103
    Figure US20070299073A1-20071227-C01104
    7.7 516.1
    57
    Figure US20070299073A1-20071227-C01105
    Figure US20070299073A1-20071227-C01106
    7.5 496.2
    58
    Figure US20070299073A1-20071227-C01107
    Figure US20070299073A1-20071227-C01108
    7.3 526.1
    59
    Figure US20070299073A1-20071227-C01109
    Figure US20070299073A1-20071227-C01110
    6.8 466.2
    60
    Figure US20070299073A1-20071227-C01111
    Figure US20070299073A1-20071227-C01112
    6.8 473.2
    61
    Figure US20070299073A1-20071227-C01113
    Figure US20070299073A1-20071227-C01114
    7.1 489.2
    62
    Figure US20070299073A1-20071227-C01115
    Figure US20070299073A1-20071227-C01116
    7.1 493.1
    63
    Figure US20070299073A1-20071227-C01117
    Figure US20070299073A1-20071227-C01118
    7.0 493.2
    64
    Figure US20070299073A1-20071227-C01119
    Figure US20070299073A1-20071227-C01120
    5.8 400.2
    65
    Figure US20070299073A1-20071227-C01121
    Figure US20070299073A1-20071227-C01122
    5.8 383.2
    66
    Figure US20070299073A1-20071227-C01123
    Figure US20070299073A1-20071227-C01124
    6.8 459.2
    67
    Figure US20070299073A1-20071227-C01125
    Figure US20070299073A1-20071227-C01126
    6.5 433.2
    68
    Figure US20070299073A1-20071227-C01127
    Figure US20070299073A1-20071227-C01128
    5.9 413.2
    69
    Figure US20070299073A1-20071227-C01129
    Figure US20070299073A1-20071227-C01130
    6.2 443.3
    70
    Figure US20070299073A1-20071227-C01131
    Figure US20070299073A1-20071227-C01132
    5.0 454.3
    71
    Figure US20070299073A1-20071227-C01133
    Figure US20070299073A1-20071227-C01134
    6.3 417.2
    72
    Figure US20070299073A1-20071227-C01135
    Figure US20070299073A1-20071227-C01136
    6.6 451.1
    73
    Figure US20070299073A1-20071227-C01137
    Figure US20070299073A1-20071227-C01138
    6.5 431.2
    74
    Figure US20070299073A1-20071227-C01139
    Figure US20070299073A1-20071227-C01140
    6.3 461.1
    75
    Figure US20070299073A1-20071227-C01141
    Figure US20070299073A1-20071227-C01142
    6.0 401.2
    76
    Figure US20070299073A1-20071227-C01143
    Figure US20070299073A1-20071227-C01144
    5.8 408.2
    77
    Figure US20070299073A1-20071227-C01145
    Figure US20070299073A1-20071227-C01146
    6.2 424.2
    78
    Figure US20070299073A1-20071227-C01147
    Figure US20070299073A1-20071227-C01148
    6.0 428.2
    79
    Figure US20070299073A1-20071227-C01149
    Figure US20070299073A1-20071227-C01150
    6.0 428.2
    80
    Figure US20070299073A1-20071227-C01151
    Figure US20070299073A1-20071227-C01152
    5.3 335.3
  • FORMULA 20
    Figure US20070299073A1-20071227-C01153
    LFPlb2-02font.xls
    Analyses
    R1 R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C01154
    Figure US20070299073A1-20071227-C01155
    6.9 487.2
    2
    Figure US20070299073A1-20071227-C01156
    Figure US20070299073A1-20071227-C01157
    6.3 461.3
    3
    Figure US20070299073A1-20071227-C01158
    Figure US20070299073A1-20071227-C01159
    6.3 447.3
    4
    Figure US20070299073A1-20071227-C01160
    Figure US20070299073A1-20071227-C01161
    6.2 493.3
    5
    Figure US20070299073A1-20071227-C01162
    Figure US20070299073A1-20071227-C01163
    6.7 482.2
    6
    Figure US20070299073A1-20071227-C01164
    Figure US20070299073A1-20071227-C01165
    7.2 509.3
    7
    Figure US20070299073A1-20071227-C01166
    Figure US20070299073A1-20071227-C01167
    7.7 473.4
    8
    Figure US20070299073A1-20071227-C01168
    Figure US20070299073A1-20071227-C01169
    5.8 472.3
    9
    Figure US20070299073A1-20071227-C01170
    Figure US20070299073A1-20071227-C01171
    7.3 507.2
    10
    Figure US20070299073A1-20071227-C01172
    Figure US20070299073A1-20071227-C01173
    6.6 459.3
    11
    Figure US20070299073A1-20071227-C01174
    Figure US20070299073A1-20071227-C01175
    6.6 487.2
    12
    Figure US20070299073A1-20071227-C01176
    Figure US20070299073A1-20071227-C01177
    6.7 470.3
    13
    Figure US20070299073A1-20071227-C01178
    Figure US20070299073A1-20071227-C01179
    7.2 538.2
    14
    Figure US20070299073A1-20071227-C01180
    Figure US20070299073A1-20071227-C01181
    6.6 456.3
    15
    Figure US20070299073A1-20071227-C01182
    Figure US20070299073A1-20071227-C01183
    6.6 431.3
    16
    Figure US20070299073A1-20071227-C01184
    Figure US20070299073A1-20071227-C01185
    6.5 439.3
    17
    Figure US20070299073A1-20071227-C01186
    Figure US20070299073A1-20071227-C01187
    7.1 517.3
    18
    Figure US20070299073A1-20071227-C01188
    Figure US20070299073A1-20071227-C01189
    6.5 491.3
    19
    Figure US20070299073A1-20071227-C01190
    Figure US20070299073A1-20071227-C01191
    6.4 477.3
    20
    Figure US20070299073A1-20071227-C01192
    Figure US20070299073A1-20071227-C01193
    6.4 523.3
    21
    Figure US20070299073A1-20071227-C01194
    Figure US20070299073A1-20071227-C01195
    6.9 512.3
    22
    Figure US20070299073A1-20071227-C01196
    Figure US20070299073A1-20071227-C01197
    7.3 539.3
    23
    Figure US20070299073A1-20071227-C01198
    Figure US20070299073A1-20071227-C01199
    7.8 503.4
    24
    Figure US20070299073A1-20071227-C01200
    Figure US20070299073A1-20071227-C01201
    6.0 502.3
    25
    Figure US20070299073A1-20071227-C01202
    Figure US20070299073A1-20071227-C01203
    7.4 537.3
    26
    Figure US20070299073A1-20071227-C01204
    Figure US20070299073A1-20071227-C01205
    6.8 489.3
    27
    Figure US20070299073A1-20071227-C01206
    Figure US20070299073A1-20071227-C01207
    6.8 517.2
    28
    Figure US20070299073A1-20071227-C01208
    Figure US20070299073A1-20071227-C01209
    6.8 500.3
    29
    Figure US20070299073A1-20071227-C01210
    Figure US20070299073A1-20071227-C01211
    7.4 562.2
    30
    Figure US20070299073A1-20071227-C01212
    Figure US20070299073A1-20071227-C01213
    6.7 486.4
    31
    Figure US20070299073A1-20071227-C01214
    Figure US20070299073A1-20071227-C01215
    6.8 461.3
    32
    Figure US20070299073A1-20071227-C01216
    Figure US20070299073A1-20071227-C01217
    6.7 469.3
    33
    Figure US20070299073A1-20071227-C01218
    Figure US20070299073A1-20071227-C01219
    7.4 532.3
    34
    Figure US20070299073A1-20071227-C01220
    Figure US20070299073A1-20071227-C01221
    6.6 506.3
    35
    Figure US20070299073A1-20071227-C01222
    Figure US20070299073A1-20071227-C01223
    6.6 492.3
    36
    Figure US20070299073A1-20071227-C01224
    Figure US20070299073A1-20071227-C01225
    6.6 538.3
    37
    Figure US20070299073A1-20071227-C01226
    Figure US20070299073A1-20071227-C01227
    7.3 527.2
    38
    Figure US20070299073A1-20071227-C01228
    Figure US20070299073A1-20071227-C01229
    7.5 554.3
    39
    Figure US20070299073A1-20071227-C01230
    Figure US20070299073A1-20071227-C01231
    8.1 518.3
    40
    Figure US20070299073A1-20071227-C01232
    Figure US20070299073A1-20071227-C01233
    6.1 517.3
    41
    Figure US20070299073A1-20071227-C01234
    Figure US20070299073A1-20071227-C01235
    8.1 552.2
    42
    Figure US20070299073A1-20071227-C01236
    Figure US20070299073A1-20071227-C01237
    7.0 504.3
    43
    Figure US20070299073A1-20071227-C01238
    Figure US20070299073A1-20071227-C01239
    7.2 532.1
    44
    Figure US20070299073A1-20071227-C01240
    Figure US20070299073A1-20071227-C01241
    7.4 515.3
    45
    Figure US20070299073A1-20071227-C01242
    Figure US20070299073A1-20071227-C01243
    8.1 583.2
    46
    Figure US20070299073A1-20071227-C01244
    Figure US20070299073A1-20071227-C01245
    6.8 501.3
    47
    Figure US20070299073A1-20071227-C01246
    Figure US20070299073A1-20071227-C01247
    6.9 476.3
    48
    Figure US20070299073A1-20071227-C01248
    Figure US20070299073A1-20071227-C01249
    7.0 484.3
    49
    Figure US20070299073A1-20071227-C01250
    Figure US20070299073A1-20071227-C01251
    7.3 565.2
    50
    Figure US20070299073A1-20071227-C01252
    Figure US20070299073A1-20071227-C01253
    6.7 539.2
    51
    Figure US20070299073A1-20071227-C01254
    Figure US20070299073A1-20071227-C01255
    6.7 525.2
    52
    Figure US20070299073A1-20071227-C01256
    Figure US20070299073A1-20071227-C01257
    6.7 571.2
    53
    Figure US20070299073A1-20071227-C01258
    Figure US20070299073A1-20071227-C01259
    7.1 560.1
    54
    Figure US20070299073A1-20071227-C01260
    Figure US20070299073A1-20071227-C01261
    7.6 587.2
    55
    Figure US20070299073A1-20071227-C01262
    Figure US20070299073A1-20071227-C01263
    8.0 551.3
    56
    Figure US20070299073A1-20071227-C01264
    Figure US20070299073A1-20071227-C01265
    6.3 550.2
    57
    Figure US20070299073A1-20071227-C01266
    Figure US20070299073A1-20071227-C01267
    7.7 585.1
    58
    Figure US20070299073A1-20071227-C01268
    Figure US20070299073A1-20071227-C01269
    7.0 537.2
    59
    Figure US20070299073A1-20071227-C01270
    Figure US20070299073A1-20071227-C01271
    7.0 565.0
    60
    Figure US20070299073A1-20071227-C01272
    Figure US20070299073A1-20071227-C01273
    7.2 548.2
    61
    Figure US20070299073A1-20071227-C01274
    Figure US20070299073A1-20071227-C01275
    7.7 616.1
    62
    Figure US20070299073A1-20071227-C01276
    Figure US20070299073A1-20071227-C01277
    7.0 534.2
    63
    Figure US20070299073A1-20071227-C01278
    Figure US20070299073A1-20071227-C01279
    7.0 509.2
    64
    Figure US20070299073A1-20071227-C01280
    Figure US20070299073A1-20071227-C01281
    6.9 517.2
    65
    Figure US20070299073A1-20071227-C01282
    Figure US20070299073A1-20071227-C01283
    6.8 467.3
    66
    Figure US20070299073A1-20071227-C01284
    Figure US20070299073A1-20071227-C01285
    6.1 444.3
    67
    Figure US20070299073A1-20071227-C01286
    Figure US20070299073A1-20071227-C01287
    6.1 427.3
    68
    Figure US20070299073A1-20071227-C01288
    Figure US20070299073A1-20071227-C01289
    6.1 473.4
    69
    Figure US20070299073A1-20071227-C01290
    Figure US20070299073A1-20071227-C01291
    6.6 462.3
    70
    Figure US20070299073A1-20071227-C01292
    Figure US20070299073A1-20071227-C01293
    7.1 489.4
    71
    Figure US20070299073A1-20071227-C01294
    Figure US20070299073A1-20071227-C01295
    7.6 453.4
    72
    Figure US20070299073A1-20071227-C01296
    Figure US20070299073A1-20071227-C01297
    5.6 452.3
    73
    Figure US20070299073A1-20071227-C01298
    Figure US20070299073A1-20071227-C01299
    7.2 487.3
    74
    Figure US20070299073A1-20071227-C01300
    Figure US20070299073A1-20071227-C01301
    6.5 439.3
    75
    Figure US20070299073A1-20071227-C01302
    Figure US20070299073A1-20071227-C01303
    6.5 467.2
    76
    Figure US20070299073A1-20071227-C01304
    Figure US20070299073A1-20071227-C01305
    6.5 450.3
    77
    Figure US20070299073A1-20071227-C01306
    Figure US20070299073A1-20071227-C01307
    7.1 518.2
    78
    Figure US20070299073A1-20071227-C01308
    Figure US20070299073A1-20071227-C01309
    6.3 436.3
    79
    Figure US20070299073A1-20071227-C01310
    Figure US20070299073A1-20071227-C01311
    6.5 411.3
    80
    Figure US20070299073A1-20071227-C01312
    Figure US20070299073A1-20071227-C01313
    6.4 419.3
  • FORMULA 21
    Figure US20070299073A1-20071227-C01314
    Analyses
    * = [M + TFA − H]
    R1 R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C01315
    Figure US20070299073A1-20071227-C01316
    7.0 551.2
    2
    Figure US20070299073A1-20071227-C01317
    Figure US20070299073A1-20071227-C01318
    7.8 627.2
    3
    Figure US20070299073A1-20071227-C01319
    Figure US20070299073A1-20071227-C01320
    7.5 601.2
    4
    Figure US20070299073A1-20071227-C01321
    Figure US20070299073A1-20071227-C01322
    7.1 581.2
    5
    Figure US20070299073A1-20071227-C01323
    Figure US20070299073A1-20071227-C01324
    7.1 611.2
    6
    Figure US20070299073A1-20071227-C01325
    Figure US20070299073A1-20071227-C01326
    7.5 622.3
    7
    Figure US20070299073A1-20071227-C01327
    Figure US20070299073A1-20071227-C01328
    7.4 585.2
    8
    Figure US20070299073A1-20071227-C01329
    Figure US20070299073A1-20071227-C01330
    7.7 619.1
    9
    Figure US20070299073A1-20071227-C01331
    Figure US20070299073A1-20071227-C01332
    7.7 599.2
    10
    Figure US20070299073A1-20071227-C01333
    Figure US20070299073A1-20071227-C01334
    7.4 629.1
    11
    Figure US20070299073A1-20071227-C01335
    Figure US20070299073A1-20071227-C01336
    7.1 569.2
    12
    Figure US20070299073A1-20071227-C01337
    Figure US20070299073A1-20071227-C01338
    7.0 576.2
    13
    Figure US20070299073A1-20071227-C01339
    Figure US20070299073A1-20071227-C01340
    7.3 592.2
    14
    Figure US20070299073A1-20071227-C01341
    Figure US20070299073A1-20071227-C01342
    7.2 596.2
    15
    Figure US20070299073A1-20071227-C01343
    Figure US20070299073A1-20071227-C01344
    7.1 596.2
    16
    Figure US20070299073A1-20071227-C01345
    Figure US20070299073A1-20071227-C01346
    6.6 503.3
    17
    Figure US20070299073A1-20071227-C01347
    Figure US20070299073A1-20071227-C01348
    7.0 551.2
    18
    Figure US20070299073A1-20071227-C01349
    Figure US20070299073A1-20071227-C01350
    7.8 627.2
    19
    Figure US20070299073A1-20071227-C01351
    Figure US20070299073A1-20071227-C01352
    7.5 601.2
    20
    Figure US20070299073A1-20071227-C01353
    Figure US20070299073A1-20071227-C01354
    7.0 581.2
    21
    Figure US20070299073A1-20071227-C01355
    Figure US20070299073A1-20071227-C01356
    7.1 611.2
    22
    Figure US20070299073A1-20071227-C01357
    Figure US20070299073A1-20071227-C01358
    7.5 622.3
    23
    Figure US20070299073A1-20071227-C01359
    Figure US20070299073A1-20071227-C01360
    7.4 585.2
    24
    Figure US20070299073A1-20071227-C01361
    Figure US20070299073A1-20071227-C01362
    7.7 619.1
    25
    Figure US20070299073A1-20071227-C01363
    Figure US20070299073A1-20071227-C01364
    7.6 599.2
    26
    Figure US20070299073A1-20071227-C01365
    Figure US20070299073A1-20071227-C01366
    7.4 629.1
    27
    Figure US20070299073A1-20071227-C01367
    Figure US20070299073A1-20071227-C01368
    7.1 569.2
    28
    Figure US20070299073A1-20071227-C01369
    Figure US20070299073A1-20071227-C01370
    6.9 576.2
    29
    Figure US20070299073A1-20071227-C01371
    Figure US20070299073A1-20071227-C01372
    7.3  704.2*
    30
    Figure US20070299073A1-20071227-C01373
    Figure US20070299073A1-20071227-C01374
    7.1 596.2
    31
    Figure US20070299073A1-20071227-C01375
    Figure US20070299073A1-20071227-C01376
    7.0 596.2
    32
    Figure US20070299073A1-20071227-C01377
    Figure US20070299073A1-20071227-C01378
    6.5 503.2
    33
    Figure US20070299073A1-20071227-C01379
    Figure US20070299073A1-20071227-C01380
    8.1 599.1
    34
    Figure US20070299073A1-20071227-C01381
    Figure US20070299073A1-20071227-C01382
    9.0 675.1
    35
    Figure US20070299073A1-20071227-C01383
    Figure US20070299073A1-20071227-C01384
    8.7 649.1
    36
    Figure US20070299073A1-20071227-C01385
    Figure US20070299073A1-20071227-C01386
    8.1 629.1
    37
    Figure US20070299073A1-20071227-C01387
    Figure US20070299073A1-20071227-C01388
    8.0 659.1
    38
    Figure US20070299073A1-20071227-C01389
    Figure US20070299073A1-20071227-C01390
    8.4 670.2
    39
    Figure US20070299073A1-20071227-C01391
    Figure US20070299073A1-20071227-C01392
    8.6 633.1
    40
    Figure US20070299073A1-20071227-C01393
    Figure US20070299073A1-20071227-C01394
    9.0 667.0
    41
    Figure US20070299073A1-20071227-C01395
    Figure US20070299073A1-20071227-C01396
    8.8 647.1
    42
    Figure US20070299073A1-20071227-C01397
    Figure US20070299073A1-20071227-C01398
    8.6 677.0
    43
    Figure US20070299073A1-20071227-C01399
    Figure US20070299073A1-20071227-C01400
    8.3 617.1
    44
    Figure US20070299073A1-20071227-C01401
    Figure US20070299073A1-20071227-C01402
    8.2 624.1
    45
    Figure US20070299073A1-20071227-C01403
    Figure US20070299073A1-20071227-C01404
    8.4 640.1
    46
    Figure US20070299073A1-20071227-C01405
    Figure US20070299073A1-20071227-C01406
    8.4 644.1
    47
    Figure US20070299073A1-20071227-C01407
    Figure US20070299073A1-20071227-C01408
    8.3 644.1
    48
    Figure US20070299073A1-20071227-C01409
    Figure US20070299073A1-20071227-C01410
    7.6 551.1
    49
    Figure US20070299073A1-20071227-C01411
    Figure US20070299073A1-20071227-C01412
    8.7 566.2
    50
    Figure US20070299073A1-20071227-C01413
    Figure US20070299073A1-20071227-C01414
    9.7 642.2
    51
    Figure US20070299073A1-20071227-C01415
    Figure US20070299073A1-20071227-C01416
    9.3 616.2
    52
    Figure US20070299073A1-20071227-C01417
    Figure US20070299073A1-20071227-C01418
    8.6 596.2
    53
    Figure US20070299073A1-20071227-C01419
    Figure US20070299073A1-20071227-C01420
    8.7 626.2
    54
    Figure US20070299073A1-20071227-C01421
    Figure US20070299073A1-20071227-C01422
    9.1 637.2
    55
    Figure US20070299073A1-20071227-C01423
    Figure US20070299073A1-20071227-C01424
    9.2 600.1
    56
    Figure US20070299073A1-20071227-C01425
    Figure US20070299073A1-20071227-C01426
    9.6 634.1
    57
    Figure US20070299073A1-20071227-C01427
    Figure US20070299073A1-20071227-C01428
    9.5 614.1
    58
    Figure US20070299073A1-20071227-C01429
    Figure US20070299073A1-20071227-C01430
    9.3 644.1
    59
    Figure US20070299073A1-20071227-C01431
    Figure US20070299073A1-20071227-C01432
    8.8 584.2
    60
    Figure US20070299073A1-20071227-C01433
    Figure US20070299073A1-20071227-C01434
    8.7 591.2
    61
    Figure US20070299073A1-20071227-C01435
    Figure US20070299073A1-20071227-C01436
    9.0 607.2
    62
    Figure US20070299073A1-20071227-C01437
    Figure US20070299073A1-20071227-C01438
    8.9 611.1
    63
    Figure US20070299073A1-20071227-C01439
    Figure US20070299073A1-20071227-C01440
    8.8 611.1
    64
    Figure US20070299073A1-20071227-C01441
    Figure US20070299073A1-20071227-C01442
    8.2 518.2
    65
    Figure US20070299073A1-20071227-C01443
    Figure US20070299073A1-20071227-C01444
    6.7 501.3
    66
    Figure US20070299073A1-20071227-C01445
    Figure US20070299073A1-20071227-C01446
    7.5 577.2
    67
    Figure US20070299073A1-20071227-C01447
    Figure US20070299073A1-20071227-C01448
    7.2 551.3
    68
    Figure US20070299073A1-20071227-C01449
    Figure US20070299073A1-20071227-C01450
    6.8 531.3
    69
    Figure US20070299073A1-20071227-C01451
    Figure US20070299073A1-20071227-C01452
    6.9 561.2
    70
    Figure US20070299073A1-20071227-C01453
    Figure US20070299073A1-20071227-C01454
    7.3 572.3
    71
    Figure US20070299073A1-20071227-C01455
    Figure US20070299073A1-20071227-C01456
    7.0 535.2
    72
    Figure US20070299073A1-20071227-C01457
    Figure US20070299073A1-20071227-C01458
    7.3 569.1
    73
    Figure US20070299073A1-20071227-C01459
    Figure US20070299073A1-20071227-C01460
    7.3 549.2
    74
    Figure US20070299073A1-20071227-C01461
    Figure US20070299073A1-20071227-C01462
    7.1 579.1
    75
    Figure US20070299073A1-20071227-C01463
    Figure US20070299073A1-20071227-C01464
    6.8 519.2
    76
    Figure US20070299073A1-20071227-C01465
    Figure US20070299073A1-20071227-C01466
    6.6 526.3
    77
    Figure US20070299073A1-20071227-C01467
    Figure US20070299073A1-20071227-C01468
    7.0 542.2
    78
    Figure US20070299073A1-20071227-C01469
    Figure US20070299073A1-20071227-C01470
    6.8 546.2
    79
    Figure US20070299073A1-20071227-C01471
    Figure US20070299073A1-20071227-C01472
    6.7 546.2
    80
    Figure US20070299073A1-20071227-C01473
    Figure US20070299073A1-20071227-C01474
    6.2 453.3
  • FORMULA 22
    Figure US20070299073A1-20071227-C01475
    Analysis
    R1 R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C01476
    Figure US20070299073A1-20071227-C01477
    6.6 605.3
    2
    Figure US20070299073A1-20071227-C01478
    Figure US20070299073A1-20071227-C01479
    6.3 579.3
    3
    Figure US20070299073A1-20071227-C01480
    Figure US20070299073A1-20071227-C01481
    6.3 565.3
    4
    Figure US20070299073A1-20071227-C01482
    Figure US20070299073A1-20071227-C01483
    6.3 611.3
    5
    Figure US20070299073A1-20071227-C01484
    Figure US20070299073A1-20071227-C01485
    6.5 600.2
    6
    Figure US20070299073A1-20071227-C01486
    Figure US20070299073A1-20071227-C01487
    6.6 627.3
    7
    Figure US20070299073A1-20071227-C01488
    Figure US20070299073A1-20071227-C01489
    6.9
    8
    Figure US20070299073A1-20071227-C01490
    Figure US20070299073A1-20071227-C01491
    5.9 590.3
    9
    Figure US20070299073A1-20071227-C01492
    Figure US20070299073A1-20071227-C01493
    6.9 625.2
    10
    Figure US20070299073A1-20071227-C01494
    Figure US20070299073A1-20071227-C01495
    6.5 577.3
    11
    Figure US20070299073A1-20071227-C01496
    Figure US20070299073A1-20071227-C01497
    6.6 (605.12) THEO
    12
    Figure US20070299073A1-20071227-C01498
    Figure US20070299073A1-20071227-C01499
    6.6 588.3
    13
    Figure US20070299073A1-20071227-C01500
    Figure US20070299073A1-20071227-C01501
    7.0 656.2
    14
    Figure US20070299073A1-20071227-C01502
    Figure US20070299073A1-20071227-C01503
    6.4 574.3
    15
    Figure US20070299073A1-20071227-C01504
    Figure US20070299073A1-20071227-C01505
    6.5 549.3
    16
    Figure US20070299073A1-20071227-C01506
    Figure US20070299073A1-20071227-C01507
    6.5 557.3
    17
    Figure US20070299073A1-20071227-C01508
    Figure US20070299073A1-20071227-C01509
    6.5 635.3
    18
    Figure US20070299073A1-20071227-C01510
    Figure US20070299073A1-20071227-C01511
    6.2 609.3
    19
    Figure US20070299073A1-20071227-C01512
    Figure US20070299073A1-20071227-C01513
    6.2 595.3
    20
    Figure US20070299073A1-20071227-C01514
    Figure US20070299073A1-20071227-C01515
    6.2 641.3
    21
    Figure US20070299073A1-20071227-C01516
    Figure US20070299073A1-20071227-C01517
    6.4 630.2
    22
    Figure US20070299073A1-20071227-C01518
    Figure US20070299073A1-20071227-C01519
    6.5 657.3
    23
    Figure US20070299073A1-20071227-C01520
    Figure US20070299073A1-20071227-C01521
    6.8 621.4
    24
    Figure US20070299073A1-20071227-C01522
    Figure US20070299073A1-20071227-C01523
    5.9
    25
    Figure US20070299073A1-20071227-C01524
    Figure US20070299073A1-20071227-C01525
    6.7 655.2
    26
    Figure US20070299073A1-20071227-C01526
    Figure US20070299073A1-20071227-C01527
    6.4 607.2
    27
    Figure US20070299073A1-20071227-C01528
    Figure US20070299073A1-20071227-C01529
    6.4 635.2
    28
    Figure US20070299073A1-20071227-C01530
    Figure US20070299073A1-20071227-C01531
    6.5 618.3
    29
    Figure US20070299073A1-20071227-C01532
    Figure US20070299073A1-20071227-C01533
    6.7 686.2
    30
    Figure US20070299073A1-20071227-C01534
    Figure US20070299073A1-20071227-C01535
    .2 OU 6.3? 604.3
    31
    Figure US20070299073A1-20071227-C01536
    Figure US20070299073A1-20071227-C01537
    6.4 579.3
    32
    Figure US20070299073A1-20071227-C01538
    Figure US20070299073A1-20071227-C01539
    6.3 587.2
    33
    Figure US20070299073A1-20071227-C01540
    Figure US20070299073A1-20071227-C01541
    7.3 650.2
    34
    Figure US20070299073A1-20071227-C01542
    Figure US20070299073A1-20071227-C01543
    7.0 624.2
    35
    Figure US20070299073A1-20071227-C01544
    Figure US20070299073A1-20071227-C01545
    7.0 610.2
    36
    Figure US20070299073A1-20071227-C01546
    Figure US20070299073A1-20071227-C01547
    7.0 656.3
    37
    Figure US20070299073A1-20071227-C01548
    Figure US20070299073A1-20071227-C01549
    7.0 645.1
    38
    Figure US20070299073A1-20071227-C01550
    Figure US20070299073A1-20071227-C01551
    7.3 672.3
    39
    Figure US20070299073A1-20071227-C01552
    Figure US20070299073A1-20071227-C01553
    7.6 636.3
    40
    Figure US20070299073A1-20071227-C01554
    Figure US20070299073A1-20071227-C01555
    7.8 635.2
    41
    Figure US20070299073A1-20071227-C01556
    Figure US20070299073A1-20071227-C01557
    7.5? 670.2?
    42
    Figure US20070299073A1-20071227-C01558
    Figure US20070299073A1-20071227-C01559
    7.3? 622.2?
    43
    Figure US20070299073A1-20071227-C01560
    Figure US20070299073A1-20071227-C01561
    7.3 650.1
    44
    Figure US20070299073A1-20071227-C01562
    Figure US20070299073A1-20071227-C01563
    7.3 633.2
    45
    Figure US20070299073A1-20071227-C01564
    Figure US20070299073A1-20071227-C01565
    7.6 701.2
    46
    Figure US20070299073A1-20071227-C01566
    Figure US20070299073A1-20071227-C01567
    7.2 594.3
    47
    Figure US20070299073A1-20071227-C01568
    Figure US20070299073A1-20071227-C01569
    7.2 602.2
    48
    Figure US20070299073A1-20071227-C01570
    Figure US20070299073A1-20071227-C01571
    7.0 (683.14) THEO
    49
    Figure US20070299073A1-20071227-C01572
    Figure US20070299073A1-20071227-C01573
    6.7 657.2
    50
    Figure US20070299073A1-20071227-C01574
    Figure US20070299073A1-20071227-C01575
    6.7 643.1
    51
    Figure US20070299073A1-20071227-C01576
    Figure US20070299073A1-20071227-C01577
    6.7 689.2
    52
    Figure US20070299073A1-20071227-C01578
    Figure US20070299073A1-20071227-C01579
    7.0? 678.1?
    53
    Figure US20070299073A1-20071227-C01580
    Figure US20070299073A1-20071227-C01581
    7.0 705.2
    54
    Figure US20070299073A1-20071227-C01582
    Figure US20070299073A1-20071227-C01583
    7.2 699.3
    55
    Figure US20070299073A1-20071227-C01584
    Figure US20070299073A1-20071227-C01585
    7.3 668.1
    56
    Figure US20070299073A1-20071227-C01586
    Figure US20070299073A1-20071227-C01587
    9.5 703.0
    57
    Figure US20070299073A1-20071227-C01588
    Figure US20070299073A1-20071227-C01589
    8.6 655.0
    58
    Figure US20070299073A1-20071227-C01590
    Figure US20070299073A1-20071227-C01591
    8.7 683.0
    59
    Figure US20070299073A1-20071227-C01592
    Figure US20070299073A1-20071227-C01593
    9.0 666.1
    60
    Figure US20070299073A1-20071227-C01594
    Figure US20070299073A1-20071227-C01595
    9.8 734.0
    61
    Figure US20070299073A1-20071227-C01596
    Figure US20070299073A1-20071227-C01597
    8.0 652.1
    62
    Figure US20070299073A1-20071227-C01598
    Figure US20070299073A1-20071227-C01599
    8.5 627.1
    63
    Figure US20070299073A1-20071227-C01600
    Figure US20070299073A1-20071227-C01601
    8.5 635.1
    64
    Figure US20070299073A1-20071227-C01602
    Figure US20070299073A1-20071227-C01603
    7.3 585.2
    65
    Figure US20070299073A1-20071227-C01604
    Figure US20070299073A1-20071227-C01605
    6.7 559.2
    66
    Figure US20070299073A1-20071227-C01606
    Figure US20070299073A1-20071227-C01607
    6.7 545.2
    67
    Figure US20070299073A1-20071227-C01608
    Figure US20070299073A1-20071227-C01609
    6.7 591.3
    68
    Figure US20070299073A1-20071227-C01610
    Figure US20070299073A1-20071227-C01611
    7.0 580.2
    69
    Figure US20070299073A1-20071227-C01612
    Figure US20070299073A1-20071227-C01613
    7.6 607.3
    70
    Figure US20070299073A1-20071227-C01614
    Figure US20070299073A1-20071227-C01615
    8.0 571.3
    71
    Figure US20070299073A1-20071227-C01616
    Figure US20070299073A1-20071227-C01617
    6.1 570.3
    72
    Figure US20070299073A1-20071227-C01618
    Figure US20070299073A1-20071227-C01619
    7.6 605.2
    73
    Figure US20070299073A1-20071227-C01620
    Figure US20070299073A1-20071227-C01621
    7.1 557.2
    74
    Figure US20070299073A1-20071227-C01622
    Figure US20070299073A1-20071227-C01623
    7.0 585.1
    75
    Figure US20070299073A1-20071227-C01624
    Figure US20070299073A1-20071227-C01625
    7.1 568.2
    76
    Figure US20070299073A1-20071227-C01626
    Figure US20070299073A1-20071227-C01627
    7.6 636.2
    77
    Figure US20070299073A1-20071227-C01628
    Figure US20070299073A1-20071227-C01629
    6.8 554.2
    78
    Figure US20070299073A1-20071227-C01630
    Figure US20070299073A1-20071227-C01631
    7.1 529.3
    79
    Figure US20070299073A1-20071227-C01632
    Figure US20070299073A1-20071227-C01633
    6.9 537.2
  • FORMULA 23
    Figure US20070299073A1-20071227-C01634
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C01635
    5.6 448.3
    2
    Figure US20070299073A1-20071227-C01636
    5.8 482.2
    3
    Figure US20070299073A1-20071227-C01637
    5.9 482.2
    4
    Figure US20070299073A1-20071227-C01638
    5.7 478.3
    5
    Figure US20070299073A1-20071227-C01639
    6.2 516.2
    6
    Figure US20070299073A1-20071227-C01640
    6.5 504.3
    7
    Figure US20070299073A1-20071227-C01641
    5.7 484.3
    8
    Figure US20070299073A1-20071227-C01642
    6.3 532.2
    9
    Figure US20070299073A1-20071227-C01643
    6.2 530.2
    10
    Figure US20070299073A1-20071227-C01644
    5.6 506.3
    11
    Figure US20070299073A1-20071227-C01645
    5.5 454.2
    12
    Figure US20070299073A1-20071227-C01646
    5.0 386.3
  • FORMULA 24
    Figure US20070299073A1-20071227-C01647
    Analysis
    R1 R2 R3 Tr [M + H]+
     1
    Figure US20070299073A1-20071227-C01648
    Figure US20070299073A1-20071227-C01649
    Figure US20070299073A1-20071227-C01650
    5.6 403.1
     2
    Figure US20070299073A1-20071227-C01651
    Figure US20070299073A1-20071227-C01652
    Figure US20070299073A1-20071227-C01653
    4.9 335.2
     3
    Figure US20070299073A1-20071227-C01654
    Figure US20070299073A1-20071227-C01655
    Figure US20070299073A1-20071227-C01656
    5.3 403.2
     4
    Figure US20070299073A1-20071227-C01657
    Figure US20070299073A1-20071227-C01658
    Figure US20070299073A1-20071227-C01659
    4.8 335.3
     5
    Figure US20070299073A1-20071227-C01660
    Figure US20070299073A1-20071227-C01661
    Figure US20070299073A1-20071227-C01662
    5.1 442.2
     6
    Figure US20070299073A1-20071227-C01663
    Figure US20070299073A1-20071227-C01664
    Figure US20070299073A1-20071227-C01665
    4.7 374.2
     7
    Figure US20070299073A1-20071227-C01666
    Figure US20070299073A1-20071227-C01667
    Figure US20070299073A1-20071227-C01668
    5.2 442.2
     8
    Figure US20070299073A1-20071227-C01669
    Figure US20070299073A1-20071227-C01670
    Figure US20070299073A1-20071227-C01671
    4.7 374.2
     9
    Figure US20070299073A1-20071227-C01672
    Figure US20070299073A1-20071227-C01673
    Figure US20070299073A1-20071227-C01674
    4.5 392.2
    10
    Figure US20070299073A1-20071227-C01675
    Figure US20070299073A1-20071227-C01676
    Figure US20070299073A1-20071227-C01677
    4.3 324.3
    11
    Figure US20070299073A1-20071227-C01678
    Figure US20070299073A1-20071227-C01679
    Figure US20070299073A1-20071227-C01680
    4.8 455.2
    12
    Figure US20070299073A1-20071227-C01681
    Figure US20070299073A1-20071227-C01682
    Figure US20070299073A1-20071227-C01683
    4.5 387.2
    13
    Figure US20070299073A1-20071227-C01684
    Figure US20070299073A1-20071227-C01685
    Figure US20070299073A1-20071227-C01686
    5.3 373.2
    14
    Figure US20070299073A1-20071227-C01687
    Figure US20070299073A1-20071227-C01688
    Figure US20070299073A1-20071227-C01689
    4.7 305.2
  • FORMULA 25
    Figure US20070299073A1-20071227-C01690
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C01691
    5.1 436.4
    2
    Figure US20070299073A1-20071227-C01692
    6.5 520.3
    3
    Figure US20070299073A1-20071227-C01693
    6.0 486.4
    4
    Figure US20070299073A1-20071227-C01694
    5.0 436.4
    5
    Figure US20070299073A1-20071227-C01695
    5.3 436.4
    6
    Figure US20070299073A1-20071227-C01696
    6.4 474.4
    7
    Figure US20070299073A1-20071227-C01697
    6.4 532.4
    8
    Figure US20070299073A1-20071227-C01698
    6.6 488.4
  • FORMULA 26
    Figure US20070299073A1-20071227-C01699
    Analysis
    R1 Tr [M + H]+
     1
    Figure US20070299073A1-20071227-C01700
    6.1 435.3
     2
    Figure US20070299073A1-20071227-C01701
    5.9 451.3
     3
    Figure US20070299073A1-20071227-C01702
    5.8 451.3
     4
    Figure US20070299073A1-20071227-C01703
    6.2 453.3
     5
    Figure US20070299073A1-20071227-C01704
    6.2 465.3
     6
    Figure US20070299073A1-20071227-C01705
    6.1 465.3
     7
    Figure US20070299073A1-20071227-C01706
    6.2 465.3
     8
    Figure US20070299073A1-20071227-C01707
    6.2 480.4
     9
    Figure US20070299073A1-20071227-C01708
    6.2 480.4
    10
    Figure US20070299073A1-20071227-C01709
    6.7 503.3
    11
    Figure US20070299073A1-20071227-C01710
    6.4 510.4
    12
    Figure US20070299073A1-20071227-C01711
    6.5 513.3
    13
    Figure US20070299073A1-20071227-C01712
    6.0 441.3
    14
    Figure US20070299073A1-20071227-C01713
    6.1 525.4
    15
    Figure US20070299073A1-20071227-C01714
    7.0 541.4
    16
    Figure US20070299073A1-20071227-C01715
    6.1 453.4
    17
    Figure US20070299073A1-20071227-C01716
    6.5 479.4
    18
    Figure US20070299073A1-20071227-C01717
    6.6 503.4
    19
    Figure US20070299073A1-20071227-C01718
    6.9 511.4
    20
    Figure US20070299073A1-20071227-C01719
    6.4 513.3
    21
    Figure US20070299073A1-20071227-C01720
    5.8 478.4
    22
    Figure US20070299073A1-20071227-C01721
    6.8 519.3
    23
    Figure US20070299073A1-20071227-C01722
    5.1 536.5
    24
    Figure US20070299073A1-20071227-C01723
    6.2 483.4
    25
    Figure US20070299073A1-20071227-C01724
    7.0 491.4
    26
    Figure US20070299073A1-20071227-C01725
    6.5 513.3
    27
    Figure US20070299073A1-20071227-C01726
    6.9 557.4
  • FORMULA 27
    Figure US20070299073A1-20071227-C01727
    Analysis
    [M +
    R1 R2 Tr H]+
     1
    Figure US20070299073A1-20071227-C01728
    Figure US20070299073A1-20071227-C01729
    6.4 478.3
     2
    Figure US20070299073A1-20071227-C01730
    Figure US20070299073A1-20071227-C01731
    5.6 444.3
     3
    Figure US20070299073A1-20071227-C01732
    Figure US20070299073A1-20071227-C01733
    4.8 394.3
     4
    Figure US20070299073A1-20071227-C01734
    Figure US20070299073A1-20071227-C01735
    4.9 394.3
     5
    Figure US20070299073A1-20071227-C01736
    Figure US20070299073A1-20071227-C01737
    4.8 394.3
     6
    Figure US20070299073A1-20071227-C01738
    Figure US20070299073A1-20071227-C01739
    6.4 478.3
     7
    Figure US20070299073A1-20071227-C01740
    Figure US20070299073A1-20071227-C01741
    5.6 444.3
     8
    Figure US20070299073A1-20071227-C01742
    Figure US20070299073A1-20071227-C01743
    4.7 394.3
     9
    Figure US20070299073A1-20071227-C01744
    Figure US20070299073A1-20071227-C01745
    4.9 394.3
    10
    Figure US20070299073A1-20071227-C01746
    Figure US20070299073A1-20071227-C01747
    4.9 424.3
    11
    Figure US20070299073A1-20071227-C01748
    Figure US20070299073A1-20071227-C01749
    6.6 508.3
    12
    Figure US20070299073A1-20071227-C01750
    Figure US20070299073A1-20071227-C01751
    5.7 474.3
    13
    Figure US20070299073A1-20071227-C01752
    Figure US20070299073A1-20071227-C01753
    4.9 424.3
    14
    Figure US20070299073A1-20071227-C01754
    Figure US20070299073A1-20071227-C01755
    5.0 424.3
    15
    Figure US20070299073A1-20071227-C01756
    Figure US20070299073A1-20071227-C01757
    4.9 424.3
    16
    Figure US20070299073A1-20071227-C01758
    Figure US20070299073A1-20071227-C01759
    6.5 508.3
    17
    Figure US20070299073A1-20071227-C01760
    Figure US20070299073A1-20071227-C01761
    5.6 474.3
    18
    Figure US20070299073A1-20071227-C01762
    Figure US20070299073A1-20071227-C01763
    4.9 424.3
    19
    Figure US20070299073A1-20071227-C01764
    Figure US20070299073A1-20071227-C01765
    5.0 424.3
    20
    Figure US20070299073A1-20071227-C01766
    Figure US20070299073A1-20071227-C01767
    4.9 424.3
    21
    Figure US20070299073A1-20071227-C01768
    Figure US20070299073A1-20071227-C01769
    6.5 508.3
    22
    Figure US20070299073A1-20071227-C01770
    Figure US20070299073A1-20071227-C01771
    5.6 474.3
    23
    Figure US20070299073A1-20071227-C01772
    Figure US20070299073A1-20071227-C01773
    4.9 424.3
    24
    Figure US20070299073A1-20071227-C01774
    Figure US20070299073A1-20071227-C01775
    5.0 424.3
  • FORMULA 28
    Figure US20070299073A1-20071227-C01776
    Analysis
    [M +
    R1 R2 Tr H]+
     1
    Figure US20070299073A1-20071227-C01777
    Figure US20070299073A1-20071227-C01778
    6.1 441.2
     2
    Figure US20070299073A1-20071227-C01779
    Figure US20070299073A1-20071227-C01780
    6.4 471.1
     3
    Figure US20070299073A1-20071227-C01781
    Figure US20070299073A1-20071227-C01782
    5.8 359.3
     4
    Figure US20070299073A1-20071227-C01783
    Figure US20070299073A1-20071227-C01784
    6.1 373.3
     5
    Figure US20070299073A1-20071227-C01785
    Figure US20070299073A1-20071227-C01786
    5.8 391.2
     6
    Figure US20070299073A1-20071227-C01787
    Figure US20070299073A1-20071227-C01788
    6.2 387.3
     7
    Figure US20070299073A1-20071227-C01789
    Figure US20070299073A1-20071227-C01790
    7.1 437.5
     8
    Figure US20070299073A1-20071227-C01791
    Figure US20070299073A1-20071227-C01792
    6.3 399.3
     9
    Figure US20070299073A1-20071227-C01793
    Figure US20070299073A1-20071227-C01794
    6.8 449.3
    10
    Figure US20070299073A1-20071227-C01795
    Figure US20070299073A1-20071227-C01796
    6.4 387.3
    11
    Figure US20070299073A1-20071227-C01797
    Figure US20070299073A1-20071227-C01798
    6.1 471.2
    12
    Figure US20070299073A1-20071227-C01799
    Figure US20070299073A1-20071227-C01800
    6.5 501.1
    13
    Figure US20070299073A1-20071227-C01801
    Figure US20070299073A1-20071227-C01802
    5.8 389.3
    14
    Figure US20070299073A1-20071227-C01803
    Figure US20070299073A1-20071227-C01804
    6.1 403.3
    15
    Figure US20070299073A1-20071227-C01805
    Figure US20070299073A1-20071227-C01806
    5.8 421.2
    16
    Figure US20070299073A1-20071227-C01807
    Figure US20070299073A1-20071227-C01808
    6.2 417.3
    17
    Figure US20070299073A1-20071227-C01809
    Figure US20070299073A1-20071227-C01810
    7.0 467.2
    18
    Figure US20070299073A1-20071227-C01811
    Figure US20070299073A1-20071227-C01812
    6.3 429.3
    19
    Figure US20070299073A1-20071227-C01813
    Figure US20070299073A1-20071227-C01814
    6.9 479.3
    20
    Figure US20070299073A1-20071227-C01815
    Figure US20070299073A1-20071227-C01816
    6.4 417.3
    21
    Figure US20070299073A1-20071227-C01817
    Figure US20070299073A1-20071227-C01818
    6.0 471.2
    22
    Figure US20070299073A1-20071227-C01819
    Figure US20070299073A1-20071227-C01820
    6.4 501.1
    23
    Figure US20070299073A1-20071227-C01821
    Figure US20070299073A1-20071227-C01822
    6.0 403.3
    24
    Figure US20070299073A1-20071227-C01823
    Figure US20070299073A1-20071227-C01824
    6.1 417.3
    25
    Figure US20070299073A1-20071227-C01825
    Figure US20070299073A1-20071227-C01826
    6.9 467.1
    26
    Figure US20070299073A1-20071227-C01827
    Figure US20070299073A1-20071227-C01828
    6.3 429.3
    27
    Figure US20070299073A1-20071227-C01829
    Figure US20070299073A1-20071227-C01830
    6.8 479.3
    28
    Figure US20070299073A1-20071227-C01831
    Figure US20070299073A1-20071227-C01832
    6.4 417.3
    29
    Figure US20070299073A1-20071227-C01833
    Figure US20070299073A1-20071227-C01834
    6.0 471.2
    30
    Figure US20070299073A1-20071227-C01835
    Figure US20070299073A1-20071227-C01836
    6.4 501.1
    31
    Figure US20070299073A1-20071227-C01837
    Figure US20070299073A1-20071227-C01838
    5.8 389.3
    32
    Figure US20070299073A1-20071227-C01839
    Figure US20070299073A1-20071227-C01840
    6.2 417.3
    33
    Figure US20070299073A1-20071227-C01841
    Figure US20070299073A1-20071227-C01842
    6.9 467.1
    34
    Figure US20070299073A1-20071227-C01843
    Figure US20070299073A1-20071227-C01844
    6.3 429.3
    35
    Figure US20070299073A1-20071227-C01845
    Figure US20070299073A1-20071227-C01846
    6.8 479.3
    36
    Figure US20070299073A1-20071227-C01847
    Figure US20070299073A1-20071227-C01848
    6.4 417.3
  • FORMULA 29
    Figure US20070299073A1-20071227-C01849
    Analysis
    R1 Tr [M + H]+
     1
    Figure US20070299073A1-20071227-C01850
    5.9 393.3
     2
    Figure US20070299073A1-20071227-C01851
    5.7 409.3
     3
    Figure US20070299073A1-20071227-C01852
    5.6 409.3
     4
    Figure US20070299073A1-20071227-C01853
    6.1 411.3
     5
    Figure US20070299073A1-20071227-C01854
    6.0 423.3
     6
    Figure US20070299073A1-20071227-C01855
    6.1 423.3
     7
    Figure US20070299073A1-20071227-C01856
    6.1 438.3
     8
    Figure US20070299073A1-20071227-C01857
    6.6 461.2
     9
    Figure US20070299073A1-20071227-C01858
    6.2 468.3
    10
    Figure US20070299073A1-20071227-C01859
    6.4 471.2
    11
    Figure US20070299073A1-20071227-C01860
    5.9 399.3
    12
    Figure US20070299073A1-20071227-C01861
    5.9 483.4
    13
    Figure US20070299073A1-20071227-C01862
    6.3 471.2
    14
    Figure US20070299073A1-20071227-C01863
    6.7 477.3
    15
    Figure US20070299073A1-20071227-C01864
    6.5 494.4
    16
    Figure US20070299073A1-20071227-C01865
    6.1 441.3
    17
    Figure US20070299073A1-20071227-C01866
    6.3 387.3
    18
    Figure US20070299073A1-20071227-C01867
    6.4 437.3
    19
    Figure US20070299073A1-20071227-C01868
    6.4 399.4
    20
    Figure US20070299073A1-20071227-C01869
    6.9 449.4
    21
    Figure US20070299073A1-20071227-C01870
    6.5 387.4
  • FORMULA 30
    Figure US20070299073A1-20071227-C01871
    Analysis
    [M +
    R1 Tr H]+
     1
    Figure US20070299073A1-20071227-C01872
    5.4 458.2
     2
    Figure US20070299073A1-20071227-C01873
    5.7 460.2
     3
    Figure US20070299073A1-20071227-C01874
    5.3 499.3
     4
    Figure US20070299073A1-20071227-C01875
    6.1 522.3
     5
    Figure US20070299073A1-20071227-C01876
    6.3 531.3
     6
    Figure US20070299073A1-20071227-C01877
    6.4 533.3
     7
    Figure US20070299073A1-20071227-C01878
    6.6 543.3
     8
    Figure US20070299073A1-20071227-C01879
    5.1 547.3
     9
    Figure US20070299073A1-20071227-C01880
    6.5 551.3
    10
    Figure US20070299073A1-20071227-C01881
    6.1 563.3
    11
    Figure US20070299073A1-20071227-C01882
    6.9 567.2
    12
    Figure US20070299073A1-20071227-C01883
    7.2 568.2
    13
    Figure US20070299073A1-20071227-C01884
    6.5 578.2
    14
    Figure US20070299073A1-20071227-C01885
    6.1 564.3
    15
    Figure US20070299073A1-20071227-C01886
    6.8 567.2
    16
    Figure US20070299073A1-20071227-C01887
    4.9 534.3
    17
    Figure US20070299073A1-20071227-C01888
    7.0 546.3
    18
    Figure US20070299073A1-20071227-C01889
    6.8 578.3
    19
    Figure US20070299073A1-20071227-C01890
    5.1 591.3
    20
    Figure US20070299073A1-20071227-C01891
    7.1 601.3
    21
    Figure US20070299073A1-20071227-C01892
    6.2 602.3
    22
    Figure US20070299073A1-20071227-C01893
    6.9 567.2
    23
    Figure US20070299073A1-20071227-C01894
    5.2 549.2
    24
    Figure US20070299073A1-20071227-C01895
    6.7 528.2
    25
    Figure US20070299073A1-20071227-C01896
    7.1 561.3
    26
    Figure US20070299073A1-20071227-C01897
    7.0 568.2
    27
    Figure US20070299073A1-20071227-C01898
    6.5 591.3
    28
    Figure US20070299073A1-20071227-C01899
    6.0 588.2
    29
    Figure US20070299073A1-20071227-C01900
    5.7 571.2
    30
    Figure US20070299073A1-20071227-C01901
    5.7 551.2
    31
    Figure US20070299073A1-20071227-C01902
    6.9 653.3
    32
    Figure US20070299073A1-20071227-C01903
    7.4 612.3
    33
    Figure US20070299073A1-20071227-C01904
    6.0 563.3
    34
    Figure US20070299073A1-20071227-C01905
    6.0 623.3
    35
    Figure US20070299073A1-20071227-C01906
    5.2 549.3
    36
    Figure US20070299073A1-20071227-C01907
    4.4 558.3
    37
    Figure US20070299073A1-20071227-C01908
    6.6 551.3
  • FORMULA 31
    Figure US20070299073A1-20071227-C01909
    Analysis
    R1 Tr [M + H]+
     1
    Figure US20070299073A1-20071227-C01910
    4.7 473.3
     2
    Figure US20070299073A1-20071227-C01911
    6.6 484.3
     3
    Figure US20070299073A1-20071227-C01912
    6.3 492.3
     4
    Figure US20070299073A1-20071227-C01913
    6.2 508.3
     5
    Figure US20070299073A1-20071227-C01914
    6.5 522.3
     6
    Figure US20070299073A1-20071227-C01915
    6.1 552.3
     7
    Figure US20070299073A1-20071227-C01916
    4.8 482.3
     8
    Figure US20070299073A1-20071227-C01917
    6.0 568.2
     9
    Figure US20070299073A1-20071227-C01918
    6.4 537.2
    10
    Figure US20070299073A1-20071227-C01919
    6.5 472.3
    11
    Figure US20070299073A1-20071227-C01920
    4.7 479.3
    12
    Figure US20070299073A1-20071227-C01921
    4.8 493.3
    13
    Figure US20070299073A1-20071227-C01922
    4.8 515.3
    14
    Figure US20070299073A1-20071227-C01923
    5.9 543.3
    15
    Figure US20070299073A1-20071227-C01924
    6.0 553.2
    16
    Figure US20070299073A1-20071227-C01925
    6.6 538.2
    17
    Figure US20070299073A1-20071227-C01926
    5.5 510.3
    18
    Figure US20070299073A1-20071227-C01927
    4.9 514.3
    19
    Figure US20070299073A1-20071227-C01928
    6.1 444.3
    20
    Figure US20070299073A1-20071227-C01929
    5.8 610.3
    21
    Figure US20070299073A1-20071227-C01930
    7.0 554.3
    22
    Figure US20070299073A1-20071227-C01931
    4.9 479.3
    23
    Figure US20070299073A1-20071227-C01932
    6.5 512.2
    24
    Figure US20070299073A1-20071227-C01933
    7.2 582.3
    25
    Figure US20070299073A1-20071227-C01934
    6.6 506.3
    26
    Figure US20070299073A1-20071227-C01935
    4.8 485.3
    27
    Figure US20070299073A1-20071227-C01936
    6.7 526.2
    28
    Figure US20070299073A1-20071227-C01937
    6.4 510.3
    29
    Figure US20070299073A1-20071227-C01938
    6.4 510.3
    30
    Figure US20070299073A1-20071227-C01939
    6.7 526.2
    31
    Figure US20070299073A1-20071227-C01940
    6.8 570.2
    32
    Figure US20070299073A1-20071227-C01941
    6.7 546.2
    33
    Figure US20070299073A1-20071227-C01942
    6.8 546.2
    34
    Figure US20070299073A1-20071227-C01943
    4.8 479.3
    35
    Figure US20070299073A1-20071227-C01944
    6.3 508.3
    36
    Figure US20070299073A1-20071227-C01945
    6.4 512.2
    37
    Figure US20070299073A1-20071227-C01946
    6.3 496.3
    38
    Figure US20070299073A1-20071227-C01947
    6.2 496.3
    39
    Figure US20070299073A1-20071227-C01948
    6.3 496.3
    40
    Figure US20070299073A1-20071227-C01949
    4.5 528.3
  • FORMULA 32
    Figure US20070299073A1-20071227-C01950
    Analysis
    R1 Tr [M + H]+
     1
    Figure US20070299073A1-20071227-C01951
    6.4 498.2
     2
    Figure US20070299073A1-20071227-C01952
    6.6 498.2
     3
    Figure US20070299073A1-20071227-C01953
    6.6 498.2
     4
    Figure US20070299073A1-20071227-C01954
    6.4 542.1
     5
    Figure US20070299073A1-20071227-C01955
    6.6 542.1
     6
    Figure US20070299073A1-20071227-C01956
    6.7 542.1
     7
    Figure US20070299073A1-20071227-C01957
    6.3 482.2
     8
    Figure US20070299073A1-20071227-C01958
    6.3 500.2
     9
    Figure US20070299073A1-20071227-C01959
    6.4 500.2
    10
    Figure US20070299073A1-20071227-C01960
    6.3 509.2
    11
    Figure US20070299073A1-20071227-C01961
    6.4 509.2
    12
    Figure US20070299073A1-20071227-C01962
    6.4 509.2
    13
    Figure US20070299073A1-20071227-C01963
    6.5 532.2
    14
    Figure US20070299073A1-20071227-C01964
    6.8 532.2
    15
    Figure US20070299073A1-20071227-C01965
    6.8 532.2
    16
    Figure US20070299073A1-20071227-C01966
    6.3 524.2
    17
    Figure US20070299073A1-20071227-C01967
    6.2 494.2
    18
    Figure US20070299073A1-20071227-C01968
    6.1 494.2
    19
    Figure US20070299073A1-20071227-C01969
    6.9 566.1
    20
    Figure US20070299073A1-20071227-C01970
    6.4 527.2
  • FORMULA 33
    Figure US20070299073A1-20071227-C01971
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C01972
    6.4 456.1
    2
    Figure US20070299073A1-20071227-C01973
    6.2 500.1
    3
    Figure US20070299073A1-20071227-C01974
    6.4 500.1
    4
    Figure US20070299073A1-20071227-C01975
    6.4 500.1
    5
    Figure US20070299073A1-20071227-C01976
    6.1 440.1
    6
    Figure US20070299073A1-20071227-C01977
    6.2 458.1
    7
    Figure US20070299073A1-20071227-C01978
    6.2 467.1
    8
    Figure US20070299073A1-20071227-C01979
    6.2 490.1
    9
    Figure US20070299073A1-20071227-C01980
    6.2 490.1
    10
    Figure US20070299073A1-20071227-C01981
    6.6 490.1
    11
    Figure US20070299073A1-20071227-C01982
    6.1 482.2
    12
    Figure US20070299073A1-20071227-C01983
    6.0 452.2
    13
    Figure US20070299073A1-20071227-C01984
    5.9 452.2
    14
    Figure US20070299073A1-20071227-C01985
    6.7 524.1
    15
    Figure US20070299073A1-20071227-C01986
    6.2 485.1
  • FORMULA 34
    Figure US20070299073A1-20071227-C01987
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C01988
    3.9 348.3
    2
    Figure US20070299073A1-20071227-C01989
    4.0 382.2
    3
    Figure US20070299073A1-20071227-C01990
    4.3 382.2
    4
    Figure US20070299073A1-20071227-C01991
    4.1 378.2
    5
    Figure US20070299073A1-20071227-C01992
    4.5 416.2
    6
    Figure US20070299073A1-20071227-C01993
    5.0 404.3
    7
    Figure US20070299073A1-20071227-C01994
    4.0 384.2
    8
    Figure US20070299073A1-20071227-C01995
    4.7 432.2
    9
    Figure US20070299073A1-20071227-C01996
    4.5 430.2
    10
    Figure US20070299073A1-20071227-C01997
    3.9 406.2
    11
    Figure US20070299073A1-20071227-C01998
    3.8 354.2
    12
    Figure US20070299073A1-20071227-C01999
    3.2 286.3
  • FORMULA 35
    Figure US20070299073A1-20071227-C02000
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02001
    3.7 358.2
    2
    Figure US20070299073A1-20071227-C02002
    3.9 360.2
    3
    Figure US20070299073A1-20071227-C02003
    3.5 399.2
    4
    Figure US20070299073A1-20071227-C02004
    4.4 422.2
    5
    Figure US20070299073A1-20071227-C02005
    4.7 431.2
    6
    Figure US20070299073A1-20071227-C02006
    4.7 433.2
    7
    Figure US20070299073A1-20071227-C02007
    5.0 443.2
    8
    Figure US20070299073A1-20071227-C02008
    3.8 447.3
    9
    Figure US20070299073A1-20071227-C02009
    4.8 451.2
    10
    Figure US20070299073A1-20071227-C02010
    4.6 463.2
    11
    Figure US20070299073A1-20071227-C02011
    5.2 467.2
    12
    Figure US20070299073A1-20071227-C02012
    5.4 468.2
    13
    Figure US20070299073A1-20071227-C02013
    4.9 478.2
    14
    Figure US20070299073A1-20071227-C02014
    4.6 464.2
    15
    Figure US20070299073A1-20071227-C02015
    5.2 467.2
    16
    Figure US20070299073A1-20071227-C02016
    3.5 434.2
    17
    Figure US20070299073A1-20071227-C02017
    5.3 446.2
    18
    Figure US20070299073A1-20071227-C02018
    5.0 478.2
    19
    Figure US20070299073A1-20071227-C02019
    3.8 491.2
    20
    Figure US20070299073A1-20071227-C02020
    5.5 501.2
    21
    Figure US20070299073A1-20071227-C02021
    4.6 502.3
    22
    Figure US20070299073A1-20071227-C02022
    5.1 467.2
    23
    Figure US20070299073A1-20071227-C02023
    5.1 467.2
    24
    Figure US20070299073A1-20071227-C02024
    5.0 428.2
    25
    Figure US20070299073A1-20071227-C02025
    5.4 461.2
    26
    Figure US20070299073A1-20071227-C02026
    5.4 468.2
    27
    Figure US20070299073A1-20071227-C02027
    5.0 491.2
    28
    Figure US20070299073A1-20071227-C02028
    4.5 488.2
    29
    Figure US20070299073A1-20071227-C02029
    4.0 471.2
    30
    Figure US20070299073A1-20071227-C02030
    4.1 451.2
    31
    Figure US20070299073A1-20071227-C02031
    5.2 553.2
    32
    Figure US20070299073A1-20071227-C02032
    5.6 512.2
    33
    Figure US20070299073A1-20071227-C02033
    4.5 463.3
    34
    Figure US20070299073A1-20071227-C02034
    4.7 523.3
    35
    Figure US20070299073A1-20071227-C02035
    3.8 449.3
    36
    Figure US20070299073A1-20071227-C02036
    3.1 458.3
    37
    Figure US20070299073A1-20071227-C02037
    4.8 451.2
  • FORMULA 36
    Figure US20070299073A1-20071227-C02038
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02039
    3.2 373.3
    2
    Figure US20070299073A1-20071227-C02040
    4.8 384.3
    3
    Figure US20070299073A1-20071227-C02041
    4.7 393.2
    4
    Figure US20070299073A1-20071227-C02042
    4.5 408.2
    5
    Figure US20070299073A1-20071227-C02043
    4.8 422.2
    6
    Figure US20070299073A1-20071227-C02044
    4.5 452.2
    7
    Figure US20070299073A1-20071227-C02045
    3.3 382.2
    8
    Figure US20070299073A1-20071227-C02046
    4.4 468.2
    9
    Figure US20070299073A1-20071227-C02047
    4.7 437.2
    10
    Figure US20070299073A1-20071227-C02048
    4.8 372.3
    11
    Figure US20070299073A1-20071227-C02049
    3.2 379.2
    12
    Figure US20070299073A1-20071227-C02050
    3.3 393.2
    13
    Figure US20070299073A1-20071227-C02051
    3.3 415.2
    14
    Figure US20070299073A1-20071227-C02052
    4.4 443.3
    15
    Figure US20070299073A1-20071227-C02053
    4.4 453.2
    16
    Figure US20070299073A1-20071227-C02054
    5.0 438.2
    17
    Figure US20070299073A1-20071227-C02055
    3.9 410.2
    18
    Figure US20070299073A1-20071227-C02056
    3.6 414.3
    19
    Figure US20070299073A1-20071227-C02057
    4.3 344.3
    20
    Figure US20070299073A1-20071227-C02058
    4.6 510.2
    21
    Figure US20070299073A1-20071227-C02059
    5.3 454.2
    22
    Figure US20070299073A1-20071227-C02060
    3.4 379.2
    23
    Figure US20070299073A1-20071227-C02061
    4.8 412.1
    24
    Figure US20070299073A1-20071227-C02062
    5.6 482.3
    25
    Figure US20070299073A1-20071227-C02063
    5.0 406.2
    26
    Figure US20070299073A1-20071227-C02064
    3.3 385.2
    27
    Figure US20070299073A1-20071227-C02065
    5.0 426.2
    28
    Figure US20070299073A1-20071227-C02066
    4.7 410.2
    29
    Figure US20070299073A1-20071227-C02067
    4.8 410.2
    30
    Figure US20070299073A1-20071227-C02068
    5.0 426.2
    31
    Figure US20070299073A1-20071227-C02069
    5.1 470.2
    32
    Figure US20070299073A1-20071227-C02070
    5.1 470.2
    33
    Figure US20070299073A1-20071227-C02071
    5.1 446.2
    34
    Figure US20070299073A1-20071227-C02072
    3.3 379.2
    35
    Figure US20070299073A1-20071227-C02073
    4.6 408.2
    36
    Figure US20070299073A1-20071227-C02074
    4.8 412.1
    37
    Figure US20070299073A1-20071227-C02075
    4.6 396.2
    38
    Figure US20070299073A1-20071227-C02076
    4.5 396.2
    39
    Figure US20070299073A1-20071227-C02077
    4.6 396.2
    40
    Figure US20070299073A1-20071227-C02078
    3.1 428.3
  • FORMULA 37
    Figure US20070299073A1-20071227-C02079
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02080
    4.4 388.5
    2
    Figure US20070299073A1-20071227-C02081
    4.5 388.3
    3
    Figure US20070299073A1-20071227-C02082
    4.2 388.3
    4
    Figure US20070299073A1-20071227-C02083
    4.4 402.3
    5
    Figure US20070299073A1-20071227-C02084
    4.4 432.3
    6
    Figure US20070299073A1-20071227-C02085
    4.2 404.3
    7
    Figure US20070299073A1-20071227-C02086
    4.7 418.3
    8
    Figure US20070299073A1-20071227-C02087
    4.9 430.5
    9
    Figure US20070299073A1-20071227-C02088
    4.6 416.4
    10
    Figure US20070299073A1-20071227-C02089
    3.9 418.3
    11
    Figure US20070299073A1-20071227-C02090
    4.8 480.2
    12
    Figure US20070299073A1-20071227-C02091
    4.5 416.4
    13
    Figure US20070299073A1-20071227-C02092
    4.8 419.3
    14
    Figure US20070299073A1-20071227-C02093
    4.8 419.3
    15
    Figure US20070299073A1-20071227-C02094
    4.7 389.3
  • FORMULA 38
    Figure US20070299073A1-20071227-C02095
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02096
    5.1 431.2
    2
    Figure US20070299073A1-20071227-C02097
    4.4 453.4
    3
    Figure US20070299073A1-20071227-C02098
    4.6 377.4
    4
    Figure US20070299073A1-20071227-C02099
    4.5 399.3
    5
    Figure US20070299073A1-20071227-C02100
    4.5 399.3
    6
    Figure US20070299073A1-20071227-C02101
    3.9 339.3
    7
    Figure US20070299073A1-20071227-C02102
    4.1 350.4
    8
    Figure US20070299073A1-20071227-C02103
    4.5 395.3
    9
    Figure US20070299073A1-20071227-C02104
    4.8 399.3
    10
    Figure US20070299073A1-20071227-C02105
    4.7 400.3
    11
    Figure US20070299073A1-20071227-C02106
    4.5 400.3
    12
    Figure US20070299073A1-20071227-C02107
    4.4 400.3
    13
    Figure US20070299073A1-20071227-C02108
    4.2 400.3
    14
    Figure US20070299073A1-20071227-C02109
    4.3 441.3
    15
    Figure US20070299073A1-20071227-C02110
    4.3 441.3
    16
    Figure US20070299073A1-20071227-C02111
    4.2 369.3
    17
    Figure US20070299073A1-20071227-C02112
    3.9 397.3
    18
    Figure US20070299073A1-20071227-C02113
    3.8 350.3
  • FORMULA 39
    Figure US20070299073A1-20071227-C02114
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02115
    4.5 397.3
    2
    Figure US20070299073A1-20071227-C02116
    4.7 397.3
    3
    Figure US20070299073A1-20071227-C02117
    4.7 397.3
    4
    Figure US20070299073A1-20071227-C02118
    4.6 441.2
    5
    Figure US20070299073A1-20071227-C02119
    4.8 441.2
    6
    Figure US20070299073A1-20071227-C02120
    4.8 441.2
    7
    Figure US20070299073A1-20071227-C02121
    4.3 391.3
    8
    Figure US20070299073A1-20071227-C02122
    4.4 381.3
    9
    Figure US20070299073A1-20071227-C02123
    4.4 381.3
    10
    Figure US20070299073A1-20071227-C02124
    4.3 408.3
    11
    Figure US20070299073A1-20071227-C02125
    4.4 408.3
    12
    Figure US20070299073A1-20071227-C02126
    4.5 408.3
    13
    Figure US20070299073A1-20071227-C02127
    4.7 431.3
    14
    Figure US20070299073A1-20071227-C02128
    4.9 431.3
    15
    Figure US20070299073A1-20071227-C02129
    5.0 431.3
    16
    Figure US20070299073A1-20071227-C02130
    4.4 393.3
    17
    Figure US20070299073A1-20071227-C02131
    4.4 393.4
    18
    Figure US20070299073A1-20071227-C02132
    4.4 393.3
    19
    Figure US20070299073A1-20071227-C02133
    4.3 363.4
    20
    Figure US20070299073A1-20071227-C02134
    3.7 406.3
  • FORMULA 40
    Figure US20070299073A1-20071227-C02135
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02136
    3.6 336.4
    2
    Figure US20070299073A1-20071227-C02137
    4.9 420.3
    3
    Figure US20070299073A1-20071227-C02138
    4.5 386.4
    4
    Figure US20070299073A1-20071227-C02139
    3.5 336.4
    5
    Figure US20070299073A1-20071227-C02140
    3.8 336.4
    6
    Figure US20070299073A1-20071227-C02141
    4.9 432.3
  • FORMULA 41
    Figure US20070299073A1-20071227-C02142
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02143
    4.5 335.3
    2
    Figure US20070299073A1-20071227-C02144
    4.3 351.3
    3
    Figure US20070299073A1-20071227-C02145
    4.2 351.3
    4
    Figure US20070299073A1-20071227-C02146
    4.6 353.3
    5
    Figure US20070299073A1-20071227-C02147
    4.6 365.3
    6
    Figure US20070299073A1-20071227-C02148
    4.6 365.3
    7
    Figure US20070299073A1-20071227-C02149
    4.6 365.3
    8
    Figure US20070299073A1-20071227-C02150
    4.5 380.3
    9
    Figure US20070299073A1-20071227-C02151
    4.6 380.3
    10
    Figure US20070299073A1-20071227-C02152
    5.1 403.2
    11
    Figure US20070299073A1-20071227-C02153
    4.7 410.3
    12
    Figure US20070299073A1-20071227-C02154
    4.9 413.2
    13
    Figure US20070299073A1-20071227-C02155
    4.3 341.3
    14
    Figure US20070299073A1-20071227-C02156
    4.6 425.3
    15
    Figure US20070299073A1-20071227-C02157
    5.4 441.3
    16
    Figure US20070299073A1-20071227-C02158
    4.5 353.3
    17
    Figure US20070299073A1-20071227-C02159
    4.9 403.3
    18
    Figure US20070299073A1-20071227-C02160
    5.3 411.3
    19
    Figure US20070299073A1-20071227-C02161
    4.7 415.2
    20
    Figure US20070299073A1-20071227-C02162
    5.2 419.3
    21
    Figure US20070299073A1-20071227-C02163
    3.9 436.4
    22
    Figure US20070299073A1-20071227-C02164
    4.6 383.3
    23
    Figure US20070299073A1-20071227-C02165
    5.4 391.4
    24
    Figure US20070299073A1-20071227-C02166
    4.9 413.2
    25
    Figure US20070299073A1-20071227-C02167
    5.4 457.4
  • FORMULA 42
    Figure US20070299073A1-20071227-C02168
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02169
    4.7 398.1
    2
    Figure US20070299073A1-20071227-C02170
    4.9 398.1
    3
    Figure US20070299073A1-20071227-C02171
    4.9 398.1
    4
    Figure US20070299073A1-20071227-C02172
    4.7 442.1
    5
    Figure US20070299073A1-20071227-C02173
    5.0 442.1
    6
    Figure US20070299073A1-20071227-C02174
    5.0 442.1
    7
    Figure US20070299073A1-20071227-C02175
    4.7 382.2
    8
    Figure US20070299073A1-20071227-C02176
    4.6 400.2
    9
    Figure US20070299073A1-20071227-C02177
    4.8 400.2
    10
    Figure US20070299073A1-20071227-C02178
    4.7 409.2
    11
    Figure US20070299073A1-20071227-C02179
    4.8 409.2
    12
    Figure US20070299073A1-20071227-C02180
    5.0 409.2
    13
    Figure US20070299073A1-20071227-C02181
    4.8 432.2
    14
    Figure US20070299073A1-20071227-C02182
    5.2 432.2
    15
    Figure US20070299073A1-20071227-C02183
    5.3 432.2
    16
    Figure US20070299073A1-20071227-C02184
    4.7 424.2
    17
    Figure US20070299073A1-20071227-C02185
    4.6 394.2
    18
    Figure US20070299073A1-20071227-C02186
    4.5 394.2
    19
    Figure US20070299073A1-20071227-C02187
    5.2 466.1
    20
    Figure US20070299073A1-20071227-C02188
    4.9 427.2
  • FORMULA 43
    Figure US20070299073A1-20071227-C02189
    Analysis
    R3 R2 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02190
    Figure US20070299073A1-20071227-C02191
    5.5 374.2
    2
    Figure US20070299073A1-20071227-C02192
    Figure US20070299073A1-20071227-C02193
    5.4 360.2
    3
    Figure US20070299073A1-20071227-C02194
    Figure US20070299073A1-20071227-C02195
    5.4 388.2
    4
    Figure US20070299073A1-20071227-C02196
    Figure US20070299073A1-20071227-C02197
    5.5 416.3
    5
    Figure US20070299073A1-20071227-C02198
    Figure US20070299073A1-20071227-C02199
    5.4 374.2
    6
    Figure US20070299073A1-20071227-C02200
    Figure US20070299073A1-20071227-C02201
    6.1 422.2
    7
    Figure US20070299073A1-20071227-C02202
    Figure US20070299073A1-20071227-C02203
    5.5 388.2
    8
    Figure US20070299073A1-20071227-C02204
    Figure US20070299073A1-20071227-C02205
    5.5 402.2
    9
    Figure US20070299073A1-20071227-C02206
    Figure US20070299073A1-20071227-C02207
    5.5 436.2
    10
    Figure US20070299073A1-20071227-C02208
    Figure US20070299073A1-20071227-C02209
    5.7 436.2
    11
    Figure US20070299073A1-20071227-C02210
    Figure US20070299073A1-20071227-C02211
    12
    Figure US20070299073A1-20071227-C02212
    Figure US20070299073A1-20071227-C02213
    5.3 340.3
    13
    Figure US20070299073A1-20071227-C02214
    Figure US20070299073A1-20071227-C02215
    5.4 368.3
    14
    Figure US20070299073A1-20071227-C02216
    Figure US20070299073A1-20071227-C02217
    5.4 396.3
    15
    Figure US20070299073A1-20071227-C02218
    Figure US20070299073A1-20071227-C02219
    5.3 354.3
    16
    Figure US20070299073A1-20071227-C02220
    Figure US20070299073A1-20071227-C02221
    6.0 402.2
    17
    Figure US20070299073A1-20071227-C02222
    Figure US20070299073A1-20071227-C02223
    5.5 368.3
    18
    Figure US20070299073A1-20071227-C02224
    Figure US20070299073A1-20071227-C02225
    5.4 382.3
    19
    Figure US20070299073A1-20071227-C02226
    Figure US20070299073A1-20071227-C02227
    5.5 416.3
    20
    Figure US20070299073A1-20071227-C02228
    Figure US20070299073A1-20071227-C02229
    416.3
  • FORMULA 44
    Figure US20070299073A1-20071227-C02230
    Analysis
    * = [M + TFA − H]−
    R1 R2 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02231
    Figure US20070299073A1-20071227-C02232
    6.0 485.3
    2
    Figure US20070299073A1-20071227-C02233
    Figure US20070299073A1-20071227-C02234
    6.2 485.3
    3
    Figure US20070299073A1-20071227-C02235
    Figure US20070299073A1-20071227-C02236
    6.2 485.3
    4
    Figure US20070299073A1-20071227-C02237
    Figure US20070299073A1-20071227-C02238
    6.1 529.2
    5
    Figure US20070299073A1-20071227-C02239
    Figure US20070299073A1-20071227-C02240
    6.2 529.2
    6
    Figure US20070299073A1-20071227-C02241
    Figure US20070299073A1-20071227-C02242
    6.3 529.2
    7
    Figure US20070299073A1-20071227-C02243
    Figure US20070299073A1-20071227-C02244
    5.9 469.3
    8
    Figure US20070299073A1-20071227-C02245
    Figure US20070299073A1-20071227-C02246
    5.9 469.3
    9
    Figure US20070299073A1-20071227-C02247
    Figure US20070299073A1-20071227-C02248
    5.9 469.3
    10
    Figure US20070299073A1-20071227-C02249
    Figure US20070299073A1-20071227-C02250
    5.8 496.3
    11
    Figure US20070299073A1-20071227-C02251
    Figure US20070299073A1-20071227-C02252
    5.9 496.3
    12
    Figure US20070299073A1-20071227-C02253
    Figure US20070299073A1-20071227-C02254
    6.0 496.3
    13
    Figure US20070299073A1-20071227-C02255
    Figure US20070299073A1-20071227-C02256
    6.2 519.3
    14
    Figure US20070299073A1-20071227-C02257
    Figure US20070299073A1-20071227-C02258
    6.4 519.3
    15
    Figure US20070299073A1-20071227-C02259
    Figure US20070299073A1-20071227-C02260
    6.4 519.3
    16
    Figure US20070299073A1-20071227-C02261
    Figure US20070299073A1-20071227-C02262
    5.9 481.3
    17
    Figure US20070299073A1-20071227-C02263
    Figure US20070299073A1-20071227-C02264
    5.9 481.3
    18
    Figure US20070299073A1-20071227-C02265
    Figure US20070299073A1-20071227-C02266
    5.9 481.3
    19
    Figure US20070299073A1-20071227-C02267
    Figure US20070299073A1-20071227-C02268
    5.8 451.3
    20
    Figure US20070299073A1-20071227-C02269
    Figure US20070299073A1-20071227-C02270
    4.9 494.4
    21
    Figure US20070299073A1-20071227-C02271
    Figure US20070299073A1-20071227-C02272
    6.5 519.2
    22
    Figure US20070299073A1-20071227-C02273
    Figure US20070299073A1-20071227-C02274
    5.7 541.3
    23
    Figure US20070299073A1-20071227-C02275
    Figure US20070299073A1-20071227-C02276
    6.0 465.3
    24
    Figure US20070299073A1-20071227-C02277
    Figure US20070299073A1-20071227-C02278
    5.4 467.3
    25
    Figure US20070299073A1-20071227-C02279
    Figure US20070299073A1-20071227-C02280
    5.9 487.3
    26
    Figure US20070299073A1-20071227-C02281
    Figure US20070299073A1-20071227-C02282
    6.0 485.3
    27
    Figure US20070299073A1-20071227-C02283
    Figure US20070299073A1-20071227-C02284
    6.1 485.3
    28
    Figure US20070299073A1-20071227-C02285
    Figure US20070299073A1-20071227-C02286
    6.2 485.3
    29
    Figure US20070299073A1-20071227-C02287
    Figure US20070299073A1-20071227-C02288
    6.0 529.2
    30
    Figure US20070299073A1-20071227-C02289
    Figure US20070299073A1-20071227-C02290
    6.2 529.2
    31
    Figure US20070299073A1-20071227-C02291
    Figure US20070299073A1-20071227-C02292
    6.2 529.2
    32
    Figure US20070299073A1-20071227-C02293
    Figure US20070299073A1-20071227-C02294
    5.8 469.3
    33
    Figure US20070299073A1-20071227-C02295
    Figure US20070299073A1-20071227-C02296
    5.9 469.3
    34
    Figure US20070299073A1-20071227-C02297
    Figure US20070299073A1-20071227-C02298
    5.9 469.3
    35
    Figure US20070299073A1-20071227-C02299
    Figure US20070299073A1-20071227-C02300
    5.8 496.3
    36
    Figure US20070299073A1-20071227-C02301
    Figure US20070299073A1-20071227-C02302
    5.9 496.3
    37
    Figure US20070299073A1-20071227-C02303
    Figure US20070299073A1-20071227-C02304
    5.9 496.3
    38
    Figure US20070299073A1-20071227-C02305
    Figure US20070299073A1-20071227-C02306
    6.2 519.3
    39
    Figure US20070299073A1-20071227-C02307
    Figure US20070299073A1-20071227-C02308
    6.4 519.3
    40
    Figure US20070299073A1-20071227-C02309
    Figure US20070299073A1-20071227-C02310
    6.4 519.3
    41
    Figure US20070299073A1-20071227-C02311
    Figure US20070299073A1-20071227-C02312
    5.9 481.3
    42
    Figure US20070299073A1-20071227-C02313
    Figure US20070299073A1-20071227-C02314
    5.8 481.3
    43
    Figure US20070299073A1-20071227-C02315
    Figure US20070299073A1-20071227-C02316
    5.8 481.3
    44
    Figure US20070299073A1-20071227-C02317
    Figure US20070299073A1-20071227-C02318
    5.8 563.3*
    45
    Figure US20070299073A1-20071227-C02319
    Figure US20070299073A1-20071227-C02320
    4.8 494.4
    46
    Figure US20070299073A1-20071227-C02321
    Figure US20070299073A1-20071227-C02322
    6.4 519.2
    47
    Figure US20070299073A1-20071227-C02323
    Figure US20070299073A1-20071227-C02324
    5.7 541.3
    48
    Figure US20070299073A1-20071227-C02325
    Figure US20070299073A1-20071227-C02326
    6.0 465.3
    49
    Figure US20070299073A1-20071227-C02327
    Figure US20070299073A1-20071227-C02328
    5.4 467.3
    50
    Figure US20070299073A1-20071227-C02329
    Figure US20070299073A1-20071227-C02330
    6.0 487.3
  • FORMULA 45
    Figure US20070299073A1-20071227-C02331
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02332
    5.9 488.4
    2
    Figure US20070299073A1-20071227-C02333
    6.1 488.4
    3
    Figure US20070299073A1-20071227-C02334
    5.9 488.4
    4
    Figure US20070299073A1-20071227-C02335
    6.0 502.4
    5
    Figure US20070299073A1-20071227-C02336
    6.0 502.4
    6
    Figure US20070299073A1-20071227-C02337
    6.0 532.4
    7
    Figure US20070299073A1-20071227-C02338
    5.7 504.4
    8
    Figure US20070299073A1-20071227-C02339
    6.3 518.4
    9
    Figure US20070299073A1-20071227-C02340
    6.4 530.4
    10
    Figure US20070299073A1-20071227-C02341
    6.2 516.4
    11
    Figure US20070299073A1-20071227-C02342
    5.5 518.4
    12
    Figure US20070299073A1-20071227-C02343
    6.4 580.3
    13
    Figure US20070299073A1-20071227-C02344
    6.1 516.4
    14
    Figure US20070299073A1-20071227-C02345
    6.4 519.3
    15
    Figure US20070299073A1-20071227-C02346
    6.4 519.3
    16
    Figure US20070299073A1-20071227-C02347
    6.3 489.4
  • FORMULA 46
    Figure US20070299073A1-20071227-C02348
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02349
    6.7 531.3
    2
    Figure US20070299073A1-20071227-C02350
    5.9 553.4
    3
    Figure US20070299073A1-20071227-C02351
    6.3 477.4
    4
    Figure US20070299073A1-20071227-C02352
    6.2 499.3
    5
    Figure US20070299073A1-20071227-C02353
    6.2 499.4
    6
    Figure US20070299073A1-20071227-C02354
    5.6 439.3
    7
    Figure US20070299073A1-20071227-C02355
    5.7 450.4
    8
    Figure US20070299073A1-20071227-C02356
    6.2 495.3
    9
    Figure US20070299073A1-20071227-C02357
    6.4 499.4
    10
    Figure US20070299073A1-20071227-C02358
    6.4 500.4
    11
    Figure US20070299073A1-20071227-C02359
    6.2 500.4
    12
    Figure US20070299073A1-20071227-C02360
    5.9 500.4
    13
    Figure US20070299073A1-20071227-C02361
    5.7 500.4
    14
    Figure US20070299073A1-20071227-C02362
    5.9 541.3
    15
    Figure US20070299073A1-20071227-C02363
    5.9 541.3
    16
    Figure US20070299073A1-20071227-C02364
    5.9 469.3
    17
    Figure US20070299073A1-20071227-C02365
    5.5 497.4
    18
    Figure US20070299073A1-20071227-C02366
    5.3 450.4
  • FORMULA 47
    Figure US20070299073A1-20071227-C02367
    Analysis
    R1 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02368
    6.2 497.3
    2
    Figure US20070299073A1-20071227-C02369
    6.3 497.3
    3
    Figure US20070299073A1-20071227-C02370
    6.4 497.3
    4
    Figure US20070299073A1-20071227-C02371
    6.2 541.2
    5
    Figure US20070299073A1-20071227-C02372
    6.4 541.2
    6
    Figure US20070299073A1-20071227-C02373
    6.5 541.2
    7
    Figure US20070299073A1-20071227-C02374
    6.0 481.3
    8
    Figure US20070299073A1-20071227-C02375
    6.1 481.3
    9
    Figure US20070299073A1-20071227-C02376
    6.1 481.3
    10
    Figure US20070299073A1-20071227-C02377
    6.0 508.3
    11
    Figure US20070299073A1-20071227-C02378
    6.1 508.3
    12
    Figure US20070299073A1-20071227-C02379
    6.1 508.3
    13
    Figure US20070299073A1-20071227-C02380
    6.4 531.3
    14
    Figure US20070299073A1-20071227-C02381
    6.6 531.3
    15
    Figure US20070299073A1-20071227-C02382
    6.6 531.3
    16
    Figure US20070299073A1-20071227-C02383
    6.1 493.4
    17
    Figure US20070299073A1-20071227-C02384
    6.0 493.4
    18
    Figure US20070299073A1-20071227-C02385
    6.0 493.4
    19
    Figure US20070299073A1-20071227-C02386
    6.0 463.4
    20
    Figure US20070299073A1-20071227-C02387
    5.0 506.4
  • FORMULA 48
    Figure US20070299073A1-20071227-C02388
    Analysis
    R1 R2 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02389
    Figure US20070299073A1-20071227-C02390
    6.9 519.2
    2
    Figure US20070299073A1-20071227-C02391
    Figure US20070299073A1-20071227-C02392
    6.5 541.3
    3
    Figure US20070299073A1-20071227-C02393
    Figure US20070299073A1-20071227-C02394
    6.7 465.3
    4
    Figure US20070299073A1-20071227-C02395
    Figure US20070299073A1-20071227-C02396
    6.3 467.3
    5
    Figure US20070299073A1-20071227-C02397
    Figure US20070299073A1-20071227-C02398
    6.6 487.2
    6
    Figure US20070299073A1-20071227-C02399
    Figure US20070299073A1-20071227-C02400
    7.0 567.0
    7
    Figure US20070299073A1-20071227-C02401
    Figure US20070299073A1-20071227-C02402
    6.7 589.1
    8
    Figure US20070299073A1-20071227-C02403
    Figure US20070299073A1-20071227-C02404
    6.9 513.2
    9
    Figure US20070299073A1-20071227-C02405
    Figure US20070299073A1-20071227-C02406
    6.5 515.1
    10
    Figure US20070299073A1-20071227-C02407
    Figure US20070299073A1-20071227-C02408
    6.8 535.1
    11
    Figure US20070299073A1-20071227-C02409
    Figure US20070299073A1-20071227-C02410
    7.2 534.1
    12
    Figure US20070299073A1-20071227-C02411
    Figure US20070299073A1-20071227-C02412
    6.8 556.2
    13
    Figure US20070299073A1-20071227-C02413
    Figure US20070299073A1-20071227-C02414
    6.8 480.1
    14
    Figure US20070299073A1-20071227-C02415
    Figure US20070299073A1-20071227-C02416
    5.8 482.1
    15
    Figure US20070299073A1-20071227-C02417
    Figure US20070299073A1-20071227-C02418
    6.7 502.1
    16
    Figure US20070299073A1-20071227-C02419
    Figure US20070299073A1-20071227-C02420
    6.3 560.1
    17
    Figure US20070299073A1-20071227-C02421
    Figure US20070299073A1-20071227-C02422
    5.5 582.2
    18
    Figure US20070299073A1-20071227-C02423
    Figure US20070299073A1-20071227-C02424
    5.8 506.3
    19
    Figure US20070299073A1-20071227-C02425
    Figure US20070299073A1-20071227-C02426
    5.1 508.2
    20
    Figure US20070299073A1-20071227-C02427
    Figure US20070299073A1-20071227-C02428
    5.7 528.2
    21
    Figure US20070299073A1-20071227-C02429
    Figure US20070299073A1-20071227-C02430
    6.5 489.1
    22
    Figure US20070299073A1-20071227-C02431
    Figure US20070299073A1-20071227-C02432
    5.7 511.2
    23
    Figure US20070299073A1-20071227-C02433
    Figure US20070299073A1-20071227-C02434
    6.1 435.2
    24
    Figure US20070299073A1-20071227-C02435
    Figure US20070299073A1-20071227-C02436
    5.4 437.2
    25
    Figure US20070299073A1-20071227-C02437
    Figure US20070299073A1-20071227-C02438
    6.0 457.2
  • FORMULA 49
    Figure US20070299073A1-20071227-C02439
    Analysis
    R1 (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C02440
    6.6 455.2
    2
    Figure US20070299073A1-20071227-C02441
    6.6 455.2
    3
    Figure US20070299073A1-20071227-C02442
    6.6 455.2
    4
    Figure US20070299073A1-20071227-C02443
    6.6 499.2
    5
    Figure US20070299073A1-20071227-C02444
    6.7 499.2
    6
    Figure US20070299073A1-20071227-C02445
    6.7 499.2
    7
    Figure US20070299073A1-20071227-C02446
    6.5 439.2
    8
    Figure US20070299073A1-20071227-C02447
    6.5 439.2
    9
    Figure US20070299073A1-20071227-C02448
    6.5 439.2
    10
    Figure US20070299073A1-20071227-C02449
    6.5 466.2
    11
    Figure US20070299073A1-20071227-C02450
    6.5 466.2
    12
    Figure US20070299073A1-20071227-C02451
    6.5 466.2
    13
    Figure US20070299073A1-20071227-C02452
    6.7 489.2
    14
    Figure US20070299073A1-20071227-C02453
    6.7 489.2
    15
    Figure US20070299073A1-20071227-C02454
    6.8 489.2
    16
    Figure US20070299073A1-20071227-C02455
    6.5 451.3
    17
    Figure US20070299073A1-20071227-C02456
    6.5 451.3
    18
    Figure US20070299073A1-20071227-C02457
    6.5 451.3
    19
    Figure US20070299073A1-20071227-C02458
    6.5 421.3
    20
    Figure US20070299073A1-20071227-C02459
    5.8 464.3
  • FORMULA 50
    Figure US20070299073A1-20071227-C02460
    Analysis
    R1 R2 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02461
    Figure US20070299073A1-20071227-C02462
    6.3 474.3
    2
    Figure US20070299073A1-20071227-C02463
    Figure US20070299073A1-20071227-C02464
    6.3 460.3
    3
    Figure US20070299073A1-20071227-C02465
    Figure US20070299073A1-20071227-C02466
    6.3 488.3
    4
    Figure US20070299073A1-20071227-C02467
    Figure US20070299073A1-20071227-C02468
    6.4 516.3
    5
    Figure US20070299073A1-20071227-C02469
    Figure US20070299073A1-20071227-C02470
    6.3 474.3
    6
    Figure US20070299073A1-20071227-C02471
    Figure US20070299073A1-20071227-C02472
    6.5 522.3
    7
    Figure US20070299073A1-20071227-C02473
    Figure US20070299073A1-20071227-C02474
    6.5 488.3
    8
    Figure US20070299073A1-20071227-C02475
    Figure US20070299073A1-20071227-C02476
    6.4 502.3
    9
    Figure US20070299073A1-20071227-C02477
    Figure US20070299073A1-20071227-C02478
    6.5 536.3
    10
    Figure US20070299073A1-20071227-C02479
    Figure US20070299073A1-20071227-C02480
    6.5 536.3
    11
    Figure US20070299073A1-20071227-C02481
    Figure US20070299073A1-20071227-C02482
    6.2 454.3
    12
    Figure US20070299073A1-20071227-C02483
    Figure US20070299073A1-20071227-C02484
    6.2 440.3
    13
    Figure US20070299073A1-20071227-C02485
    Figure US20070299073A1-20071227-C02486
    6.3 468.3
    14
    Figure US20070299073A1-20071227-C02487
    Figure US20070299073A1-20071227-C02488
    6.4 496.3
    15
    Figure US20070299073A1-20071227-C02489
    Figure US20070299073A1-20071227-C02490
    6.2 454.3
    16
    Figure US20070299073A1-20071227-C02491
    Figure US20070299073A1-20071227-C02492
    6.5 502.3
    17
    Figure US20070299073A1-20071227-C02493
    Figure US20070299073A1-20071227-C02494
    6.4 468.3
    18
    Figure US20070299073A1-20071227-C02495
    Figure US20070299073A1-20071227-C02496
    6.3 482.3
    19
    Figure US20070299073A1-20071227-C02497
    Figure US20070299073A1-20071227-C02498
    6.4 516.3
    20
    Figure US20070299073A1-20071227-C02499
    Figure US20070299073A1-20071227-C02500
    6.4 516.3
  • FORMULA 51
    Figure US20070299073A1-20071227-C02501
    Analysis
    R1 R2 R3 Tr [M + H]+
    1
    Figure US20070299073A1-20071227-C02502
    Figure US20070299073A1-20071227-C02503
    Figure US20070299073A1-20071227-C02504
    5.6 397.2
    2
    Figure US20070299073A1-20071227-C02505
    Figure US20070299073A1-20071227-C02506
    Figure US20070299073A1-20071227-C02507
    5.9 431.2
    3
    Figure US20070299073A1-20071227-C02508
    Figure US20070299073A1-20071227-C02509
    Figure US20070299073A1-20071227-C02510
    6.0 431.2
    4
    Figure US20070299073A1-20071227-C02511
    Figure US20070299073A1-20071227-C02512
    Figure US20070299073A1-20071227-C02513
    5.8 427.2
    5
    Figure US20070299073A1-20071227-C02514
    Figure US20070299073A1-20071227-C02515
    Figure US20070299073A1-20071227-C02516
    6.3 465.2
    6
    Figure US20070299073A1-20071227-C02517
    Figure US20070299073A1-20071227-C02518
    Figure US20070299073A1-20071227-C02519
    6.7 453.3
    7
    Figure US20070299073A1-20071227-C02520
    Figure US20070299073A1-20071227-C02521
    Figure US20070299073A1-20071227-C02522
    5.8 433.2
    8
    Figure US20070299073A1-20071227-C02523
    Figure US20070299073A1-20071227-C02524
    Figure US20070299073A1-20071227-C02525
    6.4 481.2
    9
    Figure US20070299073A1-20071227-C02526
    Figure US20070299073A1-20071227-C02527
    Figure US20070299073A1-20071227-C02528
    6.3 479.1
    10
    Figure US20070299073A1-20071227-C02529
    Figure US20070299073A1-20071227-C02530
    Figure US20070299073A1-20071227-C02531
    5.7 455.2
    11
    Figure US20070299073A1-20071227-C02532
    Figure US20070299073A1-20071227-C02533
    Figure US20070299073A1-20071227-C02534
    5.4 397.2
    12
    Figure US20070299073A1-20071227-C02535
    Figure US20070299073A1-20071227-C02536
    Figure US20070299073A1-20071227-C02537
    5.0 431.2
    13
    Figure US20070299073A1-20071227-C02538
    Figure US20070299073A1-20071227-C02539
    Figure US20070299073A1-20071227-C02540
    5.8 431.2
    14
    Figure US20070299073A1-20071227-C02541
    Figure US20070299073A1-20071227-C02542
    Figure US20070299073A1-20071227-C02543
    5.5 427.2
    15
    Figure US20070299073A1-20071227-C02544
    Figure US20070299073A1-20071227-C02545
    Figure US20070299073A1-20071227-C02546
    6.0 465.2
    16
    Figure US20070299073A1-20071227-C02547
    Figure US20070299073A1-20071227-C02548
    Figure US20070299073A1-20071227-C02549
    6.5 453.3
    17
    Figure US20070299073A1-20071227-C02550
    Figure US20070299073A1-20071227-C02551
    Figure US20070299073A1-20071227-C02552
    5.5 433.2
    18
    Figure US20070299073A1-20071227-C02553
    Figure US20070299073A1-20071227-C02554
    Figure US20070299073A1-20071227-C02555
    6.2 481.2
    19
    Figure US20070299073A1-20071227-C02556
    Figure US20070299073A1-20071227-C02557
    Figure US20070299073A1-20071227-C02558
    6.1 479.1
    20
    Figure US20070299073A1-20071227-C02559
    Figure US20070299073A1-20071227-C02560
    Figure US20070299073A1-20071227-C02561
    5.5 455.2
    21
    Figure US20070299073A1-20071227-C02562
    Figure US20070299073A1-20071227-C02563
    Figure US20070299073A1-20071227-C02564
    5.3 406.2
    22
    Figure US20070299073A1-20071227-C02565
    Figure US20070299073A1-20071227-C02566
    Figure US20070299073A1-20071227-C02567
    5.5 440.1
    23
    Figure US20070299073A1-20071227-C02568
    Figure US20070299073A1-20071227-C02569
    Figure US20070299073A1-20071227-C02570
    5.7 440.2
    24
    Figure US20070299073A1-20071227-C02571
    Figure US20070299073A1-20071227-C02572
    Figure US20070299073A1-20071227-C02573
    5.5 436.2
    25
    Figure US20070299073A1-20071227-C02574
    Figure US20070299073A1-20071227-C02575
    Figure US20070299073A1-20071227-C02576
    6.0 474.2
    26
    Figure US20070299073A1-20071227-C02577
    Figure US20070299073A1-20071227-C02578
    Figure US20070299073A1-20071227-C02579
    6.4 462.3
    27
    Figure US20070299073A1-20071227-C02580
    Figure US20070299073A1-20071227-C02581
    Figure US20070299073A1-20071227-C02582
    5.5 442.2
    28
    Figure US20070299073A1-20071227-C02583
    Figure US20070299073A1-20071227-C02584
    Figure US20070299073A1-20071227-C02585
    6.1 490.2
    29
    Figure US20070299073A1-20071227-C02586
    Figure US20070299073A1-20071227-C02587
    Figure US20070299073A1-20071227-C02588
    6.0 488.1
    30
    Figure US20070299073A1-20071227-C02589
    Figure US20070299073A1-20071227-C02590
    Figure US20070299073A1-20071227-C02591
    5.4 464.2
    31
    Figure US20070299073A1-20071227-C02592
    Figure US20070299073A1-20071227-C02593
    Figure US20070299073A1-20071227-C02594
    5.2 436.2
    32
    Figure US20070299073A1-20071227-C02595
    Figure US20070299073A1-20071227-C02596
    Figure US20070299073A1-20071227-C02597
    5.4 470.2
    33
    Figure US20070299073A1-20071227-C02598
    Figure US20070299073A1-20071227-C02599
    Figure US20070299073A1-20071227-C02600
    5.6 470.2
    34
    Figure US20070299073A1-20071227-C02601
    Figure US20070299073A1-20071227-C02602
    Figure US20070299073A1-20071227-C02603
    5.4 466.2
    35
    Figure US20070299073A1-20071227-C02604
    Figure US20070299073A1-20071227-C02605
    Figure US20070299073A1-20071227-C02606
    5.9 504.2
    36
    Figure US20070299073A1-20071227-C02607
    Figure US20070299073A1-20071227-C02608
    Figure US20070299073A1-20071227-C02609
    6.2 492.3
    37
    Figure US20070299073A1-20071227-C02610
    Figure US20070299073A1-20071227-C02611
    Figure US20070299073A1-20071227-C02612
    5.4 472.2
    38
    Figure US20070299073A1-20071227-C02613
    Figure US20070299073A1-20071227-C02614
    Figure US20070299073A1-20071227-C02615
    6.0 520.1
    39
    Figure US20070299073A1-20071227-C02616
    Figure US20070299073A1-20071227-C02617
    Figure US20070299073A1-20071227-C02618
    5.8 518.1
    40
    Figure US20070299073A1-20071227-C02619
    Figure US20070299073A1-20071227-C02620
    Figure US20070299073A1-20071227-C02621
    5.3 494.2
    41
    Figure US20070299073A1-20071227-C02622
    Figure US20070299073A1-20071227-C02623
    Figure US20070299073A1-20071227-C02624
    5.2 436.2
    42
    Figure US20070299073A1-20071227-C02625
    Figure US20070299073A1-20071227-C02626
    Figure US20070299073A1-20071227-C02627
    5.4 470.2
    43
    Figure US20070299073A1-20071227-C02628
    Figure US20070299073A1-20071227-C02629
    Figure US20070299073A1-20071227-C02630
    5.6 470.2
    44
    Figure US20070299073A1-20071227-C02631
    Figure US20070299073A1-20071227-C02632
    Figure US20070299073A1-20071227-C02633
    5.4 466.2
    45
    Figure US20070299073A1-20071227-C02634
    Figure US20070299073A1-20071227-C02635
    Figure US20070299073A1-20071227-C02636
    5.9 504.2
    46
    Figure US20070299073A1-20071227-C02637
    Figure US20070299073A1-20071227-C02638
    Figure US20070299073A1-20071227-C02639
    6.2 492.3
    47
    Figure US20070299073A1-20071227-C02640
    Figure US20070299073A1-20071227-C02641
    Figure US20070299073A1-20071227-C02642
    5.4 472.2
    48
    Figure US20070299073A1-20071227-C02643
    Figure US20070299073A1-20071227-C02644
    Figure US20070299073A1-20071227-C02645
    6.0 520.1
    49
    Figure US20070299073A1-20071227-C02646
    Figure US20070299073A1-20071227-C02647
    Figure US20070299073A1-20071227-C02648
    5.9 518.1
    50
    Figure US20070299073A1-20071227-C02649
    Figure US20070299073A1-20071227-C02650
    Figure US20070299073A1-20071227-C02651
    5.3 494.2
    51
    Figure US20070299073A1-20071227-C02652
    Figure US20070299073A1-20071227-C02653
    Figure US20070299073A1-20071227-C02654
    4.6 386.2
    52
    Figure US20070299073A1-20071227-C02655
    Figure US20070299073A1-20071227-C02656
    Figure US20070299073A1-20071227-C02657
    4.7 420.2
    53
    Figure US20070299073A1-20071227-C02658
    Figure US20070299073A1-20071227-C02659
    Figure US20070299073A1-20071227-C02660
    4.9 420.2
    54
    Figure US20070299073A1-20071227-C02661
    Figure US20070299073A1-20071227-C02662
    Figure US20070299073A1-20071227-C02663
    4.8 416.2
    55
    Figure US20070299073A1-20071227-C02664
    Figure US20070299073A1-20071227-C02665
    Figure US20070299073A1-20071227-C02666
    5.2 454.2
    56
    Figure US20070299073A1-20071227-C02667
    Figure US20070299073A1-20071227-C02668
    Figure US20070299073A1-20071227-C02669
    5.6 442.3
    57
    Figure US20070299073A1-20071227-C02670
    Figure US20070299073A1-20071227-C02671
    Figure US20070299073A1-20071227-C02672
    4.7 422.2
    58
    Figure US20070299073A1-20071227-C02673
    Figure US20070299073A1-20071227-C02674
    Figure US20070299073A1-20071227-C02675
    5.3 470.2
    59
    Figure US20070299073A1-20071227-C02676
    Figure US20070299073A1-20071227-C02677
    Figure US20070299073A1-20071227-C02678
    5.2 468.2
    60
    Figure US20070299073A1-20071227-C02679
    Figure US20070299073A1-20071227-C02680
    Figure US20070299073A1-20071227-C02681
    4.8 444.2
    61
    Figure US20070299073A1-20071227-C02682
    Figure US20070299073A1-20071227-C02683
    Figure US20070299073A1-20071227-C02684
    4.9 449.2
    62
    Figure US20070299073A1-20071227-C02685
    Figure US20070299073A1-20071227-C02686
    Figure US20070299073A1-20071227-C02687
    5.0 483.2
    63
    Figure US20070299073A1-20071227-C02688
    Figure US20070299073A1-20071227-C02689
    Figure US20070299073A1-20071227-C02690
    5.2 483.2
    64
    Figure US20070299073A1-20071227-C02691
    Figure US20070299073A1-20071227-C02692
    Figure US20070299073A1-20071227-C02693
    5.0 477.2
    65
    Figure US20070299073A1-20071227-C02694
    Figure US20070299073A1-20071227-C02695
    Figure US20070299073A1-20071227-C02696
    5.4 515.1
    66
    Figure US20070299073A1-20071227-C02697
    Figure US20070299073A1-20071227-C02698
    Figure US20070299073A1-20071227-C02699
    5.8 503.3
    67
    Figure US20070299073A1-20071227-C02700
    Figure US20070299073A1-20071227-C02701
    Figure US20070299073A1-20071227-C02702
    4.9 483.2
    68
    Figure US20070299073A1-20071227-C02703
    Figure US20070299073A1-20071227-C02704
    Figure US20070299073A1-20071227-C02705
    5.5 531.2
    69
    Figure US20070299073A1-20071227-C02706
    Figure US20070299073A1-20071227-C02707
    Figure US20070299073A1-20071227-C02708
    5.4 531.1
    70
    Figure US20070299073A1-20071227-C02709
    Figure US20070299073A1-20071227-C02710
    Figure US20070299073A1-20071227-C02711
    4.9 507.2
    71
    Figure US20070299073A1-20071227-C02712
    Figure US20070299073A1-20071227-C02713
    Figure US20070299073A1-20071227-C02714
    5.3 367.2
    72
    Figure US20070299073A1-20071227-C02715
    Figure US20070299073A1-20071227-C02716
    Figure US20070299073A1-20071227-C02717
    5.6 401.2
    73
    Figure US20070299073A1-20071227-C02718
    Figure US20070299073A1-20071227-C02719
    Figure US20070299073A1-20071227-C02720
    5.7 401.1
    74
    Figure US20070299073A1-20071227-C02721
    Figure US20070299073A1-20071227-C02722
    Figure US20070299073A1-20071227-C02723
    5.5 397.2
    75
    Figure US20070299073A1-20071227-C02724
    Figure US20070299073A1-20071227-C02725
    Figure US20070299073A1-20071227-C02726
    6.0 435.2
    76
    Figure US20070299073A1-20071227-C02727
    Figure US20070299073A1-20071227-C02728
    Figure US20070299073A1-20071227-C02729
    6.5 423.3
    77
    Figure US20070299073A1-20071227-C02730
    Figure US20070299073A1-20071227-C02731
    Figure US20070299073A1-20071227-C02732
    5.5 403.2
    78
    Figure US20070299073A1-20071227-C02733
    Figure US20070299073A1-20071227-C02734
    Figure US20070299073A1-20071227-C02735
    6.2 451.2
    79
    Figure US20070299073A1-20071227-C02736
    Figure US20070299073A1-20071227-C02737
    Figure US20070299073A1-20071227-C02738
    6.1 449.1
    80
    Figure US20070299073A1-20071227-C02739
    Figure US20070299073A1-20071227-C02740
    Figure US20070299073A1-20071227-C02741
    5.4 425.2
  • FORMULA 52
    Figure US20070299073A1-20071227-C02742
    Analysis
    R1 R2 Tr [M + H]+
     1
    Figure US20070299073A1-20071227-C02743
    Figure US20070299073A1-20071227-C02744
    5.9 393.2
     2
    Figure US20070299073A1-20071227-C02745
    Figure US20070299073A1-20071227-C02746
    5.7 409.2
     3
    Figure US20070299073A1-20071227-C02747
    Figure US20070299073A1-20071227-C02748
    5.6 409.2
     4
    Figure US20070299073A1-20071227-C02749
    Figure US20070299073A1-20071227-C02750
    6.0 411.2
     5
    Figure US20070299073A1-20071227-C02751
    Figure US20070299073A1-20071227-C02752
    6.0 423.2
     6
    Figure US20070299073A1-20071227-C02753
    Figure US20070299073A1-20071227-C02754
    6.0 423.2
     7
    Figure US20070299073A1-20071227-C02755
    Figure US20070299073A1-20071227-C02756
    6.0 423.2
     8
    Figure US20070299073A1-20071227-C02757
    Figure US20070299073A1-20071227-C02758
    6.0 438.2
     9
    Figure US20070299073A1-20071227-C02759
    Figure US20070299073A1-20071227-C02760
    6.0 438.2
    10
    Figure US20070299073A1-20071227-C02761
    Figure US20070299073A1-20071227-C02762
    6.5 461.1
    11
    Figure US20070299073A1-20071227-C02763
    Figure US20070299073A1-20071227-C02764
    6.1 468.2
    12
    Figure US20070299073A1-20071227-C02765
    Figure US20070299073A1-20071227-C02766
    6.4 471.1
    13
    Figure US20070299073A1-20071227-C02767
    Figure US20070299073A1-20071227-C02768
    5.8  511.2*
    14
    Figure US20070299073A1-20071227-C02769
    Figure US20070299073A1-20071227-C02770
    5.9 483.3
    15
    Figure US20070299073A1-20071227-C02771
    Figure US20070299073A1-20071227-C02772
    5.9 411.2
    16
    Figure US20070299073A1-20071227-C02773
    Figure US20070299073A1-20071227-C02774
    6.4 461.2
    17
    Figure US20070299073A1-20071227-C02775
    Figure US20070299073A1-20071227-C02776
    6.2 471.1
    18
    Figure US20070299073A1-20071227-C02777
    Figure US20070299073A1-20071227-C02778
    5.5 436.3
    19
    Figure US20070299073A1-20071227-C02779
    Figure US20070299073A1-20071227-C02780
    6.6 477.2
    20
    Figure US20070299073A1-20071227-C02781
    Figure US20070299073A1-20071227-C02782
    4.9 494.3
    21
    Figure US20070299073A1-20071227-C02783
    Figure US20070299073A1-20071227-C02784
    6.0 423.3
    22
    Figure US20070299073A1-20071227-C02785
    Figure US20070299073A1-20071227-C02786
    5.7 439.2
    23
    Figure US20070299073A1-20071227-C02787
    Figure US20070299073A1-20071227-C02788
    5.6 439.2
    24
    Figure US20070299073A1-20071227-C02789
    Figure US20070299073A1-20071227-C02790
    6.1 441.2
    25
    Figure US20070299073A1-20071227-C02791
    Figure US20070299073A1-20071227-C02792
    6.0 453.2
    26
    Figure US20070299073A1-20071227-C02793
    Figure US20070299073A1-20071227-C02794
    5.9 453.2
    27
    Figure US20070299073A1-20071227-C02795
    Figure US20070299073A1-20071227-C02796
    6.0 453.2
    28
    Figure US20070299073A1-20071227-C02797
    Figure US20070299073A1-20071227-C02798
    6.2 468.2
    29
    Figure US20070299073A1-20071227-C02799
    Figure US20070299073A1-20071227-C02800
    6.1 468.2
    30
    Figure US20070299073A1-20071227-C02801
    Figure US20070299073A1-20071227-C02802
    6.7 491.2
    31
    Figure US20070299073A1-20071227-C02803
    Figure US20070299073A1-20071227-C02804
    6.1 498.2
    32
    Figure US20070299073A1-20071227-C02805
    Figure US20070299073A1-20071227-C02806
    6.5 501.1
    33
    Figure US20070299073A1-20071227-C02807
    Figure US20070299073A1-20071227-C02808
    6.0 429.2
    34
    Figure US20070299073A1-20071227-C02809
    Figure US20070299073A1-20071227-C02810
    5.9 513.2
    35
    Figure US20070299073A1-20071227-C02811
    Figure US20070299073A1-20071227-C02812
    6.1 441.2
    36
    Figure US20070299073A1-20071227-C02813
    Figure US20070299073A1-20071227-C02814
    6.6 491.2
    37
    Figure US20070299073A1-20071227-C02815
    Figure US20070299073A1-20071227-C02816
    6.4 501.1
    38
    Figure US20070299073A1-20071227-C02817
    Figure US20070299073A1-20071227-C02818
    5.5 466.3
    39
    Figure US20070299073A1-20071227-C02819
    Figure US20070299073A1-20071227-C02820
    6.7 507.2
    40
    Figure US20070299073A1-20071227-C02821
    Figure US20070299073A1-20071227-C02822
    4.9 524.3
    41
    Figure US20070299073A1-20071227-C02823
    Figure US20070299073A1-20071227-C02824
    5.9 423.2
    42
    Figure US20070299073A1-20071227-C02825
    Figure US20070299073A1-20071227-C02826
    5.6 439.2
    43
    Figure US20070299073A1-20071227-C02827
    Figure US20070299073A1-20071227-C02828
    5.5 439.2
    44
    Figure US20070299073A1-20071227-C02829
    Figure US20070299073A1-20071227-C02830
    6.0 441.2
    45
    Figure US20070299073A1-20071227-C02831
    Figure US20070299073A1-20071227-C02832
    6.0 453.2
    46
    Figure US20070299073A1-20071227-C02833
    Figure US20070299073A1-20071227-C02834
    5.9 453.2
    47
    Figure US20070299073A1-20071227-C02835
    Figure US20070299073A1-20071227-C02836
    6.0 453.2
    48
    Figure US20070299073A1-20071227-C02837
    Figure US20070299073A1-20071227-C02838
    6.1 468.2
    49
    Figure US20070299073A1-20071227-C02839
    Figure US20070299073A1-20071227-C02840
    6.1 468.2
    50
    Figure US20070299073A1-20071227-C02841
    Figure US20070299073A1-20071227-C02842
    6.6 491.1
    51
    Figure US20070299073A1-20071227-C02843
    Figure US20070299073A1-20071227-C02844
    6.2 498.2
    52
    Figure US20070299073A1-20071227-C02845
    Figure US20070299073A1-20071227-C02846
    6.4 501.1
    53
    Figure US20070299073A1-20071227-C02847
    Figure US20070299073A1-20071227-C02848
    5.8 429.2
    54
    Figure US20070299073A1-20071227-C02849
    Figure US20070299073A1-20071227-C02850
    5.8 513.2
    55
    Figure US20070299073A1-20071227-C02851
    Figure US20070299073A1-20071227-C02852
    6.0 441.2
    56
    Figure US20070299073A1-20071227-C02853
    Figure US20070299073A1-20071227-C02854
    6.5 491.2
    57
    Figure US20070299073A1-20071227-C02855
    Figure US20070299073A1-20071227-C02856
    6.3 501.1
    58
    Figure US20070299073A1-20071227-C02857
    Figure US20070299073A1-20071227-C02858
    5.4 466.3
    59
    Figure US20070299073A1-20071227-C02859
    Figure US20070299073A1-20071227-C02860
    6.6 507.2
    60
    Figure US20070299073A1-20071227-C02861
    Figure US20070299073A1-20071227-C02862
    4.9 524.3
    61
    Figure US20070299073A1-20071227-C02863
    Figure US20070299073A1-20071227-C02864
    5.9 423.2
    62
    Figure US20070299073A1-20071227-C02865
    Figure US20070299073A1-20071227-C02866
    5.6 439.2
    63
    Figure US20070299073A1-20071227-C02867
    Figure US20070299073A1-20071227-C02868
    5.5 439.2
    64
    Figure US20070299073A1-20071227-C02869
    Figure US20070299073A1-20071227-C02870
    6.0 441.2
    65
    Figure US20070299073A1-20071227-C02871
    Figure US20070299073A1-20071227-C02872
    6.0 453.2
    66
    Figure US20070299073A1-20071227-C02873
    Figure US20070299073A1-20071227-C02874
    5.9 453.2
    67
    Figure US20070299073A1-20071227-C02875
    Figure US20070299073A1-20071227-C02876
    6.0 453.2
    68
    Figure US20070299073A1-20071227-C02877
    Figure US20070299073A1-20071227-C02878
    6.0 468.2
    69
    Figure US20070299073A1-20071227-C02879
    Figure US20070299073A1-20071227-C02880
    6.0 468.2
    70
    Figure US20070299073A1-20071227-C02881
    Figure US20070299073A1-20071227-C02882
    6.6 491.1
    71
    Figure US20070299073A1-20071227-C02883
    Figure US20070299073A1-20071227-C02884
    6.2 498.2
    72
    Figure US20070299073A1-20071227-C02885
    Figure US20070299073A1-20071227-C02886
    6.4 501.1
    73
    Figure US20070299073A1-20071227-C02887
    Figure US20070299073A1-20071227-C02888
    5.9 429.2
    74
    Figure US20070299073A1-20071227-C02889
    Figure US20070299073A1-20071227-C02890
    5.8 513.3
    75
    Figure US20070299073A1-20071227-C02891
    Figure US20070299073A1-20071227-C02892
    6.0 441.2
    76
    Figure US20070299073A1-20071227-C02893
    Figure US20070299073A1-20071227-C02894
    6.5 491.2
    77
    Figure US20070299073A1-20071227-C02895
    Figure US20070299073A1-20071227-C02896
    6.3 501.1
    78
    Figure US20070299073A1-20071227-C02897
    Figure US20070299073A1-20071227-C02898
    5.4 466.3
    79
    Figure US20070299073A1-20071227-C02899
    Figure US20070299073A1-20071227-C02900
    6.6 507.2
  • FORMULA 53
    Figure US20070299073A1-20071227-C02901
    Analysis
    Tr
    R1 R2 (min) [M + H]+
     1
    Figure US20070299073A1-20071227-C02902
    Figure US20070299073A1-20071227-C02903
    5.2 416.2
     2
    Figure US20070299073A1-20071227-C02904
    Figure US20070299073A1-20071227-C02905
    5.5 418.1
     3
    Figure US20070299073A1-20071227-C02906
    Figure US20070299073A1-20071227-C02907
    5.0 430.2
     4
    Figure US20070299073A1-20071227-C02908
    Figure US20070299073A1-20071227-C02909
    5.0 457.2
     5
    Figure US20070299073A1-20071227-C02910
    Figure US20070299073A1-20071227-C02911
    5.9 480.2
     6
    Figure US20070299073A1-20071227-C02912
    Figure US20070299073A1-20071227-C02913
    6.1 491.2
     7
    Figure US20070299073A1-20071227-C02914
    Figure US20070299073A1-20071227-C02915
    6.4 501.2
     8
    Figure US20070299073A1-20071227-C02916
    Figure US20070299073A1-20071227-C02917
    4.9 505.2
     9
    Figure US20070299073A1-20071227-C02918
    Figure US20070299073A1-20071227-C02919
    6.3 509.2
    10
    Figure US20070299073A1-20071227-C02920
    Figure US20070299073A1-20071227-C02921
    5.9 521.2
    11
    Figure US20070299073A1-20071227-C02922
    Figure US20070299073A1-20071227-C02923
    6.7 525.2
    12
    Figure US20070299073A1-20071227-C02924
    Figure US20070299073A1-20071227-C02925
    7.0 526.2
    13
    Figure US20070299073A1-20071227-C02926
    Figure US20070299073A1-20071227-C02927
    6.3 536.2
    14
    Figure US20070299073A1-20071227-C02928
    Figure US20070299073A1-20071227-C02929
    5.9 522.2
    15
    Figure US20070299073A1-20071227-C02930
    Figure US20070299073A1-20071227-C02931
    6.7 525.2
    16
    Figure US20070299073A1-20071227-C02932
    Figure US20070299073A1-20071227-C02933
    4.6 492.2
    17
    Figure US20070299073A1-20071227-C02934
    Figure US20070299073A1-20071227-C02935
    6.9 504.2
    18
    Figure US20070299073A1-20071227-C02936
    Figure US20070299073A1-20071227-C02937
    5.4 472.2
    19
    Figure US20070299073A1-20071227-C02938
    Figure US20070299073A1-20071227-C02939
    5.9 506.2
    20
    Figure US20070299073A1-20071227-C02940
    Figure US20070299073A1-20071227-C02941
    6.6 536.2
    21
    Figure US20070299073A1-20071227-C02942
    Figure US20070299073A1-20071227-C02943
    4.9 549.2
    22
    Figure US20070299073A1-20071227-C02944
    Figure US20070299073A1-20071227-C02945
    6.9 559.2
    23
    Figure US20070299073A1-20071227-C02946
    Figure US20070299073A1-20071227-C02947
    6.0 560.2
    24
    Figure US20070299073A1-20071227-C02948
    Figure US20070299073A1-20071227-C02949
    6.7 525.2
    25
    Figure US20070299073A1-20071227-C02950
    Figure US20070299073A1-20071227-C02951
    5.0 507.2
    26
    Figure US20070299073A1-20071227-C02952
    Figure US20070299073A1-20071227-C02953
    6.9 519.2
    27
    Figure US20070299073A1-20071227-C02954
    Figure US20070299073A1-20071227-C02955
    5.0 416.2
    28
    Figure US20070299073A1-20071227-C02956
    Figure US20070299073A1-20071227-C02957
    6.4 549.2
    29
    Figure US20070299073A1-20071227-C02958
    Figure US20070299073A1-20071227-C02959
    5.8 546.2
    30
    Figure US20070299073A1-20071227-C02960
    Figure US20070299073A1-20071227-C02961
    5.5 509.2
    31
    Figure US20070299073A1-20071227-C02962
    Figure US20070299073A1-20071227-C02963
    6.8 611.2
    32
    Figure US20070299073A1-20071227-C02964
    Figure US20070299073A1-20071227-C02965
    7.2 570.2
    33
    Figure US20070299073A1-20071227-C02966
    Figure US20070299073A1-20071227-C02967
    5.8 521.2
    34
    Figure US20070299073A1-20071227-C02968
    Figure US20070299073A1-20071227-C02969
    5.8 581.2
    35
    Figure US20070299073A1-20071227-C02970
    Figure US20070299073A1-20071227-C02971
    5.1 507.2
    36
    Figure US20070299073A1-20071227-C02972
    Figure US20070299073A1-20071227-C02973
    4.2 516.3
    37
    Figure US20070299073A1-20071227-C02974
    Figure US20070299073A1-20071227-C02975
    6.4 509.2
    38
    Figure US20070299073A1-20071227-C02976
    Figure US20070299073A1-20071227-C02977
    6.7 537.2
    39
    Figure US20070299073A1-20071227-C02978
    Figure US20070299073A1-20071227-C02979
    5.1 396.2
    40
    Figure US20070299073A1-20071227-C02980
    Figure US20070299073A1-20071227-C02981
    5.4 398.2
    41
    Figure US20070299073A1-20071227-C02982
    Figure US20070299073A1-20071227-C02983
    5.0 410.2
    42
    Figure US20070299073A1-20071227-C02984
    Figure US20070299073A1-20071227-C02985
    4.9 437.2
    43
    Figure US20070299073A1-20071227-C02986
    Figure US20070299073A1-20071227-C02987
    5.8 460.2
    44
    Figure US20070299073A1-20071227-C02988
    Figure US20070299073A1-20071227-C02989
    6.0 471.3
    45
    Figure US20070299073A1-20071227-C02990
    Figure US20070299073A1-20071227-C02991
    6.4 481.2
    46
    Figure US20070299073A1-20071227-C02992
    Figure US20070299073A1-20071227-C02993
    4.8 485.3
    47
    Figure US20070299073A1-20071227-C02994
    Figure US20070299073A1-20071227-C02995
    6.2 489.2
    48
    Figure US20070299073A1-20071227-C02996
    Figure US20070299073A1-20071227-C02997
    5.8 501.3
    49
    Figure US20070299073A1-20071227-C02998
    Figure US20070299073A1-20071227-C02999
    6.7 505.2
    50
    Figure US20070299073A1-20071227-C03000
    Figure US20070299073A1-20071227-C03001
    6.9 506.3
    51
    Figure US20070299073A1-20071227-C03002
    Figure US20070299073A1-20071227-C03003
    6.2 516.2
    52
    Figure US20070299073A1-20071227-C03004
    Figure US20070299073A1-20071227-C03005
    5.9 502.2
    53
    Figure US20070299073A1-20071227-C03006
    Figure US20070299073A1-20071227-C03007
    6.6 505.2
    54
    Figure US20070299073A1-20071227-C03008
    Figure US20070299073A1-20071227-C03009
    4.5 472.3
    55
    Figure US20070299073A1-20071227-C03010
    Figure US20070299073A1-20071227-C03011
    6.8 484.3
    56
    Figure US20070299073A1-20071227-C03012
    Figure US20070299073A1-20071227-C03013
    5.3 452.3
    57
    Figure US20070299073A1-20071227-C03014
    Figure US20070299073A1-20071227-C03015
    5.8 486.3
    58
    Figure US20070299073A1-20071227-C03016
    Figure US20070299073A1-20071227-C03017
    6.5 516.3
    59
    Figure US20070299073A1-20071227-C03018
    Figure US20070299073A1-20071227-C03019
    4.8 529.2
    60
    Figure US20070299073A1-20071227-C03020
    Figure US20070299073A1-20071227-C03021
    6.9 539.2
    61
    Figure US20070299073A1-20071227-C03022
    Figure US20070299073A1-20071227-C03023
    6.0 540.2
    62
    Figure US20070299073A1-20071227-C03024
    Figure US20070299073A1-20071227-C03025
    6.6 505.2
    63
    Figure US20070299073A1-20071227-C03026
    Figure US20070299073A1-20071227-C03027
    4.9 487.3
    64
    Figure US20070299073A1-20071227-C03028
    Figure US20070299073A1-20071227-C03029
    6.9 499.3
    65
    Figure US20070299073A1-20071227-C03030
    Figure US20070299073A1-20071227-C03031
    4.9 396.2
    66
    Figure US20070299073A1-20071227-C03032
    Figure US20070299073A1-20071227-C03033
    6.3 529.2
    67
    Figure US20070299073A1-20071227-C03034
    Figure US20070299073A1-20071227-C03035
    5.7 526.3
    68
    Figure US20070299073A1-20071227-C03036
    Figure US20070299073A1-20071227-C03037
    5.4 489.2
    69
    Figure US20070299073A1-20071227-C03038
    Figure US20070299073A1-20071227-C03039
    6.7 591.3
    70
    Figure US20070299073A1-20071227-C03040
    Figure US20070299073A1-20071227-C03041
    7.2 550.3
    71
    Figure US20070299073A1-20071227-C03042
    Figure US20070299073A1-20071227-C03043
    5.7 501.3
    72
    Figure US20070299073A1-20071227-C03044
    Figure US20070299073A1-20071227-C03045
    5.7 561.3
    73
    Figure US20070299073A1-20071227-C03046
    Figure US20070299073A1-20071227-C03047
    5.0 487.3
    74
    Figure US20070299073A1-20071227-C03048
    Figure US20070299073A1-20071227-C03049
    4.1 496.4
    75
    Figure US20070299073A1-20071227-C03050
    Figure US20070299073A1-20071227-C03051
    6.3 489.3
    76
    Figure US20070299073A1-20071227-C03052
    Figure US20070299073A1-20071227-C03053
    6.7 517.2
  • FORMULA 54
    Figure US20070299073A1-20071227-C03054
    Analysis
    Tr
    R1 R2 (min) [M + H]+
     1
    Figure US20070299073A1-20071227-C03055
    Figure US20070299073A1-20071227-C03056
    4.4 431.2
     2
    Figure US20070299073A1-20071227-C03057
    Figure US20070299073A1-20071227-C03058
    6.3 442.2
     3
    Figure US20070299073A1-20071227-C03059
    Figure US20070299073A1-20071227-C03060
    6.1 450.2
     4
    Figure US20070299073A1-20071227-C03061
    Figure US20070299073A1-20071227-C03062
    5.9 466.2
     5
    Figure US20070299073A1-20071227-C03063
    Figure US20070299073A1-20071227-C03064
    6.2 480.2
     6
    Figure US20070299073A1-20071227-C03065
    Figure US20070299073A1-20071227-C03066
    5.9 510.2
     7
    Figure US20070299073A1-20071227-C03067
    Figure US20070299073A1-20071227-C03068
    4.5 440.2
     8
    Figure US20070299073A1-20071227-C03069
    Figure US20070299073A1-20071227-C03070
    5.8 526.2
     9
    Figure US20070299073A1-20071227-C03071
    Figure US20070299073A1-20071227-C03072
    6.1 495.2
    10
    Figure US20070299073A1-20071227-C03073
    Figure US20070299073A1-20071227-C03074
    6.3 430.3
    11
    Figure US20070299073A1-20071227-C03075
    Figure US20070299073A1-20071227-C03076
    4.5 437.2
    12
    Figure US20070299073A1-20071227-C03077
    Figure US20070299073A1-20071227-C03078
    4.5 451.2
    13
    Figure US20070299073A1-20071227-C03079
    Figure US20070299073A1-20071227-C03080
    4.5 473.3
    14
    Figure US20070299073A1-20071227-C03081
    Figure US20070299073A1-20071227-C03082
    5.7 501.3
    15
    Figure US20070299073A1-20071227-C03083
    Figure US20070299073A1-20071227-C03084
    5.8 511.2
    16
    Figure US20070299073A1-20071227-C03085
    Figure US20070299073A1-20071227-C03086
    6.4 496.2
    17
    Figure US20070299073A1-20071227-C03087
    Figure US20070299073A1-20071227-C03088
    5.3 468.2
    18
    Figure US20070299073A1-20071227-C03089
    Figure US20070299073A1-20071227-C03090
    4.7 472.3
    19
    Figure US20070299073A1-20071227-C03091
    Figure US20070299073A1-20071227-C03092
    5.8 402.2
    20
    Figure US20070299073A1-20071227-C03093
    Figure US20070299073A1-20071227-C03094
    5.6 568.2
    21
    Figure US20070299073A1-20071227-C03095
    Figure US20070299073A1-20071227-C03096
    6.8 512.2
    22
    Figure US20070299073A1-20071227-C03097
    Figure US20070299073A1-20071227-C03098
    4.6 437.2
    23
    Figure US20070299073A1-20071227-C03099
    Figure US20070299073A1-20071227-C03100
    6.3 470.2
    24
    Figure US20070299073A1-20071227-C03101
    Figure US20070299073A1-20071227-C03102
    7.0 540.2
    25
    Figure US20070299073A1-20071227-C03103
    Figure US20070299073A1-20071227-C03104
    6.4 464.2
    26
    Figure US20070299073A1-20071227-C03105
    Figure US20070299073A1-20071227-C03106
    4.5 443.3
    27
    Figure US20070299073A1-20071227-C03107
    Figure US20070299073A1-20071227-C03108
    6.5 484.2
    28
    Figure US20070299073A1-20071227-C03109
    Figure US20070299073A1-20071227-C03110
    6.2 468.2
    29
    Figure US20070299073A1-20071227-C03111
    Figure US20070299073A1-20071227-C03112
    6.2 468.2
    30
    Figure US20070299073A1-20071227-C03113
    Figure US20070299073A1-20071227-C03114
    6.5 484.2
    31
    Figure US20070299073A1-20071227-C03115
    Figure US20070299073A1-20071227-C03116
    6.6 528.1
    32
    Figure US20070299073A1-20071227-C03117
    Figure US20070299073A1-20071227-C03118
    6.5 504.2
    33
    Figure US20070299073A1-20071227-C03119
    Figure US20070299073A1-20071227-C03120
    6.5 504.2
    34
    Figure US20070299073A1-20071227-C03121
    Figure US20070299073A1-20071227-C03122
    4.5 437.2
    35
    Figure US20070299073A1-20071227-C03123
    Figure US20070299073A1-20071227-C03124
    6.1 466.2
    36
    Figure US20070299073A1-20071227-C03125
    Figure US20070299073A1-20071227-C03126
    6.2 470.2
    37
    Figure US20070299073A1-20071227-C03127
    Figure US20070299073A1-20071227-C03128
    6.0 454.2
    38
    Figure US20070299073A1-20071227-C03129
    Figure US20070299073A1-20071227-C03130
    6.0 454.2
    39
    Figure US20070299073A1-20071227-C03131
    Figure US20070299073A1-20071227-C03132
    6.0 454.2
    40
    Figure US20070299073A1-20071227-C03133
    Figure US20070299073A1-20071227-C03134
    4.3 486.3
    41
    Figure US20070299073A1-20071227-C03135
    Figure US20070299073A1-20071227-C03136
    4.4 411.3
    42
    Figure US20070299073A1-20071227-C03137
    Figure US20070299073A1-20071227-C03138
    6.3 422.3
    43
    Figure US20070299073A1-20071227-C03139
    Figure US20070299073A1-20071227-C03140
    6.0 430.3
    44
    Figure US20070299073A1-20071227-C03141
    Figure US20070299073A1-20071227-C03142
    5.9 446.2
    45
    Figure US20070299073A1-20071227-C03143
    Figure US20070299073A1-20071227-C03144
    6.2 460.3
    46
    Figure US20070299073A1-20071227-C03145
    Figure US20070299073A1-20071227-C03146
    5.8 490.3
    47
    Figure US20070299073A1-20071227-C03147
    Figure US20070299073A1-20071227-C03148
    4.4 420.3
    48
    Figure US20070299073A1-20071227-C03149
    Figure US20070299073A1-20071227-C03150
    5.7 506.3
    49
    Figure US20070299073A1-20071227-C03151
    Figure US20070299073A1-20071227-C03152
    6.1 475.2
    50
    Figure US20070299073A1-20071227-C03153
    Figure US20070299073A1-20071227-C03154
    6.2 410.3
    51
    Figure US20070299073A1-20071227-C03155
    Figure US20070299073A1-20071227-C03156
    4.4 417.2
    52
    Figure US20070299073A1-20071227-C03157
    Figure US20070299073A1-20071227-C03158
    4.4 431.2
    53
    Figure US20070299073A1-20071227-C03159
    Figure US20070299073A1-20071227-C03160
    4.4 453.3
    54
    Figure US20070299073A1-20071227-C03161
    Figure US20070299073A1-20071227-C03162
    5.7 481.3
    55
    Figure US20070299073A1-20071227-C03163
    Figure US20070299073A1-20071227-C03164
    5.7 491.2
    56
    Figure US20070299073A1-20071227-C03165
    Figure US20070299073A1-20071227-C03166
    6.4 476.3
    57
    Figure US20070299073A1-20071227-C03167
    Figure US20070299073A1-20071227-C03168
    5.2 448.2
    58
    Figure US20070299073A1-20071227-C03169
    Figure US20070299073A1-20071227-C03170
    4.6 452.3
    59
    Figure US20070299073A1-20071227-C03171
    Figure US20070299073A1-20071227-C03172
    5.7 382.3
    60
    Figure US20070299073A1-20071227-C03173
    Figure US20070299073A1-20071227-C03174
    5.5 548.2
    61
    Figure US20070299073A1-20071227-C03175
    Figure US20070299073A1-20071227-C03176
    6.7 492.3
    62
    Figure US20070299073A1-20071227-C03177
    Figure US20070299073A1-20071227-C03178
    4.5 417.2
    63
    Figure US20070299073A1-20071227-C03179
    Figure US20070299073A1-20071227-C03180
    6.2 450.2
    64
    Figure US20070299073A1-20071227-C03181
    Figure US20070299073A1-20071227-C03182
    7.0 520.3
    65
    Figure US20070299073A1-20071227-C03183
    Figure US20070299073A1-20071227-C03184
    6.3 444.3
    66
    Figure US20070299073A1-20071227-C03185
    Figure US20070299073A1-20071227-C03186
    4.4 423.3
    67
    Figure US20070299073A1-20071227-C03187
    Figure US20070299073A1-20071227-C03188
    6.4 464.2
    68
    Figure US20070299073A1-20071227-C03189
    Figure US20070299073A1-20071227-C03190
    6.1 448.2
    69
    Figure US20070299073A1-20071227-C03191
    Figure US20070299073A1-20071227-C03192
    6.2 448.2
    70
    Figure US20070299073A1-20071227-C03193
    Figure US20070299073A1-20071227-C03194
    6.4 464.2
    71
    Figure US20070299073A1-20071227-C03195
    Figure US20070299073A1-20071227-C03196
    6.5 510.1
    72
    Figure US20070299073A1-20071227-C03197
    Figure US20070299073A1-20071227-C03198
    6.5 484.2
    73
    Figure US20070299073A1-20071227-C03199
    Figure US20070299073A1-20071227-C03200
    6.5 484.2
    74
    Figure US20070299073A1-20071227-C03201
    Figure US20070299073A1-20071227-C03202
    4.4 417.2
    75
    Figure US20070299073A1-20071227-C03203
    Figure US20070299073A1-20071227-C03204
    6.0 446.2
    76
    Figure US20070299073A1-20071227-C03205
    Figure US20070299073A1-20071227-C03206
    6.2 450.2
    77
    Figure US20070299073A1-20071227-C03207
    Figure US20070299073A1-20071227-C03208
    6.0 434.2
    78
    Figure US20070299073A1-20071227-C03209
    Figure US20070299073A1-20071227-C03210
    5.9 434.2
    79
    Figure US20070299073A1-20071227-C03211
    Figure US20070299073A1-20071227-C03212
    6.0 434.2
    80
    Figure US20070299073A1-20071227-C03213
    Figure US20070299073A1-20071227-C03214
    4.1 466.3
  • FORMULA 55
    Figure US20070299073A1-20071227-C03215
    Analysis
    Tr [M +
    R1 R2 (min) H]+
     1
    Figure US20070299073A1-20071227-C03216
    Figure US20070299073A1-20071227-C03217
    6.4 486.2
     2
    Figure US20070299073A1-20071227-C03218
    Figure US20070299073A1-20071227-C03219
    6.6 486.2
     3
    Figure US20070299073A1-20071227-C03220
    Figure US20070299073A1-20071227-C03221
    6.6 486.2
     4
    Figure US20070299073A1-20071227-C03222
    Figure US20070299073A1-20071227-C03223
    6.4 530.1
     5
    Figure US20070299073A1-20071227-C03224
    Figure US20070299073A1-20071227-C03225
    6.7 530.1
     6
    Figure US20070299073A1-20071227-C03226
    Figure US20070299073A1-20071227-C03227
    6.6 530.1
     7
    Figure US20070299073A1-20071227-C03228
    Figure US20070299073A1-20071227-C03229
    6.3 470.2
     8
    Figure US20070299073A1-20071227-C03230
    Figure US20070299073A1-20071227-C03231
    6.3 488.2
     9
    Figure US20070299073A1-20071227-C03232
    Figure US20070299073A1-20071227-C03233
    6.4 488.2
    10
    Figure US20070299073A1-20071227-C03234
    Figure US20070299073A1-20071227-C03235
    6.3 497.2
    11
    Figure US20070299073A1-20071227-C03236
    Figure US20070299073A1-20071227-C03237
    6.4 497.2
    12
    Figure US20070299073A1-20071227-C03238
    Figure US20070299073A1-20071227-C03239
    6.4 497.2
    13
    Figure US20070299073A1-20071227-C03240
    Figure US20070299073A1-20071227-C03241
    6.4 520.2
    14
    Figure US20070299073A1-20071227-C03242
    Figure US20070299073A1-20071227-C03243
    6.8 520.2
    15
    Figure US20070299073A1-20071227-C03244
    Figure US20070299073A1-20071227-C03245
    6.8 520.2
    16
    Figure US20070299073A1-20071227-C03246
    Figure US20070299073A1-20071227-C03247
    6.3 512.2
    17
    Figure US20070299073A1-20071227-C03248
    Figure US20070299073A1-20071227-C03249
    6.2 482.2
    18
    Figure US20070299073A1-20071227-C03250
    Figure US20070299073A1-20071227-C03251
    6.1 482.2
    19
    Figure US20070299073A1-20071227-C03252
    Figure US20070299073A1-20071227-C03253
    6.8 554.1
    20
    Figure US20070299073A1-20071227-C03254
    Figure US20070299073A1-20071227-C03255
    6.4 515.1
    21
    Figure US20070299073A1-20071227-C03256
    Figure US20070299073A1-20071227-C03257
    6.7 534.0
    22
    Figure US20070299073A1-20071227-C03258
    Figure US20070299073A1-20071227-C03259
    6.9 534.0
    23
    Figure US20070299073A1-20071227-C03260
    Figure US20070299073A1-20071227-C03261
    6.8 534.0
    24
    Figure US20070299073A1-20071227-C03262
    Figure US20070299073A1-20071227-C03263
    6.7 578.0
    25
    Figure US20070299073A1-20071227-C03264
    Figure US20070299073A1-20071227-C03265
    6.9 578.0
    26
    Figure US20070299073A1-20071227-C03266
    Figure US20070299073A1-20071227-C03267
    6.9 578.0
    27
    Figure US20070299073A1-20071227-C03268
    Figure US20070299073A1-20071227-C03269
    6.6 518.1
    28
    Figure US20070299073A1-20071227-C03270
    Figure US20070299073A1-20071227-C03271
    6.6 536.1
    29
    Figure US20070299073A1-20071227-C03272
    Figure US20070299073A1-20071227-C03273
    6.7 536.1
    30
    Figure US20070299073A1-20071227-C03274
    Figure US20070299073A1-20071227-C03275
    6.6 545.0
    31
    Figure US20070299073A1-20071227-C03276
    Figure US20070299073A1-20071227-C03277
    6.7 545.0
    32
    Figure US20070299073A1-20071227-C03278
    Figure US20070299073A1-20071227-C03279
    6.7 545.0
    33
    Figure US20070299073A1-20071227-C03280
    Figure US20070299073A1-20071227-C03281
    6.7 568.0
    34
    Figure US20070299073A1-20071227-C03282
    Figure US20070299073A1-20071227-C03283
    7.1 568.0
    35
    Figure US20070299073A1-20071227-C03284
    Figure US20070299073A1-20071227-C03285
    7.1 568.0
    36
    Figure US20070299073A1-20071227-C03286
    Figure US20070299073A1-20071227-C03287
    6.6 560.1
    37
    Figure US20070299073A1-20071227-C03288
    Figure US20070299073A1-20071227-C03289
    6.5 530.1
    38
    Figure US20070299073A1-20071227-C03290
    Figure US20070299073A1-20071227-C03291
    6.4 530.1
    39
    Figure US20070299073A1-20071227-C03292
    Figure US20070299073A1-20071227-C03293
    7.1 602.0
    40
    Figure US20070299073A1-20071227-C03294
    Figure US20070299073A1-20071227-C03295
    6.7 563.0
    41
    Figure US20070299073A1-20071227-C03296
    Figure US20070299073A1-20071227-C03297
    6.6 501.1
    42
    Figure US20070299073A1-20071227-C03298
    Figure US20070299073A1-20071227-C03299
    6.8 501.1
    43
    Figure US20070299073A1-20071227-C03300
    Figure US20070299073A1-20071227-C03301
    6.8 501.1
    44
    Figure US20070299073A1-20071227-C03302
    Figure US20070299073A1-20071227-C03303
    6.7 545.0
    45
    Figure US20070299073A1-20071227-C03304
    Figure US20070299073A1-20071227-C03305
    6.9 545.0
    46
    Figure US20070299073A1-20071227-C03306
    Figure US20070299073A1-20071227-C03307
    6.9 545.0
    47
    Figure US20070299073A1-20071227-C03308
    Figure US20070299073A1-20071227-C03309
    6.5 485.1
    48
    Figure US20070299073A1-20071227-C03310
    Figure US20070299073A1-20071227-C03311
    6.5 503.2
    49
    Figure US20070299073A1-20071227-C03312
    Figure US20070299073A1-20071227-C03313
    6.7 503.2
    50
    Figure US20070299073A1-20071227-C03314
    Figure US20070299073A1-20071227-C03315
    6.6 512.2
    51
    Figure US20070299073A1-20071227-C03316
    Figure US20070299073A1-20071227-C03317
    6.6 512.2
    52
    Figure US20070299073A1-20071227-C03318
    Figure US20070299073A1-20071227-C03319
    6.6 512.2
    53
    Figure US20070299073A1-20071227-C03320
    Figure US20070299073A1-20071227-C03321
    6.7 535.1
    54
    Figure US20070299073A1-20071227-C03322
    Figure US20070299073A1-20071227-C03323
    7.1 535.1
    55
    Figure US20070299073A1-20071227-C03324
    Figure US20070299073A1-20071227-C03325
    7.1 535.1
    56
    Figure US20070299073A1-20071227-C03326
    Figure US20070299073A1-20071227-C03327
    6.4 527.2
    57
    Figure US20070299073A1-20071227-C03328
    Figure US20070299073A1-20071227-C03329
    6.3 497.2
    58
    Figure US20070299073A1-20071227-C03330
    Figure US20070299073A1-20071227-C03331
    6.2 497.2
    59
    Figure US20070299073A1-20071227-C03332
    Figure US20070299073A1-20071227-C03333
    7.2 569.1
    60
    Figure US20070299073A1-20071227-C03334
    Figure US20070299073A1-20071227-C03335
    6.7 530.1
    61
    Figure US20070299073A1-20071227-C03336
    Figure US20070299073A1-20071227-C03337
    5.9 527.2
    62
    Figure US20070299073A1-20071227-C03338
    Figure US20070299073A1-20071227-C03339
    6.2 527.2
    63
    Figure US20070299073A1-20071227-C03340
    Figure US20070299073A1-20071227-C03341
    6.1 527.2
    64
    Figure US20070299073A1-20071227-C03342
    Figure US20070299073A1-20071227-C03343
    5.9 571.1
    65
    Figure US20070299073A1-20071227-C03344
    Figure US20070299073A1-20071227-C03345
    6.3 571.1
    66
    Figure US20070299073A1-20071227-C03346
    Figure US20070299073A1-20071227-C03347
    6.2 571.1
    67
    Figure US20070299073A1-20071227-C03348
    Figure US20070299073A1-20071227-C03349
    5.9 511.3
    68
    Figure US20070299073A1-20071227-C03350
    Figure US20070299073A1-20071227-C03351
    5.8 529.2
    69
    Figure US20070299073A1-20071227-C03352
    Figure US20070299073A1-20071227-C03353
    6.0 529.2
    70
    Figure US20070299073A1-20071227-C03354
    Figure US20070299073A1-20071227-C03355
    5.8 538.2
    71
    Figure US20070299073A1-20071227-C03356
    Figure US20070299073A1-20071227-C03357
    5.9 538.2
    72
    Figure US20070299073A1-20071227-C03358
    Figure US20070299073A1-20071227-C03359
    6.0 538.2
    73
    Figure US20070299073A1-20071227-C03360
    Figure US20070299073A1-20071227-C03361
    6.0 561.2
    74
    Figure US20070299073A1-20071227-C03362
    Figure US20070299073A1-20071227-C03363
    6.4 561.2
    75
    Figure US20070299073A1-20071227-C03364
    Figure US20070299073A1-20071227-C03365
    6.5 561.0
    76
    Figure US20070299073A1-20071227-C03366
    Figure US20070299073A1-20071227-C03367
    5.8 553.3
    77
    Figure US20070299073A1-20071227-C03368
    Figure US20070299073A1-20071227-C03369
    5.7 523.3
    78
    Figure US20070299073A1-20071227-C03370
    Figure US20070299073A1-20071227-C03371
    5.6 523.3
    79
    Figure US20070299073A1-20071227-C03372
    Figure US20070299073A1-20071227-C03373
    6.5 595.2
    80
    Figure US20070299073A1-20071227-C03374
    Figure US20070299073A1-20071227-C03375
    6.0 556.2
  • FORMULA 56
    Figure US20070299073A1-20071227-C03376
    Analysis
    Tr [M +
    R1 R2 (min) H]+
     1
    Figure US20070299073A1-20071227-C03377
    Figure US20070299073A1-20071227-C03378
    5.6 485.2
     2
    Figure US20070299073A1-20071227-C03379
    Figure US20070299073A1-20071227-C03380
    5.8 485.2
     3
    Figure US20070299073A1-20071227-C03381
    Figure US20070299073A1-20071227-C03382
    6.0 485.2
     4
    Figure US20070299073A1-20071227-C03383
    Figure US20070299073A1-20071227-C03384
    5.8 529.2
     5
    Figure US20070299073A1-20071227-C03385
    Figure US20070299073A1-20071227-C03386
    6.0 529.2
     6
    Figure US20070299073A1-20071227-C03387
    Figure US20070299073A1-20071227-C03388
    6.0 529.2
     7
    Figure US20070299073A1-20071227-C03389
    Figure US20070299073A1-20071227-C03390
    5.5 469.2
     8
    Figure US20070299073A1-20071227-C03391
    Figure US20070299073A1-20071227-C03392
    5.7 469.3
     9
    Figure US20070299073A1-20071227-C03393
    Figure US20070299073A1-20071227-C03394
    5.6 469.2
    10
    Figure US20070299073A1-20071227-C03395
    Figure US20070299073A1-20071227-C03396
    5.5 496.3
    11
    Figure US20070299073A1-20071227-C03397
    Figure US20070299073A1-20071227-C03398
    5.6 496.3
    12
    Figure US20070299073A1-20071227-C03399
    Figure US20070299073A1-20071227-C03400
    5.6 496.3
    13
    Figure US20070299073A1-20071227-C03401
    Figure US20070299073A1-20071227-C03402
    6.0 519.2
    14
    Figure US20070299073A1-20071227-C03403
    Figure US20070299073A1-20071227-C03404
    6.2 519.2
    15
    Figure US20070299073A1-20071227-C03405
    Figure US20070299073A1-20071227-C03406
    6.2 519.2
    16
    Figure US20070299073A1-20071227-C03407
    Figure US20070299073A1-20071227-C03408
    5.5 481.1
    17
    Figure US20070299073A1-20071227-C03409
    Figure US20070299073A1-20071227-C03410
    5.5 481.2
    18
    Figure US20070299073A1-20071227-C03411
    Figure US20070299073A1-20071227-C03412
    5.4 481.2
    19
    Figure US20070299073A1-20071227-C03413
    Figure US20070299073A1-20071227-C03414
    5.4 451.2
    20
    Figure US20070299073A1-20071227-C03415
    Figure US20070299073A1-20071227-C03416
    4.3 494.2
    21
    Figure US20070299073A1-20071227-C03417
    Figure US20070299073A1-20071227-C03418
    6.1 533.1
    22
    Figure US20070299073A1-20071227-C03419
    Figure US20070299073A1-20071227-C03420
    6.2 533.1
    23
    Figure US20070299073A1-20071227-C03421
    Figure US20070299073A1-20071227-C03422
    6.3 533.1
    24
    Figure US20070299073A1-20071227-C03423
    Figure US20070299073A1-20071227-C03424
    6.1 577.0
    25
    Figure US20070299073A1-20071227-C03425
    Figure US20070299073A1-20071227-C03426
    6.3 577.0
    26
    Figure US20070299073A1-20071227-C03427
    Figure US20070299073A1-20071227-C03428
    6.3 577.0
    27
    Figure US20070299073A1-20071227-C03429
    Figure US20070299073A1-20071227-C03430
    5.9 517.1
    28
    Figure US20070299073A1-20071227-C03431
    Figure US20070299073A1-20071227-C03432
    6.0 517.1
    29
    Figure US20070299073A1-20071227-C03433
    Figure US20070299073A1-20071227-C03434
    6.0 517.1
    30
    Figure US20070299073A1-20071227-C03435
    Figure US20070299073A1-20071227-C03436
    5.8 544.1
    31
    Figure US20070299073A1-20071227-C03437
    Figure US20070299073A1-20071227-C03438
    6.0 544.1
    32
    Figure US20070299073A1-20071227-C03439
    Figure US20070299073A1-20071227-C03440
    6.0 544.1
    33
    Figure US20070299073A1-20071227-C03441
    Figure US20070299073A1-20071227-C03442
    6.3 567.1
    34
    Figure US20070299073A1-20071227-C03443
    Figure US20070299073A1-20071227-C03444
    6.5 567.1
    35
    Figure US20070299073A1-20071227-C03445
    Figure US20070299073A1-20071227-C03446
    6.5 567.1
    36
    Figure US20070299073A1-20071227-C03447
    Figure US20070299073A1-20071227-C03448
    5.9 529.1
    37
    Figure US20070299073A1-20071227-C03449
    Figure US20070299073A1-20071227-C03450
    5.9 529.1
    38
    Figure US20070299073A1-20071227-C03451
    Figure US20070299073A1-20071227-C03452
    5.9 529.1
    39
    Figure US20070299073A1-20071227-C03453
    Figure US20070299073A1-20071227-C03454
    5.9 499.1
    40
    Figure US20070299073A1-20071227-C03455
    Figure US20070299073A1-20071227-C03456
    4.7 542.1
    41
    Figure US20070299073A1-20071227-C03457
    Figure US20070299073A1-20071227-C03458
    6.2 500.2
    42
    Figure US20070299073A1-20071227-C03459
    Figure US20070299073A1-20071227-C03460
    6.4 500.2
    43
    Figure US20070299073A1-20071227-C03461
    Figure US20070299073A1-20071227-C03462
    6.9 500.1
    44
    Figure US20070299073A1-20071227-C03463
    Figure US20070299073A1-20071227-C03464
    6.8 544.0
    45
    Figure US20070299073A1-20071227-C03465
    Figure US20070299073A1-20071227-C03466
    7.0 544.0
    46
    Figure US20070299073A1-20071227-C03467
    Figure US20070299073A1-20071227-C03468
    7.0 544.0
    47
    Figure US20070299073A1-20071227-C03469
    Figure US20070299073A1-20071227-C03470
    6.5 484.2
    48
    Figure US20070299073A1-20071227-C03471
    Figure US20070299073A1-20071227-C03472
    6.6 484.2
    49
    Figure US20070299073A1-20071227-C03473
    Figure US20070299073A1-20071227-C03474
    6.6 484.2
    50
    Figure US20070299073A1-20071227-C03475
    Figure US20070299073A1-20071227-C03476
    6.4 511.2
    51
    Figure US20070299073A1-20071227-C03477
    Figure US20070299073A1-20071227-C03478
    6.6 511.2
    52
    Figure US20070299073A1-20071227-C03479
    Figure US20070299073A1-20071227-C03480
    6.6 511.2
    53
    Figure US20070299073A1-20071227-C03481
    Figure US20070299073A1-20071227-C03482
    7.0 534.1
    54
    Figure US20070299073A1-20071227-C03483
    Figure US20070299073A1-20071227-C03484
    7.1 534.1
    55
    Figure US20070299073A1-20071227-C03485
    Figure US20070299073A1-20071227-C03486
    7.2 534.1
    56
    Figure US20070299073A1-20071227-C03487
    Figure US20070299073A1-20071227-C03488
    6.6 496.2
    57
    Figure US20070299073A1-20071227-C03489
    Figure US20070299073A1-20071227-C03490
    6.5 496.2
    58
    Figure US20070299073A1-20071227-C03491
    Figure US20070299073A1-20071227-C03492
    6.5 496.2
    59
    Figure US20070299073A1-20071227-C03493
    Figure US20070299073A1-20071227-C03494
    6.5 466.2
    60
    Figure US20070299073A1-20071227-C03495
    Figure US20070299073A1-20071227-C03496
    5.4 509.2
    61
    Figure US20070299073A1-20071227-C03497
    Figure US20070299073A1-20071227-C03498
    5.8 526.2
    62
    Figure US20070299073A1-20071227-C03499
    Figure US20070299073A1-20071227-C03500
    6.0 526.3
    63
    Figure US20070299073A1-20071227-C03501
    Figure US20070299073A1-20071227-C03502
    6.0 526.3
    64
    Figure US20070299073A1-20071227-C03503
    Figure US20070299073A1-20071227-C03504
    5.9 570.2
    65
    Figure US20070299073A1-20071227-C03505
    Figure US20070299073A1-20071227-C03506
    6.1 570.1
    66
    Figure US20070299073A1-20071227-C03507
    Figure US20070299073A1-20071227-C03508
    6.1 570.1
    67
    Figure US20070299073A1-20071227-C03509
    Figure US20070299073A1-20071227-C03510
    5.6 510.3
    68
    Figure US20070299073A1-20071227-C03511
    Figure US20070299073A1-20071227-C03512
    5.7 510.3
    69
    Figure US20070299073A1-20071227-C03513
    Figure US20070299073A1-20071227-C03514
    5.6 537.2
    70
    Figure US20070299073A1-20071227-C03515
    Figure US20070299073A1-20071227-C03516
    5.7 537.2
    71
    Figure US20070299073A1-20071227-C03517
    Figure US20070299073A1-20071227-C03518
    5.7 537.3
    72
    Figure US20070299073A1-20071227-C03519
    Figure US20070299073A1-20071227-C03520
    6.1 560.2
    73
    Figure US20070299073A1-20071227-C03521
    Figure US20070299073A1-20071227-C03522
    6.2 560.2
    74
    Figure US20070299073A1-20071227-C03523
    Figure US20070299073A1-20071227-C03524
    6.3 560.2
    75
    Figure US20070299073A1-20071227-C03525
    Figure US20070299073A1-20071227-C03526
    5.7 522.3
    76
    Figure US20070299073A1-20071227-C03527
    Figure US20070299073A1-20071227-C03528
    5.6 522.3
    77
    Figure US20070299073A1-20071227-C03529
    Figure US20070299073A1-20071227-C03530
    5.6 522.3
    78
    Figure US20070299073A1-20071227-C03531
    Figure US20070299073A1-20071227-C03532
    5.6 492.3
    79
    Figure US20070299073A1-20071227-C03533
    Figure US20070299073A1-20071227-C03534
    4.7 535.3
  • FORMULA 57
    Figure US20070299073A1-20071227-C03535
    Analysis
    Tr
    R1 R2 (min) [M + H]+
     1
    Figure US20070299073A1-20071227-C03536
    Figure US20070299073A1-20071227-C03537
    14.4 414.2
     2
    Figure US20070299073A1-20071227-C03538
    Figure US20070299073A1-20071227-C03539
     6.4 418.2
     3
    Figure US20070299073A1-20071227-C03540
    Figure US20070299073A1-20071227-C03541
    11.1 445.3
     4
    Figure US20070299073A1-20071227-C03542
    Figure US20070299073A1-20071227-C03543
    10.8 457.3
     5
    Figure US20070299073A1-20071227-C03544
    Figure US20070299073A1-20071227-C03545
    14.3 462.2
     6
    Figure US20070299073A1-20071227-C03546
    Figure US20070299073A1-20071227-C03547
    14.5 466.1
     7
    Figure US20070299073A1-20071227-C03548
    Figure US20070299073A1-20071227-C03549
    14.5 489.2
     8
    Figure US20070299073A1-20071227-C03550
    Figure US20070299073A1-20071227-C03551
    12.2 519.4
     9
    Figure US20070299073A1-20071227-C03552
    Figure US20070299073A1-20071227-C03553
    10.1 466.1
    10
    Figure US20070299073A1-20071227-C03554
    Figure US20070299073A1-20071227-C03555
    14.8 486.1
    11
    Figure US20070299073A1-20071227-C03556
    Figure US20070299073A1-20071227-C03557
    12.1 459.3
    12
    Figure US20070299073A1-20071227-C03558
    Figure US20070299073A1-20071227-C03559
    14.4 480.1
    13
    Figure US20070299073A1-20071227-C03560
    Figure US20070299073A1-20071227-C03561
    14.8 476.1
    14
    Figure US20070299073A1-20071227-C03562
    Figure US20070299073A1-20071227-C03563
    14.4 442.1
    15
    Figure US20070299073A1-20071227-C03564
    Figure US20070299073A1-20071227-C03565
    14.8 504.1
    16
    Figure US20070299073A1-20071227-C03566
    Figure US20070299073A1-20071227-C03567
    14.7 470.1
    17
    Figure US20070299073A1-20071227-C03568
    Figure US20070299073A1-20071227-C03569
    14.7 574.1
    18
    Figure US20070299073A1-20071227-C03570
    Figure US20070299073A1-20071227-C03571
    15.0 526.2
    19
    Figure US20070299073A1-20071227-C03572
    Figure US20070299073A1-20071227-C03573
    12.0 454.3
    20
    Figure US20070299073A1-20071227-C03574
    Figure US20070299073A1-20071227-C03575
     8.0 529.1
    21
    Figure US20070299073A1-20071227-C03576
    Figure US20070299073A1-20071227-C03577
    14.4 414.2
    22
    Figure US20070299073A1-20071227-C03578
    Figure US20070299073A1-20071227-C03579
     6.3 418.2
    23
    Figure US20070299073A1-20071227-C03580
    Figure US20070299073A1-20071227-C03581
    11.3 445.3
    24
    Figure US20070299073A1-20071227-C03582
    Figure US20070299073A1-20071227-C03583
    10.7 457.3
    25
    Figure US20070299073A1-20071227-C03584
    Figure US20070299073A1-20071227-C03585
    14.3 462.2
    26
    Figure US20070299073A1-20071227-C03586
    Figure US20070299073A1-20071227-C03587
    14.6 466.1
    27
    Figure US20070299073A1-20071227-C03588
    Figure US20070299073A1-20071227-C03589
    14.5 489.2
    28
    Figure US20070299073A1-20071227-C03590
    Figure US20070299073A1-20071227-C03591
    12.2 519.2
    29
    Figure US20070299073A1-20071227-C03592
    Figure US20070299073A1-20071227-C03593
    11.7 466.1
    30
    Figure US20070299073A1-20071227-C03594
    Figure US20070299073A1-20071227-C03595
    14.8 486.1
    31
    Figure US20070299073A1-20071227-C03596
    Figure US20070299073A1-20071227-C03597
    12.0 459.3
    32
    Figure US20070299073A1-20071227-C03598
    Figure US20070299073A1-20071227-C03599
    14.4 480.1
    33
    Figure US20070299073A1-20071227-C03600
    Figure US20070299073A1-20071227-C03601
    14.8 476.2
    34
    Figure US20070299073A1-20071227-C03602
    Figure US20070299073A1-20071227-C03603
    14.4 442.1
    35
    Figure US20070299073A1-20071227-C03604
    Figure US20070299073A1-20071227-C03605
    14.7 504.1
    36
    Figure US20070299073A1-20071227-C03606
    Figure US20070299073A1-20071227-C03607
    14.7 470.1
    37
    Figure US20070299073A1-20071227-C03608
    Figure US20070299073A1-20071227-C03609
    14.7 574.1
    38
    Figure US20070299073A1-20071227-C03610
    Figure US20070299073A1-20071227-C03611
    14.9 526.2
    39
    Figure US20070299073A1-20071227-C03612
    Figure US20070299073A1-20071227-C03613
    11.8 454.3
    40
    Figure US20070299073A1-20071227-C03614
    Figure US20070299073A1-20071227-C03615
     8.5 529.1
    41
    Figure US20070299073A1-20071227-C03616
    Figure US20070299073A1-20071227-C03617
    14.3 394.2
    42
    Figure US20070299073A1-20071227-C03618
    Figure US20070299073A1-20071227-C03619
     6.0 398.2
    43
    Figure US20070299073A1-20071227-C03620
    Figure US20070299073A1-20071227-C03621
    14.2 442.2
    44
    Figure US20070299073A1-20071227-C03622
    Figure US20070299073A1-20071227-C03623
    14.6 446.2
    45
    Figure US20070299073A1-20071227-C03624
    Figure US20070299073A1-20071227-C03625
    14.6 469.2
    46
    Figure US20070299073A1-20071227-C03626
    Figure US20070299073A1-20071227-C03627
    10.7 446.2
    47
    Figure US20070299073A1-20071227-C03628
    Figure US20070299073A1-20071227-C03629
    14.8 466.2
    48
    Figure US20070299073A1-20071227-C03630
    Figure US20070299073A1-20071227-C03631
    11.8 439.3
    49
    Figure US20070299073A1-20071227-C03632
    Figure US20070299073A1-20071227-C03633
    14.4 460.1
    50
    Figure US20070299073A1-20071227-C03634
    Figure US20070299073A1-20071227-C03635
    14.8 456.2
    51
    Figure US20070299073A1-20071227-C03636
    Figure US20070299073A1-20071227-C03637
    14.4 422.1
    52
    Figure US20070299073A1-20071227-C03638
    Figure US20070299073A1-20071227-C03639
    14.8 484.1
    53
    Figure US20070299073A1-20071227-C03640
    Figure US20070299073A1-20071227-C03641
    14.7 450.1
    54
    Figure US20070299073A1-20071227-C03642
    Figure US20070299073A1-20071227-C03643
    14.7 554.1
    55
    Figure US20070299073A1-20071227-C03644
    Figure US20070299073A1-20071227-C03645
    15.0 506.2
    56
    Figure US20070299073A1-20071227-C03646
    Figure US20070299073A1-20071227-C03647
    11.6 434.3
    57
    Figure US20070299073A1-20071227-C03648
    Figure US20070299073A1-20071227-C03649
     8.1 509.1
    58
    Figure US20070299073A1-20071227-C03650
    Figure US20070299073A1-20071227-C03651
    14.4 394.2
    59
    Figure US20070299073A1-20071227-C03652
    Figure US20070299073A1-20071227-C03653
    11.4 398.2
    60
    Figure US20070299073A1-20071227-C03654
    Figure US20070299073A1-20071227-C03655
    14.2 442.2
    61
    Figure US20070299073A1-20071227-C03656
    Figure US20070299073A1-20071227-C03657
    14.6 446.2
    62
    Figure US20070299073A1-20071227-C03658
    Figure US20070299073A1-20071227-C03659
    14.6 469.2
    63
    Figure US20070299073A1-20071227-C03660
    Figure US20070299073A1-20071227-C03661
    11.0 446.2
    64
    Figure US20070299073A1-20071227-C03662
    Figure US20070299073A1-20071227-C03663
    14.8 466.2
    65
    Figure US20070299073A1-20071227-C03664
    Figure US20070299073A1-20071227-C03665
    11.8 439.3
    66
    Figure US20070299073A1-20071227-C03666
    Figure US20070299073A1-20071227-C03667
    14.4 460.2
    67
    Figure US20070299073A1-20071227-C03668
    Figure US20070299073A1-20071227-C03669
    14.8 456.2
    68
    Figure US20070299073A1-20071227-C03670
    Figure US20070299073A1-20071227-C03671
    14.3 422.1
    69
    Figure US20070299073A1-20071227-C03672
    Figure US20070299073A1-20071227-C03673
    14.7 484.2
    70
    Figure US20070299073A1-20071227-C03674
    Figure US20070299073A1-20071227-C03675
    14.6 450.2
    71
    Figure US20070299073A1-20071227-C03676
    Figure US20070299073A1-20071227-C03677
    14.7 554.1
    72
    Figure US20070299073A1-20071227-C03678
    Figure US20070299073A1-20071227-C03679
    14.9 506.2
    73
    Figure US20070299073A1-20071227-C03680
    Figure US20070299073A1-20071227-C03681
    11.7 434.3
    74
    Figure US20070299073A1-20071227-C03682
    Figure US20070299073A1-20071227-C03683
     8.4 509.2
  • FORMULA 58
    Figure US20070299073A1-20071227-C03684
    Analysis
    R1 R2 Tr (min) [M + H]+
    1
    Figure US20070299073A1-20071227-C03685
    Figure US20070299073A1-20071227-C03686
    12.9 422.2
    2
    Figure US20070299073A1-20071227-C03687
    Figure US20070299073A1-20071227-C03688
    13.3 456.2
    3
    Figure US20070299073A1-20071227-C03689
    Figure US20070299073A1-20071227-C03690
    12.9 436.2
    4
    Figure US20070299073A1-20071227-C03691
    Figure US20070299073A1-20071227-C03692
    13.6 472.3
    5
    Figure US20070299073A1-20071227-C03693
    Figure US20070299073A1-20071227-C03694
    14.5 514.2
    6
    Figure US20070299073A1-20071227-C03695
    Figure US20070299073A1-20071227-C03696
    14.6 506.3
    7
    Figure US20070299073A1-20071227-C03697
    Figure US20070299073A1-20071227-C03698
    14.2 490.2
    8
    Figure US20070299073A1-20071227-C03699
    Figure US20070299073A1-20071227-C03700
    13.6 494.2
    9
    Figure US20070299073A1-20071227-C03701
    Figure US20070299073A1-20071227-C03702
    13.3 458.2
    10
    Figure US20070299073A1-20071227-C03703
    Figure US20070299073A1-20071227-C03704
    13.2 467.2
    11
    Figure US20070299073A1-20071227-C03705
    Figure US20070299073A1-20071227-C03706
    13.2 438.2
    12
    Figure US20070299073A1-20071227-C03707
    Figure US20070299073A1-20071227-C03708
    13.8 466.2
    13
    Figure US20070299073A1-20071227-C03709
    Figure US20070299073A1-20071227-C03710
    13.9 452.2
    14
    Figure US20070299073A1-20071227-C03711
    Figure US20070299073A1-20071227-C03712
    13.8 488.2
    15
    Figure US20070299073A1-20071227-C03713
    Figure US20070299073A1-20071227-C03714
    14.8 544.2
    16
    Figure US20070299073A1-20071227-C03715
    Figure US20070299073A1-20071227-C03716
    14.3 480.2
    17
    Figure US20070299073A1-20071227-C03717
    Figure US20070299073A1-20071227-C03718
    14.2 472.2
    18
    Figure US20070299073A1-20071227-C03719
    Figure US20070299073A1-20071227-C03720
    14.7 446.3
    19
    Figure US20070299073A1-20071227-C03721
    Figure US20070299073A1-20071227-C03722
    10.4 475.2
    20
    Figure US20070299073A1-20071227-C03723
    Figure US20070299073A1-20071227-C03724
    13.8 496.2
    21
    Figure US20070299073A1-20071227-C03725
    Figure US20070299073A1-20071227-C03726
    13.1 422.2
    22
    Figure US20070299073A1-20071227-C03727
    Figure US20070299073A1-20071227-C03728
    13.4 456.2
    23
    Figure US20070299073A1-20071227-C03729
    Figure US20070299073A1-20071227-C03730
    13.1 436.2
    24
    Figure US20070299073A1-20071227-C03731
    Figure US20070299073A1-20071227-C03732
    13.7 472.3
    25
    Figure US20070299073A1-20071227-C03733
    Figure US20070299073A1-20071227-C03734
    14.7 514.2
    26
    Figure US20070299073A1-20071227-C03735
    Figure US20070299073A1-20071227-C03736
    14.7 506.3
    27
    Figure US20070299073A1-20071227-C03737
    Figure US20070299073A1-20071227-C03738
    14.3 490.2
    28
    Figure US20070299073A1-20071227-C03739
    Figure US20070299073A1-20071227-C03740
    13.7 494.2
    29
    Figure US20070299073A1-20071227-C03741
    Figure US20070299073A1-20071227-C03742
    13.4 458.2
    30
    Figure US20070299073A1-20071227-C03743
    Figure US20070299073A1-20071227-C03744
    13.6 467.2
    31
    Figure US20070299073A1-20071227-C03745
    Figure US20070299073A1-20071227-C03746
    13.3 438.2
    32
    Figure US20070299073A1-20071227-C03747
    Figure US20070299073A1-20071227-C03748
    13.9 466.2
    33
    Figure US20070299073A1-20071227-C03749
    Figure US20070299073A1-20071227-C03750
    13.9 452.2
    34
    Figure US20070299073A1-20071227-C03751
    Figure US20070299073A1-20071227-C03752
    14.0 488.2
    35
    Figure US20070299073A1-20071227-C03753
    Figure US20070299073A1-20071227-C03754
    15.1 544.2
    36
    Figure US20070299073A1-20071227-C03755
    Figure US20070299073A1-20071227-C03756
    14.5 480.2
    37
    Figure US20070299073A1-20071227-C03757
    Figure US20070299073A1-20071227-C03758
    14.2 472.2
    38
    Figure US20070299073A1-20071227-C03759
    Figure US20070299073A1-20071227-C03760
    13.8 496.2
    39
    Figure US20070299073A1-20071227-C03761
    Figure US20070299073A1-20071227-C03762
    13.1 402.2
    40
    Figure US20070299073A1-20071227-C03763
    Figure US20070299073A1-20071227-C03764
    13.6 436.2
    41
    Figure US20070299073A1-20071227-C03765
    Figure US20070299073A1-20071227-C03766
    13.6 452.2
    42
    Figure US20070299073A1-20071227-C03767
    Figure US20070299073A1-20071227-C03768
    14.8 494.2
    43
    Figure US20070299073A1-20071227-C03769
    Figure US20070299073A1-20071227-C03770
    14.9 486.3
    44
    Figure US20070299073A1-20071227-C03771
    Figure US20070299073A1-20071227-C03772
    14.3 470.2
    45
    Figure US20070299073A1-20071227-C03773
    Figure US20070299073A1-20071227-C03774
    13.7 474.3
    46
    Figure US20070299073A1-20071227-C03775
    Figure US20070299073A1-20071227-C03776
    13.4 436.2
    47
    Figure US20070299073A1-20071227-C03777
    Figure US20070299073A1-20071227-C03778
    13.2 418.2
    48
    Figure US20070299073A1-20071227-C03779
    Figure US20070299073A1-20071227-C03780
    13.6 446.2
    49
    Figure US20070299073A1-20071227-C03781
    Figure US20070299073A1-20071227-C03782
    10.0 432.1
    50
    Figure US20070299073A1-20071227-C03783
    Figure US20070299073A1-20071227-C03784
    10.1 468.1
    51
    Figure US20070299073A1-20071227-C03785
    Figure US20070299073A1-20071227-C03786
    14.2 460.2
    52
    Figure US20070299073A1-20071227-C03787
    Figure US20070299073A1-20071227-C03788
    14.0 452.2
    53
    Figure US20070299073A1-20071227-C03789
    Figure US20070299073A1-20071227-C03790
    14.8 426.3
    54
    Figure US20070299073A1-20071227-C03791
    Figure US20070299073A1-20071227-C03792
    10.4 455.3
    55
    Figure US20070299073A1-20071227-C03793
    Figure US20070299073A1-20071227-C03794
    13.9 476.2
    56
    Figure US20070299073A1-20071227-C03795
    Figure US20070299073A1-20071227-C03796
    13.5 436.2
    57
    Figure US20070299073A1-20071227-C03797
    Figure US20070299073A1-20071227-C03798
    14.9 486.3
    58
    Figure US20070299073A1-20071227-C03799
    Figure US20070299073A1-20071227-C03800
    14.4 470.2
    59
    Figure US20070299073A1-20071227-C03801
    Figure US20070299073A1-20071227-C03802
    13.8 474.3
    60
    Figure US20070299073A1-20071227-C03803
    Figure US20070299073A1-20071227-C03804
    13.4 438.2
    61
    Figure US20070299073A1-20071227-C03805
    Figure US20070299073A1-20071227-C03806
    13.3 447.2
    62
    Figure US20070299073A1-20071227-C03807
    Figure US20070299073A1-20071227-C03808
    13.1 418.2
    63
    Figure US20070299073A1-20071227-C03809
    Figure US20070299073A1-20071227-C03810
    13.5 446.2
    64
    Figure US20070299073A1-20071227-C03811
    Figure US20070299073A1-20071227-C03812
    13.5 432.2
    65
    Figure US20070299073A1-20071227-C03813
    Figure US20070299073A1-20071227-C03814
    13.7 466.2
    66
    Figure US20070299073A1-20071227-C03815
    Figure US20070299073A1-20071227-C03816
    14.7 524.2
    67
    Figure US20070299073A1-20071227-C03817
    Figure US20070299073A1-20071227-C03818
    14.3 460.2
    68
    Figure US20070299073A1-20071227-C03819
    Figure US20070299073A1-20071227-C03820
    14.2 452.2
    69
    Figure US20070299073A1-20071227-C03821
    Figure US20070299073A1-20071227-C03822
    13.8 476.2

Claims (43)

1. A compound of the formula (I),
Figure US20070299073A1-20071227-C03823
the racemic-diastereomeric mixtures and optical isomers of said compound of formula (I) and pharmaceutically-acceptable salts thereof,
wherein
Figure US20070299073A1-20071227-P00900
represents an optional bond;
R1 is H, —(CH2)m—C(O)—(CH2)m-Z1, —(CH2)m-Z1, —(CH2)m—O-Z1 or —[(C1-C6)alkyl]p-C(O)—NH—(CH2)m-Z3;
Z1 is an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazolyl, indolyl,
Figure US20070299073A1-20071227-C03824
R2 is H or (C1-C6)alkyl;
or R1 and R2 are taken together with the nitrogen atoms to which they are attached to form a compound of formula (Ia), (Ib) or (Ic),
Figure US20070299073A1-20071227-C03825
R3 is —(CH2)m-E-(CH2)m-Z2;
E is O, S, —C(O)—, —C(O)—O—, —NH—C(O)—O— or a bond;
Z2 is H, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, (C1-C12)alkylguanidino, or an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl and naphthyl;
R4 is H or —(CH2)m-A1;
A1 is —C(═Y)—N(X1X2), —C(═Y)—X2, —C(═NH)—X2 or X2;
Y is O or S;
X1 is H, (C1-C12)alkyl, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m—N-di-(C1-C6)alkyl or —(CH2)m-aryl;
X2 is —(CH2)m—Y1—X3 or optionally substituted (C1-C12)alkyl;
Y1 is O, S, NH, C═O, (C2-C12)alkenyl having one or more double bonds, —NH—CO—, —CO—NH—, —NH—CO—O—(CH2)m—, —C≡C—, SO2 or a bond;
X3 is H, an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)alkoxy, aryloxy, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —CH-di-(C1-C12)alkoxy, pyrrolidinyl, pyridinyl, thiophene, imidazolyl, piperidinyl, piperazinyl, benzothiazolyl, furanyl, indolyl, morpholino, benzo[b]furanyl, quinolinyl, isoquinolinyl, —(CH2)m-phenyl, naphthyl, fluorenyl, phthalamidyl, pyrimidinyl,
Figure US20070299073A1-20071227-C03826
or X1 and X2 are taken together with the nitrogen to which they are attached to form an optionally substituted moiety selected from the group consisting of thiazolyl
Figure US20070299073A1-20071227-C03827
Y2 is CH—X4, N—X4, —C(X4X4), O or S;
X4 for each occurrence is independently —(CH2)m—Y3—X5;
 Y3 is —C(O)—, —C(O)O— or a bond;
 X5 is hydroxy, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, or an optionally substituted moiety selected from the group consisting of aryl, aryl(C1-C4)alkyl, furanyl, pyridinyl, indolyl, —CH(phenyl)2,
Figure US20070299073A1-20071227-C03828
R5 is (C1-C12)alkyl, [(C1-C6)alkyl]m-C(O)—O-Z5, [(C1-C6)alkyl]p-C(O)—NH—(CH2)p-Z3 or optionally substituted aryl;
Z3 for each occurrence is independently amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —NH—C(O)—O—(CH2)m-phenyl —NH—C(O)—O—(CH2)m—(C1-C6)alkyl or an optionally substituted moiety selected from the group consisting of imidazolyl, pyridinyl, morpholino, piperidinyl, piperazinyl, pyrazolidinyl, furanyl and thiophene;
R6 is H or (C1-C6)alkyl;
R7 is (C1-C12)alkyl or —(CH2)m-Z4;
Z4 is an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, indolyl, thiophene, benzo[b]furan, benzo[b]thiophene, isoxazolyl,
Figure US20070299073A1-20071227-C03829
Z5 is H, (C1-C12)alkyl, (CH2)m-aryl;
wherein an optionally substituted moiety is optionally substituted by one or more substituents, each independently selected from the group consisting of Cl, F, Br, I, CF3, CN, N3, NO2, OH, SO2NH2, —OCF3, (C1-C12)alkoxy, —(CH2)m-phenyl-(X6)n, —S-phenyl-(X6)n, —S—(C1-C12)alkyl, —O—(CH2)m-phenyl-(X6)n, —(CH2)m—C(O)—O—(C1-C6)alkyl, —(CH2)m—C(O)—(C1-C6)alkyl, —O—(CH2)m—NH2, —O—(CH2)m—NH—(C1-C6)alkyl, —O—(CH2)m—N-di-((C1-C6)alkyl) and —[(C1-C12)alkyl]p-(X6)n;
X6 for each occurrence is independently selected from the group consisting of hydrogen, Cl, F, Br, I, NO2, N3, CN, OH, —CF3, —OCF3, (C1-C12)alkyl, (C1-C12)alkoxy,
—(CH2)m—NH2, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m—N-di-((C1-C6)alkyl) and —(CH2)m-phenyl;
m for each occurrence is independently 0 or an integer from 1 to 6;
n for each occurrence is independently an integer from 1 to 5; and
p for each occurrence is independently 0 or 1;
provided that:
(a) when R5 is (C1-C12)alkyl, or —C(O)—O-Z5 and Z5 is (C1-C12)alkyl or optionally substituted aryl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl or Z4 and Z4 is thiophene or optionally substituted phenyl, then R3 is not —C(O)—O—(CH2)m-Z where m is 0 and Z is H or (C1-C12)alkyl or where m is 1 to 6 and Z is H;
(b) when R5 is (C1-C12)alkyl or optionally substituted phenyl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl and R3 is —O—(CH2)-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl, and naphthyl;
(c) when R5 is H or (C1-C12)alkyl; R6 is (C1-C6)alkyl; R7 is (C1-C12)alkyl; and R3 is —O-Z2 or —S-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, thiophene, benzothienyl and indolyl; and
(d) at least one m in the definition of R3 must be an integer from 1 to 6.
2. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —CH2-phenyl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
where A1 is —C(═Y)—N(X1X2);
Y is O; X1 is H or methyl;
X2 is —(CH2)m—Y1—X3;
m in the definition of X2 is 0, 1, 2 or 3; Y1 is a bond or O; and X3 is N-methylpyrrolidin-2-yl, diethylamino, pyridinyl, thiophene, imidazolyl, diethoxymethyl, 1-benzyl-piperidin-4-yl, optionally substituted phenyl or
Figure US20070299073A1-20071227-C03830
3. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —CH2-phenyl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
where A1 is —C(═Y)—N(X1X2);
Y is O;
X1 is benzyl and X2 is 2-hydroxyethyl;
or X1 and X2 are taken together with the nitrogen atom to which they are attached to form
Figure US20070299073A1-20071227-C03831
where Y2 is C—X4 or N—X4;
X4 is —(CH2)m—Y3—X5 where m in the definition of X4 is 0 or 1; and
X5 is selected from the group consisting of furanyl, benzyl, phenyl, amino,
Figure US20070299073A1-20071227-C03832
4. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —CH2-phenyl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
where A1 is —C(═Y)—X2;
Y is O; X2 is —(CH2)m—Y1—X3;
where m in the definition of X2 is 0, 1 or 2;
Y1 is O, —NH—CO—, —CO—NH—, —NH—CO—O—CH2—, SO2 or a bond; and
X3 is methyl, furanyl, pentyl, phenyl, indolyl, p-NO2-phenyl, naphthyl, fluorenyl, —CH(phenyl)2, benzothiazolyl, phthalamidyl, N,N-dimethylamino,
Figure US20070299073A1-20071227-C03833
5. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;
A1 is —C(═Y)—N(X1X2);
Y is O or S; X1 is H; X2 is —(CH2)m—Y1—X3;
m in the definition of X2 is 0, 1 or 2;
Y1 is a bond; and X3 is phenyl, o-Cl-phenyl, m-Cl-phenyl, p-phenyloxy-phenyl, 2,6-di-isopropylphenyl, m-CF3-phenyl, p-ethoxycarbonyl-phenyl, 2,4-difluorophenyl, m-NO2-phenyl, p-benzyloxyphenyl, o-isopropylphenyl, n-hexyl, 4-morpholino, naphthyl or
Figure US20070299073A1-20071227-C03834
6. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;
where A1 is —C(═Y)—X2;
Y is O; X2 is —(CH2)m—Y1—X3;
where m in the definition of X2 is 0, 1 or 2;
Y1 is O, —CO—NH—, —NH—CO—O—CH2-or a bond; and X3 is methyl, 3-pentyl, phenyl, p-NO2-phenyl, phthalamidyl, N,N-dimethylamino, p-aminophenyl, fluorenyl or
Figure US20070299073A1-20071227-C03835
7. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;
where A1 is —C(═Y)—N(X1X2);
Y is O; X1 is hydrogen; X2 is —(CH2)m—Y1—X3;
where m in the definition of X2 is 0, 1, 2 or 3;
Y1 is O, or a bond; and X3 is cyclopentyl, 4-OH-butyl, N,N-diethylamino, N-methyl-pyrrolidin-3-yl, —CH(ethoxy)2, phenyl, p-SO2NH2-phenyl p-OH-phenyl, o-CF3-phenyl, p-Cl-phenyl, —CH(phenyl)2,
Figure US20070299073A1-20071227-C03836
8. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —CH2-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl or t-Bu; R6 is H;
where A1 is —C(═Y)—X2;
Y is O; X2 is —(CH2)m—Y1—X3;
where m in the definition of X2 is 0, 1, 2 or 3;
Y1 is —NH—CO, —C═C—, —C≡C— or a bond; and X3 is t-butyl, 1-methylcarbonyl-piperidin-4-yl, phenyl, p-Cl-phenyl, m-CF3-phenyl, 4-nitro-naphthyl, p-methoxy-phenyl, m-(phenylethyl)-phenyl, indol-3-yl or p-aminophenyl.
9. (canceled)
10. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —CH2-indol-3-yl, —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl, o-methoxyphenyl, p-methoxyphenyl, p-Br-phenyl, p-nitro-phenyl or p-N,N-diethylamino-phenyl; R6 is H;
where A1 is —C(═Y)—X2;
Y is O; X2 is —(CH2)m—Y1X3;
where m in the definition of X2 is 1;
Y1 is a bond; and X3 is phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, o-Cl-phenyl, m-Cl-phenyl, p-Cl-phenyl, o-nitro-phenyl, m-nitro-phenyl, p-nitro-phenyl, o-CF3-phenyl, m-CF3-phenyl, p-CF3-phenyl, o-F-phenyl, m-F-phenyl, p-F-phenyl, N,N-di-methylamino-phenyl, o-OMe-phenyl, m-OMe-phenyl, p-OMe-phenyl, 3,4-di-Cl-phenyl, 3,4,5-tri-OMe-phenyl, p-Me-phenyl, p-OH-phenyl or 2,4-di-F-phenyl.
11. (canceled)
12. A compound according to claim 10 wherein R5 is phenyl and R3 is —(CH2)-indol-3-yl and the stereochemistry at the carbon to which R3 is attached is the R-configuration.
13. A compound according to claim 10 wherein R5 is o-OMe-phenyl and R3 is —(CH2)-indol-3-yl and the stereochemistry at the carbon to which R3 is attached is the R-configuration.
14. A compound according to claim 10 wherein R5 is o-OMe-phenyl and R3 is —(CH2)-indol-3-yl and the stereochemistry at the carbon to which R3 is attached is the S-configuration.
15. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
where A1 is —C(═Y)—X2;
Y is O; X2 is —(CH2)m—Y1—X3;
where m in the definition of X2 is 0,1 or 2;
Y1 is S, SO2 or a bond; and X3 is phenyl, 3,4-di-Cl-phenyl, 3,4,5-tri-OMe-phenyl, p-Me-phenyl, p-OH-phenyl, 2,4-di-F-phenyl, 2-furanyl, 2-pyridinyl, 3-pyridinyl, naphthyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 8-quinolinyl, 1-isoquinolinyl, 2-thiophene or 2-pyrimidinyl.
16. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
where A1 is —C(═Y)—X2;
Y is O; X2 is —(CH2)m—Y1—X3;
where m in the definition of X2 is 0, 1, 2 or 3;
Y1 is a bond; and X3 is 5-indolyl, 3-indolyl, 4-indolyl, 2-indolyl, 5-OMe-indol-3-yl, 5-OMe-indol-2-yl, 5-OH-indol-2-yl, 5-OH-indol-3-yl, 5-Br-indol-3-yl, 2-Me-indol-3-yl, 2-benzothiophene, 3-benzothiophene or 2-benzofuran.
17. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —(CH2)m-indol-3-yl, —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl, o-OMe-phenyl or p-OMe-phenyl; R6 is H;
where A1 is X2;
X2 is —(CH2)m—Y1—X3;
where m in the definition of X2 is 1, 2 or 3;
Y1 is S, O or a bond; and X3 is phenyl, o-OH-phenyl, p-OH-phenyl, o-F-phenyl, m-F-phenyl, p-F-phenyl, o-CF3-phenyl, o-OMe-phenyl, m-OMe-phenyl, o-nitro-phenyl, p-nitro-phenyl, 3,4-di-Cl-phenyl, 2-nitro-3-OMe-phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, 2-thiophene, 3,4,5-tri-OMe-phenyl, p-N,N-dimethylamino-phenyl, p-OCF3-phenyl, p-(3-(N,N-dimethylamino)propoxy)phenyl, 3-F-4-OMe-phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-Cl-quinolin-3-yl, 2-quinolinly, methyl, n-butyl, n-pentyl, n-hexyl, 3,3-dimethyl-butyl, benzyl, cyclohexyl or p-t-Bu-phenyl.
18. A compound according to claim 1 wherein R1 is H; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu or —(CH2)4—NH2; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
where A1 is X2;
X2 is —(CH2)m—Y1—X3;
where m in the definition of X2 is 1, 2 or 3;
Y1 is O or a bond; and X3 is phenyl, o-OH-phenyl, p-OH-phenyl, o-F-phenyl, m-F-phenyl, p-F-phenyl, o-CF3-phenyl, o-OMe-phenyl, m-OMe-phenyl, p-OMe-phenyl, o-nitro-phenyl, p-nitro-phenyl, 3,4-di-Cl-phenyl, 2-nitro-3-OMe-phenyl, o-Br-phenyl, m-Br-phenyl, p-Br-phenyl, p-phenyl-phenyl, 2-thiophene, 3,4,5-tri-OMe-phenyl, p-N,N-dimethylamino-phenyl, p-benzyloxy-phenyl, p-OCF3-phenyl, p-(3-(N,N-dimethylamino)propoxy)phenyl, 3-F-4-OMe-phenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-Cl-quinolin-3-yl, 2-quinolinly, 3-indolyl, 6-methoxycarbonyl-indol-3-yl, 1-methyl-indol-3-yl, 2-methyl-indol-3-yl, methyl, n-butyl, n-pentyl, n-hexyl, 3,3-dimethyl-butyl, benzyl, cyclohexyl or p-t-Bu-phenyl.
19. A compound according to claim 1 wherein R1 is —(CH2)—CO-Z1; R2 is H; R3 is —(CH2)4—NH—CO—O-t-Bu, —(CH2)4—NH—CO—O-benzyl, —(CH2)-phenyl or —(CH2)-indol-3-yl; R4 is —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl; R6 is H;
where Z1 is ethyl, phenyl, p-OMe-phenyl, p-phenyl-phenyl, p-Cl-phenyl, p-Br-phenyl, p-N3-phenyl, p-F-phenyl, m-nitro-phenyl, p-nitro-phenyl, p-CN-phenyl, 2,5-di-OMe-phenyl, 3,4-di-Cl-phenyl, N,N-dimethylamino-phenyl, 3-methyl-4-Cl-phenyl or naphthyl;
A1 is —C(═Y)—X2;
Y is O; X2 is —(CH2)m—Y1—X3;
where m in the definition of X2 is 0;
Y1 is O; and X3 is t-Bu.
20. A compound according to claim 1 wherein R1 is —(CH2)—CO—(CH2)m-Z1 where m in the definition of R1 is 0, 1 or 2; R2 is H; R3 is —(CH2)-indol-3-yl or —(CH2)4—NH—CO—O-t-Bu; R4 is H or —(CH2)m-A1 where m in the definition of R4 is 0; R5 is phenyl, o-OMe-phenyl, p-nitro-phenyl, p-Br-phenyl, t-Bu, —CH(CH3)2—CO—NH—(CH2)2—CO—O-t-Bu, —CH(CH3)2—CO—NH—(CH2)3-imidazol-1-yl, —CH(CH3)2—CO—NH—(CH2)2-pyridin-2-yl, —CH(CH3)2—CO—NH—(CH2)3-4-morpholino, —CH(CH3)2-CO—NH—(CH2)-pyridin-4-yl or —CH(CH3)2—CO—NH—(CH2)2—N,N-diethylamino; R6 is H;
where Z1 is ethyl, propyl, phenyl, p-OMe-phenyl, p-Cl-phenyl, p-Br-phenyl, p-F-phenyl, p-nitro-phenyl, m-nitro-phenyl, p-CN-phenyl, p-N3-phenyl, p-phenyl-phenyl, 3-Me-4-Cl-phenyl, p-N,N-diethylamino-phenyl, 2,5-di-OMe-phenyl, 3,4-di-Cl-phenyl, 3,4-di-F-phenyl, p-OCF3-phenyl, p-benzyloxy-phenyl, p-pentyl-phenyl, 3,4,5-tri-OMe-phenyl, 3-nitro-4-Cl-phenyl, 3-Cl-4-nitro-phenyl, 3-methyl-5-chloro-benzothiophen-2-yl, 2-benzofuranyl, 3-benzothiophene, 3-phenyl-isoxazol-5-yl, 3-(2,4-di-Cl-phenyl)-isoxazol-5-yl, 3-indolyl, 5-Br-thiophen-2-yl, naphthyl,
Figure US20070299073A1-20071227-C03837
A1 is —C(═Y)—X2;
Y is O; X2 is —(CH2)m—Y1—X3;
where m in the definition of X2 is 0;
Y1 is O; and X3 is t-Bu.
21. A compound according to claim 1 wherein R1 and R2 are taken together to form a compound of formula (Ib) or (Ic);
R3 is —(CH2)-indol-3-yl, —(CH2)-phenyl, —(CH2)4—NH—CO—O-benzyl or —(CH2)4—NH2;
R5 is phenyl, o-OMe-phenyl, p-OMe-phenyl, p-Br-phenyl, p-nitro-phenyl, t-Bu or —CH(CH3)2—CO—NH—(CH2)2—NH2; R6 is H;
R7 is ethyl, propyl, phenyl, p-OMe-phenyl, p-Cl-phenyl, p-Br-phenyl, p-F-phenyl, p-nitro-phenyl, m-nitro-phenyl, p-CN-phenyl, p-N3-phenyl, p-phenyl-phenyl, 3-Me-4-Cl-phenyl, p-N,N-diethylamino-phenyl, 2,5-di-OMe-phenyl, 3,4-di-Cl-phenyl, 3,4-di-F-phenyl, p-OCF3-phenyl, p-benzyloxy-phenyl, p-pentyl-phenyl, 3,4,5-tri-OMe-phenyl, 3-nitro-4-Cl-phenyl, 3-Cl-4-nitro-phenyl, 3-methyl-5-chloro-benzothiophen-2-yl, 2-bezofuranyl, 3-benzothiophene, 3-phenyl-isoxazol-5-yl, 3-(2,4-di-Cl-phenyl)-isoxazol-5-yl, 3-indolyl, 5-Br-thiophen-2-yl, naphthyl,
Figure US20070299073A1-20071227-C03838
22. A compound of the formula (II),
Figure US20070299073A1-20071227-C03839
the racemic-diastereomeric mixtures and optical isomers of said compound of formula (II), the pharmaceutically-acceptable salts or prodrugs thereof or a pharmaceutically acceptable salt of said prodrug,
wherein
Figure US20070299073A1-20071227-P00900
represents an optional bond;
R1 is H, —(CH2)m—C(O)—(CH2)m-Z1, —(CH2)m-Z1, —(CH2)m—O-Z1 or —(C0-C6)alkyl-C(O)—NH—(CH2)m-Z3;
Z1 is an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, benzo[b]thiophene, phenyl, naphthyl, benzo[b]furanyl, thiophene, isoxazolyl, indolyl,
Figure US20070299073A1-20071227-C03840
R2 is H or (C1-C6)alkyl;
or R1 and R2 are taken together with the nitrogen atoms to which they are attached to form a compound of formula (IIa), (IIb) or (IIc),
Figure US20070299073A1-20071227-C03841
R3 is —(CH2)m-E-(CH2)m-Z2;
E is O, S, —C(O)—, —C(O)—O—, —NH—C(O)—O—, —N(C1-C6)alkyl-C(O)—O— or a bond;
Z2 is H, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, (C1-C12)alkylguanidino, or an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl and naphthyl;
R4 is H or —(CH2)m-A1;
A1 is —C(═Y)—N(X1X2), —C(═Y)—X2, —C(═NH)—X2 or X2;
Y is O or S;
X1 is H, (C1-C12)alkyl, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m—N-di-(C1-C6)alkyl or —(CH2)m-aryl;
X2 is —(CH2)m—Y1—X3 or optionally substituted (C1-C12)alkyl;
Y1 is O, S, NH, C═O, (C2-C12)alkenyl having one or more double bonds, —NH—CO—, —CO—NH—, —NH—CO—O—(CH2)m—, —C≡C—, SO2 or a bond;
X3 is H, an optionally substituted moiety selected from the group consisting of (C1-C12)alkyl, (C3-C8)cycloalkyl, (C1-C12)alkoxy, aryloxy, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —CH-di-(C1-C12)alkoxy, pyrrolidinyl, pyridinyl, thiophene, imidazolyl, piperidinyl, piperazinyl, benzothiazolyl, furanyl, indolyl, morpholino, benzo[b]furanyl, quinolinyl, isoquinolinyl, —(CH2)m-phenyl, naphthyl, fluorenyl, phthalamidyl, pyrimidinyl,
Figure US20070299073A1-20071227-C03842
or X1 and X2 are taken together with the nitrogen to which they are attached to form an optionally substituted moiety selected from the group consisting of thiazolyl,
Figure US20070299073A1-20071227-C03843
Y2 is CH—X4, N—X4, —C(X4X4), O or S;
X4 for each occurrence is independently H or —(CH2)m—Y3—X5;
 Y3 is —C(O)—, —C(O)O— or a bond;
 X5 is hydroxy, (C1-C12)alkyl, amino, (C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, or an optionally substituted moiety selected from the group consisting of aryl, aryl(C1-C4)alkyl, furanyl, pyridinyl, indolyl, piperidinyl, —CH(phenyl)2,
Figure US20070299073A1-20071227-C03844
R5 is (C1-C12)alkyl, (C0-C6)alkyl-C(O)—O-Z5, (Co-C6)alkyl-C(O)—NH—(CH2)m-Z3 or optionally substituted aryl;
Z3 for each occurrence is independently amino, (C1-C12)alkylamino, amino(C1-C12)alkyl, (C5-C7)cycloalkylamino, amino(C5-C7)cycloalkyl, N-(C1-C12)alkylamino, N,N-di-(C1-C12)alkylamino, —NH—C(O)—O—(CH2)m-phenyl, —NH—C(O)—O—(CH2)m-(C1-C6)alkyl,
Figure US20070299073A1-20071227-C03845
or an optionally substituted moiety selected from the group consisting of imidazolyl, pyridinyl, morpholino, piperidinyl, piperazinyl, pyrazolidinyl, furanyl, phenyl, indolyl and thiophene, provided that when m is 0 in the formula for R5 then Z3 is not —NH—C(O)—O—(CH2)m-phenyl or —NH—C(O)—O—(CH2)m—(C1-C6)alkyl;
R6 is H or (C1-C6)alkyl;
R7 is (C1-C12)alkyl or —(CH2)m-Z4;
Z4 is an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, indolyl, thiophene, benzo[b]furan, benzo[b]thiophene, isoxazolyl,
Figure US20070299073A1-20071227-C03846
Z5 is H, (C1-C12)alkyl, or —(CH2)m-aryl;
wherein an optionally substituted moiety is optionally substituted by one or more substituents, each independently selected from the group consisting of Cl, F, Br, I, CF3, CN, N3, NO2, OH, SO2NH2, —OCF3, (C1-C12)alkoxy, —(CH2)m-phenyl-(X6)n, —S-phenyl-(X6)n, —S—(C1-C12)alkyl, —O—(CH2)m-phenyl-(X6)n, —(CH2)m—C(O)—O—(C1-C6)alkyl, —(CH2)m—C(O)—(C1-C6)alkyl, —O—(CH2)m—NH2, —O—(CH2)m—NH—(C1-C6)alkyl, —O—(CH2)m—N-di-((C1-C6)alkyl), —(C0-C12)alkyl-(X6)n and —(CH2)m-phenyl-X7;
X6 for each occurrence is independently selected from the group consisting of hydrogen, Cl, F, Br, I, NO2, N3, CN, OH, —CF3, —OCF3, (C1-C12)alkyl, (C1-C12)alkoxy, —(CH2)m—NH2, —(CH2)m—NH—(C1-C6)alkyl, —(CH2)m—N-di-((C1-C6)alkyl) and —(CH2)m-phenyl;
X7 is —NH—C(═NH.HI)—X8, wherein X8 is thiophene, (C1-C6)alkyl or phenyl;
m for each occurrence is independently 0 or an integer from 1 to 6; and
n for each occurrence is independently an integer from 1 to 5;
provided that:
(a) when R5 is (C1-C12)alkyl, or —C(O)—O-Z5 and Z5 is (C1-C12)alkyl or optionally substituted aryl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl or Z4 and Z4 is thiophene or optionally substituted phenyl, then R3 is not —C(O)—O—(CH2)m-Z where m is 0 and Z is H or (C1-C12)alkyl or where m is 1 to 6 and Z is H;
(b) when R5 is (C1-C12)alkyl or optionally substituted phenyl; R6 is H or (C1-C6)alkyl; R7 is (C1-C12)alkyl and R3 is —O—(CH2)-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, indolyl, imidazolyl, thiophene, benzothiophene, pyridinyl, and naphthyl; and
(c) when R5 is H or (C1-C12)alkyl; R6 is (C1-C6)alkyl; R7 is (C1-C12)alkyl; and R3 is —O-Z2 or —S-Z2, then Z2 is not an optionally substituted moiety selected from the group consisting of phenyl, naphthyl, thiophene, benzothienyl and indolyl.
23. A compound according to claim 22 of the formula
Figure US20070299073A1-20071227-C03847
wherein
Z3 is —CH2—NH2, —(CH2)2—NH2, —(CH2)3—NH2 or
Figure US20070299073A1-20071227-C03848
X1 is —(CH2)2—N(CH3)2 and X2 is benzyl; or
X1 and X2 are taken together with the nitrogen atom to which they are attached, to form
Figure US20070299073A1-20071227-C03849
24. (canceled)
25. A compound according to claim 22 of the formula
Figure US20070299073A1-20071227-C03850
wherein X2 is p-chloro-phenyl, p-methoxy-phenyl, 2,4-difluoro-phenyl or thienyl.
26. A compound according to claim 22 of the formula
Figure US20070299073A1-20071227-C03851
wherein X2 is p-chloro-phenyl, p-methoxy-phenyl, phenyl or thienyl.
27. (canceled)
28. (canceled)
29. A compound according to claim 22 of the formula
Figure US20070299073A1-20071227-C03852
30. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
31. A method of eliciting an agonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject.
32. A method of eliciting an antagonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject.
33. A method of binding one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject.
34. A method of treating acromegaly, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux, Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, polycystic ovary disease, cancer, cancer cachexia, hypotension, postprandial hypotension, panic attacks, GH secreting adenomas or TSH secreting adenomas, in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject.
35. A method of treating diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon, Nephropathy, peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis, gastrointestinal hormone secreting tumors, angiogenesis, inflammatory disorders, chronic allograft rejection, angioplasty, graft vessel bleeding or gastrointestinal bleeding in a subject in need thereof, which comprises administering a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said subject.
36. A method of inhibiting the proliferation of helicobacter pylori in a subject in need thereof, which comprises administering a compound according claim 1 or a pharmaceutically acceptable salt thereof, to said subject.
37. A pharmaceutical composition comprising a compound according to claim 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
38. A method of eliciting an agonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim 22 or a pharmaceutically acceptable salt thereof to said subject.
39. A method of eliciting an antagonist effect from one or more of a somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim 22 or a pharmaceutically acceptable salt thereof to said subject.
40. A method of binding one or more somatostatin subtype receptor in a subject in need thereof, which comprises administering a compound according to claim 22 or a pharmaceutically acceptable salt thereof to said subject.
41. A method of treating acromegaly, restenosis, Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux, Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, Paget's disease, polycystic ovary disease, cancer, cancer cachexia, hypotension, postprandial hypotension, panic attacks, GH secreting adenomas or TSH secreting adenomas, in a subject in need thereof, which comprises administering a compound according to claim 22 or a pharmaceutically acceptable salt thereof to said subject.
42. A method of treating diabetes mellitus, hyperlipidemia, insulin insensitivity, Syndrome X, angiopathy, proliferative retinopathy, dawn phenomenon, Nephropathy, peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, Dumping syndrome, watery diarrhea syndrome, acute or chronic pancreatitis, gastrointestinal hormone secreting tumors, angiogenesis, inflammatory disorders, chronic allograft rejection, angioplasty, graft vessel bleeding or gastrointestinal bleeding in a subject in need thereof, which comprises administering a compound according to claim 22 or a pharmaceutically acceptable salt thereof to said subject.
43. A method of inhibiting the proliferation of helicobacter pylori in a subject in need thereof, which comprises administering a compound according claim 22 or a pharmaceutically acceptable salt thereof, to said subject.
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