Abstract: Disclosed are a low molecular polypeptide for preventing and treating inflammation, a preparation method and the use thereof and a pharmaceutical composition containing the polypeptide, wherein the polypeptide can penetrate the eye tissue barrier, can maintain a high concentration in neutral tears, aqueous humour and vitreous humour, and can be used to treat inflammation.

Abstract: A chemoselective chemical ligation method is disclosed. The method joins two peptide segments efficiently to produce a larger peptide or protein, by generating a natural peptide bond (Xaa-Ser and Xaa-Thr) at the ligation site (Xaa represents any 5 amino acid). The method requires two steps (FIG. 1 (a)): a) reacting the starting peptide(s) to form an acetal intermediate with an acetal group at the ligation site; b) converting said acetal intermediate to a desired peptide or protein with said natural peptide bond.

Abstract: The invention relates to a method for homogeneous solution phase peptide synthesis (HSPPS) of a N-terminal peptide fragment PEP-N and a C-terminal peptide fragment C-PEP, with C-PEP carrying a specific diketopiperazine (DKP) comprising C-terminal protecting group, which contains a handle group HG, with HG being connected to the C-terminus of the peptide fragment; thereby this specific DKP comprising C-terminal protecting group can be selectively cleaved from the peptide as a conventionally used C-terminal protecting group. By the use of this DKP and HG comprising C-terminal protecting group, certain process steps in convergent peptide synthesis based on a combination of HSPPS and solid phase peptide synthesis (SPPS) can be avoided.

Abstract: Method for preparing a peptide assembly of n fragments and n?1 amino acids bearing a thiol function, represented by the formula: A1-C1-A2-C2-A3- . . . -Ci?1-Ai- . . . -Cn?1-An ??(I) in which A1, A2, A3, . . . Ai . . . An are peptide fragments, C1, C2, C3 . . . Ci?1 . . . Cn?1 are amino acid residues bearing a thiol function, n is comprised between 3 and 50, and i is 2 to n, in which a peptide-thioester is prepared of formula: A1-SR (II) in which A1 is a peptide fragment and SR is an alkyl thioester residue, R being alkyl optionally substituted, starting from a bis(2-sulphanylethyl)amino peptide.

Abstract: The present invention relates to the preparation of insulinotropic peptides that are synthesized using a solid and solution phase (“hybrid”) approach. Generally, the approach includes synthesizing three different peptide intermediate fragments using solid phase chemistry. Solution phase chemistry is then used to add additional amino acid material to one of the fragments. The fragments are then coupled together in the solution phase. The use of a pseudoproline in one of the fragments eases solid phase synthesis of that fragment and also eases subsequent solution phase coupling of this fragment to other fragments. The present invention is very useful for forming insulinotropic peptides such as Exenatide(1-39) and its natural and non-natural counterparts.

Abstract: Disclosed are peptide structures that are stable in aqueous and non-aqueous media where a first linear peptide chain comprising alternating D,L- or L,D-amino acids having an N and C termini is joined by at least one turn region to a second linear peptide chain comprising alternating D,L- or L,D-amino acids having an N and C termini. The peptide chains can be joined at the C terminus of one of the linear peptide chains with an N terminus of the other linear peptide chain, a C terminus of one of the linear peptide chains with a C terminus of the other linear peptide chain, or an N terminus of one of the linear peptide chains with an N terminus of the other linear peptide chain.

Abstract: Disclosed is a method of making peptide structures that are stable in aqueous and non-aqueous media where a first linear peptide chain comprising alternating D,L- or L,D-amino acids having an N and C termini is joined by at least one turn region to a second linear peptide chain comprising alternating D,L- or L,D-amino acids having an N and C termini. The peptide chains can be joined at the C terminus of one of the linear peptide chains with an N terminus of the other linear peptide chain, a C terminus of one of the linear peptide chains with a C terminus of the other linear peptide chain, or an N terminus of one of the linear peptide chains with an N terminus of the other linear peptide chain.

Abstract: The invention relates to a method for linking two or more molecular substances, by means of adapter segments, which bring about a targeted interaction based upon the affinity of proline-rich amino acid sequences and protein domains of the type WW.

Abstract: The present invention relates to novel bio-active peptide hormone, process for the production of the same, and use of the same. The present invention identified novel bioactive peptide precursor and salts thereof which can be used as drugs, for example therapeutic polypeptides, ligands to discover relevant targets (e.g. GPCRs) or targets for drug intervention.

Abstract: The present invention concerns methods and compositions for synthesizing a polypeptide using kinetically controlled reactions involving fragments of the polypeptide for a fully convergent process. In more specific embodiments, a ligation involves reacting a first peptide having a protected cysteyl group at its N-terminal and a phenylthioester at its C-terminal with a second peptide having a cysteine residue at its N-termini and a thioester at its C-termini to form a ligation product. Subsequent reactions may involve deprotecting the cysteyl group of the resulting ligation product and/or converting the thioester into a thiophenylester.

Abstract: The present invention relates to synthetic peptides having selectively protected amines of untargeted sites and to methods for production thereof and for specifically conjugating PEG to targeted sites of the synthetic peptides using the same. The present invention provides a much higher yield of PEG conjugated peptides in which PEG is specifically combined to amines at targeted sites.

Abstract: A method of ligating two or more molecules, for example, peptides to peptides or peptides to labels is provided. The method may comprise the steps: a) providing a first oligopeptide having a reactive moiety, which is a hydrazine moiety, a hydrazide moiety or an amino-óxy moiety b) providing a second oligopeptide having an activated ester moiety, c)allowing the reactive moiety of the first oligopeptide to react with the activated ester moiety of the second oligopeptide to form an oligopeptide product, in which the first and second oligopeptides are linked via a linking moiety having Formula I, II or III. The second oligopeptide may preferably be generated by thiol reagent induced cleavage of an intein fusion protein. The invention further provides labelling and ligation methods in which protein hydrazides are ligated by reaction of the hydrazide moiety with an aldehyde functionality or a ketone functionality.

Abstract: A process for producing a polypeptide, by reacting a peptide component (A) represented by formula (1) below with a peptide component (B) represented by formula (2) below and optionally a compound (C) represented by formula (3) below, to obtain said polypeptide: (1) X-(Pro-Y-Gly)n-OH, wherein: X represents H or the group HOOC—(CH2)m—CO— and m denotes an integer of 1 to 18, Y represents Pro or Hyp, and n denotes an integer of 1 to 20; (2) X-(Z)r—OH, wherein X represents H or the group HOOC—(CH2)m—CO— and m denotes an integer of 1 to 18, Z represents a peptide chain comprising 1 to 10 amino acid residue(s), and r denotes an integer of 1 to 20; and (3) H2N—R—NH2, wherein R represents a linear or branched alkylene group; and further wherein the ratio of the peptide component (A) relative to the peptide component (B) is 100/0 to 30/70 (mol %); provided that in the case where X represents the group HOOC—(CH2)m—CO— and m has the same meaning as defined above in formula (1) and/or (2), the amount of compou

Abstract: Protein and polypeptide derivatives and their salts are claimed characterized in that a protein or polypeptide is conjugated via an intermediate grouping containing at least one radical of the formula —C(R)?N— (or —N?C(R)—) or —CH(R)—NH— (or —NH—CH(R)—), wherein R is hydrogen or a hydrocarbon residue which may be substituted, with the same or a different protein or polypeptide, with a reporter group or a cytotoxic agent as well as a process for their preparation and the novel intermediates therefor.

Abstract: A polymer is prepared by self-assembly of a plurality of monomeric polypeptide units. The polymer tends to form a nanotube and is capable of encapsulating a particular drug molecule. Once encapsulated in the polymer of the present invention, the drug molecule may be delivered to a particular location of human body to effectively cure a disease or treat a symptom. Generally, the monomeric polypeptide unit of the present invention has a sequence found in Pyrodictium abyssi, a microorganism that produces an extracellular network having hollow protein tubes, or a sequence substantially identical thereto. The monomeric polypeptide may be mass produced using recombinant biotechnologies and be polymerized into the polymer of the present invention. One or more additional targeting vector may be attached to the monomeric polypeptide unit or the polymer to facilitate the targeting of the drug molecule that may be held there within.

Abstract: Proteins of moderate size having native peptide backbones are produced by a method of native chemical ligation. Native chemical ligation employs a chemoselective reaction of two unprotected peptide segments to produce a transient thioester-linked intermediate. The transient thioester-linked intermediate then spontaneously undergoes a rearrangement to provide the full length ligation product having a native peptide bond at the ligation site. Full length ligation products are chemically identical to proteins produced by cell free synthesis. Full length ligation products may be refolded and/or oxidized, as allowed, to form native disulfide-containing protein molecules. The technique of native chemical ligation is employable for chemically synthesizing full length proteins.

Abstract: The invention provides for a polypeptide, which is useful as a biomaterial and free from infection. The polypeptide comprises a peptide unit of formula (1), and optionally one or more units of formulae (2) to (3): (1) [—(OC—(CH2)m—CO)p-(Pro-Y-Gly)n-]a; (2) [—(OC—(CH2)m—CO)q-(Z)r-]b; and (3) [—HN—R—NH—]c, wherein “m” is 1-18 , “p” and “q” are identical or different, and each is 0 or 1 , “Y” is Pro or Hyp, and “n”1-20 ; “Z” is a peptide chain comprising 1-10 amino acids, “r”1-20 , and “R” is a linear or branched alkylene group; the molar ratio of “a” to “b”[a/b] is 100/0 to 30/70 ; when p=1 and q=0, c=a, when p=0 and q=1, c=b, when p=1 and q=1, c=a+b, and when p=0 and q=0, c=0; and the polypeptide shows a peak of molecular weight in a range from 1×104 to 100×104 in the molecular weight distribution.

Abstract: A human prolactin-binding protein and compositions and methods using this protein are provided.

Abstract: This invention relates to an improved process for the minimization of acid-catalyzed reactions of certain echinocandins of the kind disclosed in U.S. Pat. No. 5,378,804. The process involves the use of a boronic acid.

Abstract: Protein and polypeptid derivatives and their salts are claimed characterized in that a protein or polypeptide is conjugated via an intermediate grouping containing at least one radical of the formula —C(R)?N— (or —N?C(R)—) or —CH(R)—NH— (or —NH—CH(R)—), wherein R is hydrogen or a hydrocarbon residue which may be substituted, with the same or a different protein or polypeptide, with a reporter group or a cytotoxic agent as well as a process for their preparation and the novel intermediates therefor.

Abstract: The present invention provides methods, apparatus and kits for synthesizing assembled peptides and proteins on a solid phase with sequential ligation of three or more unprotected peptide segments using chemoselective and mild ligation chemistries in aqueous solution. Also provided are methods of monitoring solid phase sequential ligation reactions using MALDI or electrospray ionization mass spectrometry of reaction products.

Abstract: A process is disclosed for using bis-(trichloromethyl)carbonate (triphosgene), diphosgene or phosgene as efficient and effective coupling reagents during coupling of carbohydrates to peptide chains. This process is particularly useful for the coupling to sterically hindered amino acid residues, or for other difficult couplings. The reagents can be used for the derivatization of peptides by formation of a bond between a free amine on a peptide and a carbohydrate.

Abstract: The present invention provides methods, apparatus and kits for synthesizing assembled peptides and proteins on a solid phase with sequential ligation of three or more unprotected peptide segments using chemoselective and mild ligation chemistries in aqueous solution. Also provided are methods of monitoring solid phase sequential ligation reactions using MALDI or electrospray ionization mass spectrometry of reaction products.

Abstract: The present invention concerns methods and compositions for extending the technique of native chemical ligation of a wider range of peptides, polypeptides, other polymers and other molecules via an amide bond (see FIG. 1). The invention further provides methods and uses for such proteins and derivatized proteins. The invention is particularly suitable for use in the synthesis of optionally polymer-modified, synthetic bioactive proteins, and of pharmaceutical compositions that contain such proteins.

Abstract: Methods and reagents for the formation of amide bonds between an activated carboxylic acid derivative and an azide useful in the synthesis of peptides, proteins and derivatized or labeled amino acids, peptide or proteins. The method involves the formation of a phosphinothioester which reacts with an azide resulting in amide formation. The invention provides phosphinothiol reagents which convert activated carboxylic acid derivatives to phosphinothioesters which then react with azides to form an amide bond. The methods and reagents of the invention can be used for stepwise synthesis of peptides on solid supports or for the ligation to two or more amino acids, two or more peptide or two or more protein fragments.

Abstract: A method for modifying the cyclic peptide ring system of Echinocandin-type compounds to produce new analogs having antifungal activity is provided. The inventive process comprises opening the cyclic peptide ring, cleaving the terminal ornithine unit, inserting at least one new amino acid or other synthetic unit and closing the ring to produce a new cyclic peptide ring structure. The process allows one to incorporate features such as water-solubility into the cyclic peptide ring nucleus, sites for further modification, increase or decrease the number of amino acid or peptide units within the ring nucleus, and increase or decrease the total number of members within the ring. The invention further provides novel Echinocandin type compounds and their use as antifungal or anti-parasitic agents.

Abstract: A fragment condensation process for the synthesis of analogs of parathyroid hormone (PTH) and parathyroid hormone related peptide (PTHrP), in which amino acid residues (22-31) form a synthetic amphipathic ?-helix, is provided.

Abstract: Process for the preparation of the cyclic pentapeptide cyclo(Arg-Gly-Asp-DPhe-NMeVal) by cyclization of a linear pentapeptide selected from the group consisting of H-Arg(Pbf)-Gly-Asp(OBzl)-DPhe-NMeVal-OH, H-Gly-Asp(OBzl)-DPhe-NMeVal-Arg(Pbf)-OH, H-Asp(OBzl)-DPhe-NMeVal-Arg(Pbf)-Gly-OH, H-DPhe-NMeVal-Arg(Pbf)-Gly-Asp(OBzl)-OH or H-NMeVal-Arg(Pbf)-Gly-Asp (OBzl)-DPhe-OH, subsequent protective group removal and, if appropriate, further conversion into its physiologically acceptable salts.

Abstract: A system for producing a library of oligomer comprising at least two monomers in a positionally determined array comprise a plurality of synthesis supports, a first plurality of support carriers wherein each carrier has a uniform array of distinct support holding positions for the synthesis supports; means for contacting each array of synthesis supports with a different monomer to provide a first chemical transformation of the synthesis supports; a second plurality of support carriers wherein each carrier has a uniform array of distinct support holding positions for receiving the chemically transformed synthesis supports contained in the first plurality of support carriers; transfer apparatus for transferring a selected row or column of synthesis supports from each of the first plurality of carriers to each of the second plurality of carriers to enable the supports in the second to undergo at least a second chemical transformation; and whereby each support position in each carrier identifies the chemical comp

Abstract: Processes for the preparation of modified proteins comprising the coupling of a first peptide segment having a haloacyl group at the N-terminus thereof with a second peptide sequent having a carbonylthiol group at the C-terminus thereof are disclosed. Novel modified proteins produced by the process are also disclosed.

Abstract: Disclosed is a synthetic method for the preparation of analogs of Didemnin A (1), particularly the Amino-Hip analog of Didemnin A, also known as “AipDidemnin A” (8).

Abstract: The present invention provides methods, apparatus and kits for synthesizing assembled peptides and proteins on a solid phase with sequential ligation of three or more unprotected peptide segments using chemoselective and mild ligation chemistries in aqueous solution. Also provided are methods of monitoring solid phase sequential ligation reactions using MALDI or electrospray ionization mass spectrometry of reaction products.

Abstract: This invention relates to a novel process for the synthesis of vasoactive intestinal peptide analog Ac(1-31)-NH2 from four protected peptide fragments.

Abstract: A method for peptide synthesis is disclosed that requires neither protecting groups nor activation of the C-&agr; carboxyl groups. The method comprises ligating a first molecule to a second molecule by promoting the orthogonal coupling of the molecules to each other. In an aspect of this method, an acyl-type reaction occurs between the molecules. The method contemplates the joining of molecules of variant size to each other, as well as the coupling of multiple identical molecules. The invention also covers the ligation of unprotected peptide, proteins or nonpeptide segments to prepare therapeutic products and synthetic vaccines with linear, circularized, or branched backbone structures, as well as the site-specific modification of peptides or proteins by lipidation and pegylation.

Abstract: Disclosed herein is a process whereby oligopeptides are ligated to form ligation peptide products. In the first step, two starting oligopeptides are ligated to form an intermediate having an amino-thioester linkage. In the second step, the aminothioester linkage undergoes a rearrangement to form a peptide having an N-substituted amide linkage. In an optional third step, the N-substitution of the amide linkage is chemically removed to form a native peptide linkage.

Abstract: The present invention relates to a class of pentapeptide analogs of LHRH. These compounds are useful in the treatment of disease conditions which are mediated by reproductive hormones, including benign prostate hyperplasia, prostate tumors, breast and ovaries tumors, cryptorchidism, hirsuitism, gastric motility disorders, dysmenorrhea, and endometriosis.

Abstract: The present invention provides a method for producing a peptide thiol ester using fluoren-9-ylmethoxycarbonylamino acid (Fmoc-amino acid). The method is for peptide synthesis and involves (1) using and removing the Fmoc group bound as the protective group to the amino group of amino acid, fixed on a resin via the thiol ester bond, a specific reagent is used to remove an Fmoc group from the amino acid thiol ester resin; (2) adding Fmoc-amino acid to the Fmoc-freed resin and then removing the Fmoc group, repeatedly, to prepare the Fmoc-peptide thiol ester resin; and (3) treating sequentially, the Fmoc-peptide thiol ester resin with a cleavage reagent and with a reagent capable of removing the Fmoc group.

Abstract: A method is provided which facilitates and enables the production of a wide range of complex conjugates composed of similar or dissimilar units linked together by amide bonds. Said method for the production of acylthio derivatives, R′—CO—SA, involves reaction of a carboxylate, R′—CO—O− (or carboxylic acid R′—CO—OH) with an iso-thiouronium derivative (bearing SA) in the presence of base. Nucleophilic counterion forms of the iso-thiouronium salts confer significant rate enhancement. The processes are simple, generally applicable, efficient, and do not require the employment of noxious reagents. The production of complex protein-like products by the intermediary of acylthio esters generated by the process of this invention, provides a method which is compatible with mild methods of chain assembly; and is preferably applied when the second component in the ligation bears an amino terminal cysteine residue.

Abstract: A method for preparing a peptide derivative of formula (I) or a salt thereof: which method comprises the steps of removing two MBzl groups from a compound of formula (II) or a salt thereof: wherein MBzl represents a 4-methoxybenzyl group which serves as a protective group for a thiol group, and R1 and R2 represent hydrogen or a protective group for Trp or Arg respectively; and subsequently oxidizing in an aqueous medium having a pH from 4 to 6 to form an intramolecular disulphide bond; intermediates useful for preparing the compounds of formula (I) and preparation of the intermediates.

Abstract: Canine interleukin 12 and a method for producing it by genetic engineering are disclosed. The canine interleukin 12 includes a protein having an amino acid sequence substantially the same as SEQ ID NO:1 or SEQ ID NO:11 or corresponds to part of either of SEQ ID NOS:1 and 11, and a protein having an amino acid sequence substantially the same as SEQ ID NO:2 or SEQ ID NO:12 or corresponds to part of either of SEQ ID NOS:2 and 12, and relates to a production method thereof. There is also an immune disease remedy and preventive agent for dogs and cats containing canine interleukin 12, and a method of treating immune disease and a preventive method for dogs and cats using the immune disease remedy or preventive agent.

Abstract: The present invention relates to a process for forming an N-&agr;-amino protected amino acid fluoride in situ by reacting an N-&agr;-amino protected amino acid with an ionic fluoride salt in the presence of a peptide coupling agent. It is also directed to the use of the amino acid fluoride thus formed in peptide synthesis.

Abstract: Proteins of moderate size having native peptide backbones are produced by a method of native chemical ligation. Native chemical ligation employs a chemoselective reaction of two unprotected peptide segments to produce a transient thioester-linked intermediate. The transient thioester-linked intermediate then spontaneously undergoes a rearrangement to provide the full length ligation product having a native peptide bond at the ligation site. Full length ligation products are chemically identical to proteins produced by cell free synthesis. Full length ligation products may be refolded and/or oxidized, as allowed, to form native disulfide-containing protein molecules. The technique of native chemical ligation is employable for chemically synthesizing full length proteins.

Abstract: The present invention relates, first, to methods for the synthesis of peptides, in particular T-20 (also referred to as "DP-178"; SEQ ID NO:1) and T-20-like peptides. Such methods utilize solid and liquid phase synthesis procedures to synthesize and combine groups of specific peptide fragments to yield the peptide of interest. The present invention further relates to individual peptide fragments which act as intermediates in the synthesis of the peptides of interest (e.g., T-20). The present invention still further relates to groups of such peptide intermediate fragments which can be utilized together to produce full length T-20 and T-20-like peptides.

Abstract: The invention relates to improved liquid phase processes for the preparation of the 21 residue protein component, (Lys-Leu.sub.4).sub.4 -Lys, of the pulmonary surfactant KL-4. These process are amenable to large scale synthesis and one process employs a method of saponifying an ester which reduces the inherent racemization of the .alpha.-carbon.

Abstract: A liquid phase process for preparing GnRH peptide analogs of the formula:G-AA.sub.1 -(A)D-Phe-AA.sub.3 -AA.sub.4 -(R.sub.2)-AA.sub.5 -AA.sub.6 AA.sub.7 -AA.sub.8 -Pro-AA.sub.10 -NH.sub.2Formula 1which comprises:(a) reacting a peptide of the formula:T-(R.sub.2)AA.sub.5 -AA.sub.6 -Xwhere T is (P.sub.2)AA4 orP.sub.2 and X is AA.sub.7 --OH or is --OH, with a peptide of the formula:X'-AA.sub.8 -Pro-AA.sub.10 -NH.sub.2or acid-addition salt form thereof, where X' is AA.sub.7 when X is absent and X' selected from P-Ala, Gly, GABA, the D- and L- isomers of Ala, amino isobutyric acid, 6-amino-hexanoic acid, Ser, Thr, His, Tyr, Asn, and Gln' is absent when X is AA.sub.7 --OH;in a liquid reaction medium in the presence of a peptide coupling reagent and a strong organic amine base to obtain a product of the formula:T-(R.sub.2)AA.sub.5 -AA.sub.6 -AA.sub.7 -AA.sub.8 -Pro-AA.sub.10 -NH.sub.2(b) removing the P.sub.

Abstract: This invention provides a method for preparing molecules that bind to a preselected receptor, whereby the receptor itself acts as an agent for either joining two ligand fragments to form a composite, tight binding ligand, or selects a composite ligand from a mixture in solution where ligand fragments are being joined and unjoined reversibly under equilibrium conditions.

Abstract: A cyclic hexapeptide represented by the formula:cyclo?A--Asp(R.sup.1)--Y--NH--CHR.sup.2 --CO--C--D--Trp(N.sup.in --R.sup.3)--! (I)wherein A is a D-acidic-.alpha.-amino acid residue; Y is an acidic-.alpha.-amino acid residue; C is an L-.alpha.-amino acid residue; R.sup.1 is a group represented by the formula: ##STR1## wherein X.sup.1 and X.sup.2 are independently H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or nitro, and may bind together to form a ring in cooperation with the adjacent carbon atom; R.sup.2 is C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-3 alkyl, C.sub.1-6 alkylthio-C.sub.1-3 alkyl, C.sub.3-7 cycloalkylthio-C.sub.1-3 alkyl, C.sub.1-5 alkoxy-C.sub.1-3 alkyl, C.sub.3-7 cycloalkoxy-C.sub.1-3 alkyl, C.sub.1-6 alkylthio, C.sub.3-7 cycloalkylthio, C.sub.1-5 alkoxy or C.sub.3-7 cycloalkoxy; R.sup.3 is H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, --COR.sup.4, --COOR.sup.5 or --CONHR.sup.6 ; when X.sup.1, X.sup.2 and R.sup.3 are all hydrogen atoms, R.sup.

Abstract: Disclosed herein are template assembled synthetic protein (TASP) molecules that contain dendritic linkage units having the structure .psi. (CO--S--CH.sub.2 --CO--NH). Also disclosed are methods of preparing the template assembled synthetic proteins.

Abstract: This invention relates to a process for forming an amide or an ester from a reaction between an amine or an alcohol, respectively and an acylating derivative of a carboxylic acid, in the presence of an effective amount of a compound having the formula: and N-oxides thereof and salts thereof.

Abstract: This invention relates to a process for forming an amide or an ester from a reaction between an amine or an alcohol, respectively and an acylating derivative of a carboxylic acid, in the presence of an effective amount of a compound having the formula: and N-oxides thereof and salts thereof.