Dpp1 5 29204ru 04 08 2011 – 10 6 – ar


valid until 2018/1/23

Dpp1 5 29204ru 04 08 2011

Dpp1 5 29204ru 04 08 2011

Dpp1 5 29204ru 04 08 2011

Dpp1 5 29204ru 04 08 2011

Dpp1 5 29204ru 04 08 2011

23.01.2018 – The crosslinked polymer PIIT-BOCx exhibited a favourable solvent-resistant property which was beneficial for application in solution-processable multiple-layer electronic devices. There remains a need for inhibitors of DPP-1 for the treatment of DPP-1 mediated disorders and conditions, including but not limited to rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism.

Kilos una dpp1 5 29204ru 04 08 2011 resident evil gratuit

Dpp1 5 29204ru 04 08 2011

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1. 8A mL round bottom flask was charged with 4- 2-aminobromo-phenylethynyl -piperidinecarboxylic acid tert-butyl ester 5. The resulting mixture was extracted two times with ethyl acetate mL.
2. 3 Further, one skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.http://softik.org/1click-dvd-copy-5-9-1-7-keygen-7/ http://softik.org/1click-dvd-copy-5-9-1-9-7/Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

3. 7 Other suitable oxygen protecting groups may be found in texts such as T. The vessel was then flushed with argon and sealed. http://softik.org/ccleaner-windows-7-5-core/Additional development work continued on the ventilation infrastructure including the Golden Point shaft which was at a depth of 78 metres at quarter end. Aggregate cash costs increased due to rising input prices across the industry.

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Dpp1 5 29204ru 04 08 2011

4. 6 Example 12 Compound 14 S amino thiophenyl 4- 6- 4- trifluoromethyl phenyl benzo[d]thiazolyl piperazinyl propanone STEP A: Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating:Dpp1 5 29204ru 04 08 2011Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. In one of the early studies, Sun et al.

5. 2 For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

6. 7 The organic layer was dried over sodium sulfate, filtered and concentrated to a residue.

7. 8 Accordingly, no assurance can be given that the indicated amount of gold will be recovered or at the rates estimated.

Dpp1 5 29204ru 04 08 2011 free grime fighter

To date, versatile polymer semiconductors have been reported for field-effect transistors FETs. And the third-generation donor—acceptor D—A polymers have been among the most intensively studied semiconductors.

Meanwhile, there are a variety of methods adopted for the enhancement of performance. To the best of our knowledge, a p-type polymer semiconductor with a highest hole mobility of This review describes building block selection, backbone halogenation, side chain engineering and random copolymerization, which are the effective synthesis approaches applied in this field, affording assistance for developing high-performance polymer semiconductors in the future.

His research interests dpp1 on molecular materials and devices for organic field-effect transistors. In Aprilhe became a project associate professor at the Department of Chemistry, University of Tokyo.

His research interests include organic—inorganic hybrid perovskite electronics and functional organic field-effect transistors. Inhe moved to Tianjin University.

His research focuses on molecular electronics, and he has more than refereed publications with over 11 citations. He graduated from Nanjing University inand received a doctorate from the Tokyo Institute of Technology, Japan, in He was selected as an Academician of CAS in His research interests include molecular materials and devices, the synthesis and applications of carbon nanomaterials, and organic electronics.

He has more than refereed publications with over 22 citations. This fused ring structure polymer showed a p-type semiconductor behaviour with a hole mobility of 0. Later on, Chen 7 et al.

Besides, the HOMO delocalization and coplanarity of a molecule could also be affected by the flanking aryl units, eventually resulting in good or bad charge-carrier hopping between the molecules.

And, there are few reports regarding its use for OFETs except organic solar cells. Additionally, the larger size of TT than thiophene also has a negative impact on the solubility of the polymer, which causes poorer molecular packing during the device fabrication process and eventually leads to undesirable electrical properties.

It is worth mentioning that researchers have proved that DPP4 flanked by furan possesses better solubility in chlorine-free solution than analogous thiophene-based DPP1.

Selenium, as an element in the same group as sulfur, possesses more electrons and is of a larger size than sulfur. For example, inChoi et al. From the theoretical calculations, it was revealed that DPP6 flanked by two phenyl substituents had a larger band gap and a less coplanar structure, which is detrimental to its amibipolar properties and intermolecular charge transfer.

However, when the two pyridine units were adjacent to the DPP core instead of benzene or thiophene, low-lying HOMO—LUMO levels and fine coplanarity were observed from calculations and experiments, 41 which benefited the electrical performance.

More detailed discussion on such a structure will be displayed in the later content. Different from polymers based on symmetric units, the asymmetric units DPP10—DPP12 can provide a conjugated polymer with some special properties such as good solubility.

As the two different flanking aromatic substituents are adjacent to the DPP core, the synthesis method of asymmetric DPPs is different from the methods used for symmetric DPPs as shown in Scheme 1which required two steps to obtain a high yield by linking two different kinds of aromatic nitriles adjacent to the molecular backbone Scheme 2.

For example, DPP12, as an acceptor monomer, with adjacent aromatic substituents of thiophene and 3-methylthiophene on each side, copolymerized with thiophene contributes a high hole mobility to the PDPP26 polymer Fig.

In one of the early studies, Sun et al. Notably, DPP7 has a highly coplanar structure because of the weak steric hindrance between the 2-pyridinyl substituents and the DPP core.

Apart from that, pyridine is a relatively electron-deficient structure, as a result of which, the LUMO energy level could be reduced. Compared with the polymer PDPP3 whose linkage is vinylene, PDPP47 showed ambipolar behaviour caused by the more electron-withdrawing property of acetylene and conformation-insensitive charge transport.

As a result, DPP was a donor and benzobisthiadiazole was an acceptor in the polymer PDPP50, which presented an excellent fine ambipolar property with a hole mobility of 1. Besides, as a similar structure to IID3, IID4 has also been mentioned for a small molecule semiconductor but not a polymer.

The OFETs based on it showed a hole mobility of 0. Such a phenomenon may be caused by the molecular orientation packing, which will be discussed in detail in the later section. The author also demonstrated that a polymer 29204ru a high molecular weight has better charge transporting properties than that of a polymer with a low molecular weight.

The brominated monomer of IID6 Fig. Replacement of the aromatic benzene ring with pyridine results in a lower lying LUMO to afford a more electron-deficient acceptor owing to the electron-deficient feature of the pyridinic nitrogen.

Such effects were proved in theoretical calculations and experiments. Replacement of the central benzodifurandione ring by benzodipyrrole-dione 76, IID16 as in Fig.

For IID16 and IID17 based polymers, the additional N -substituted alkyl chains afford the improvement of solubility of such conjugated polymers in solvent which is beneficial to the processing of the polymers.

TID-based polymer semiconductors have only been mentioned in organic solar cells. Tetraazabenzodifluoranthene diimides BFI, Fig. Benzothiadiazole also played the acceptor role in donor—acceptor polymers when a suitable co-monomer was chosen.

Indacenodithieno-[3,2- b ]thiophene of a largely conjugated structure and fine planarity was copolymerized with BTz. Linear alkyl chains connected to indacenodithieno[3,2- b ]thiophene gave the polymer PBTz1 Fig.

Naphthobischalcogenadiazole NCzwas also studied. The results showed that NCz2 Fig. Recently, bay-annulated indigo BAIan old natural dye, was also studied as the electron-deficient building block.

As a side note, BAI may be a potential electron-deficient unit for high-performance polymer semiconductors. As shown in Fig. But their OFET performance still needs to be improved.

Subsequently, Wang et al. Such polymers did not show promising OFET performance, but the charge polarity of the polymers was proved to be influenced as the polymers PseS Table 5 and PseN Table 5 exhibit ambipolar properties while PSN Table 5 showed p-channel charge transporting behaviour.

Thiadizoloquinoxaline TQas another structure containing thiadiazole, was also investigated. Compared to the BBT acceptor, TQ 2011 have more sites to be alkylated, which will influence the solubility, structure, and packing of the corresponding polymers.

Ina phenyl-flanked benzodipyrrolidone BPP in Fig. Similarly, Li and co-workers reported polymers consisting of a kind of aromatic lactam unit — pyrimido[4,5- g ]quinazoline-4,9-dione PQ.

Osaka and co-workers firstly incorporated the quinacridone unit into polymers for OFETs. Among them, PQTE exhibited the highest hole mobility of 0. Following the above-mentioned fluorothiophene studies, difluorothiophene was also used as the building block for fluorinated conjugated polymers.

Inin order to explore the effect of fluorination of the co-monomer 2011 the charge carrier mobility, optical properties, and crystallinity of dpp1 aryl-flanked DPP based polymers, Mueller et al.

They found that the crystallinity of the DPP-based polymers could be improved by fluorination irrespective of the different flanking aryl units. This conclusion was also proved by Gao et al.

This can be explained by the fact that the LUMO level of polymer semiconductors can be reduced by 29204ru contributing to easier electron injection from the electrode in OFET devices.

Therefore, the influence of fluorination on DPP-based polymers still needs to be deeply studied. Prior to difluorothiophene as the fluorinated building block for polymer semiconductors, a fluorinated phenyl unit was also incorporated into the DPP-based polymer backbone.

InPark et al. The results 29204ru that the diverse fluorination substitution positions on diphenylethene caused a different OFET performance of the polymers because of the distinct intra- and intermolecular interactions and backbone conformations.

There are also many other non-covalent interactions existing in polymers. The above-mentioned fluorination process belongs to the charge donor fluorination.

Besides, charge acceptor fluorination has also been reported. Compared to the charge donor fluorination, it may be more difficult to fluorinate the charge acceptors in terms of their complicated chemical structures.

Fluorinated IID-based polymers were investigated in The electron mobility of the IID-based polymers was improved from 0. Characterization by grazing incident X-ray diffraction GIXRD and tapping-mode atomic force microscopy AFM also revealed the different interchain interactions and stronger crystalline tendencies caused by fluorination of the IID core.

Additionally, there are also some donor fluorinations reported dpp1 IID-based polymers. But both of them did not exhibit high performance.

Then, Hu et al. It was shown that fluorination on the donor unit resulted in stronger temperature-dependent aggregation than fluorination on the acceptor unit. But the OFET performance was not mentioned.

Subsequently, Gao et al. Isoindigo-based polymers with different backbone conformations were also studied via different fluorination positions. Such a phenomenon could be attributed to the different backbone conformations leading to the different interchain interactions and film microstructures.

Other fluorinated polymers based on monofluorobenzothiadiazole FBT and difluorobenzothiadiazole 2FBT were reported in numerous studies. The results showed that the non-covalent interaction and the solid-state order were enhanced by fluorine substitution, eventually resulting in an improvement in OFET performance.

Supposedly, for polymer fluorination, when the effect of the solid-state order enhancement is greater than the effect of the HOMO—LUMO level reduction, the hole mobility will be increased.

In contrast, the hole transport is restricted as the reduction effect of the HOMO—LUMO levels is greater than the solid-state order enhancement effect. Additionally, a decrease in both hole mobility and electron mobility was also characterized for the fluorination of some polymers.

In addition, high-performance with a hole mobility of 9. Compared with linear side chains, branched side chains 2011 attracted more attention from researchers as they can provide better solubility for polymers.

InKim et al. Therefore, there was a clear trend observed that the hole mobility of PQA2Ts increased with a longer group. Additionally, for IID-based polymers, the thin-film microstructure, crystallinity and domain size but not the length of the spacers played a more important role for thin film charge transport characteristics when the carbon number of the alkyl spacer was three and over three.

InJenekhe et al. Later on, Kim et al. It was suggested that the crystallinity of PDPP-Th-Se could be systematically manipulated by adjusting the ratio between two different electron donors — selenophene and thiophene.

The melting and crystallization temperatures as well as the crystallinity of PPTPV were improved following the enhancement of the Se content, which resulted in the enhancement of the OFET performance.

Dpp1 5 29204ru 04 08 2011 abril

The use of a compound as in claim 19, for use in a method for treating a disorder selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism, in a subject in need thereof. The brominated monomer of IID6 Fig. In an embodiment of the present invention a is 0. Initial velocity rates were plotted vs. A mL round bottom flask was charged with S tert-butoxycarbonylamino thiophenyl propanoic acid

Dpp1 5 29204ru 04 08 2011 office 2010 portugues

The OFETs based on it showed a hole mobility of 0. Such a phenomenon may be caused by the molecular orientation packing, which will be discussed in detail in the later section. The author also demonstrated that a polymer with a high molecular weight has better charge transporting properties than that of a polymer with a low molecular weight.

The brominated monomer of IID6 Fig. Replacement of the aromatic benzene ring with pyridine results in a lower lying LUMO to afford a more electron-deficient acceptor owing to the electron-deficient feature of the pyridinic nitrogen.

Such effects were proved in theoretical calculations and experiments. Replacement of the central benzodifurandione ring by benzodipyrrole-dione 76, IID16 as in Fig. For IID16 and IID17 based polymers, the additional N -substituted alkyl chains afford the improvement of solubility of such conjugated polymers in solvent which is beneficial to the processing of the polymers.

TID-based polymer semiconductors have only been mentioned in organic solar cells. Tetraazabenzodifluoranthene diimides BFI, Fig. Benzothiadiazole also played the acceptor role in donor—acceptor polymers when a suitable co-monomer was chosen.

Indacenodithieno-[3,2- b ]thiophene of a largely conjugated structure and fine planarity was copolymerized with BTz. Linear alkyl chains connected to indacenodithieno[3,2- b ]thiophene gave the polymer PBTz1 Fig.

Naphthobischalcogenadiazole NCz , was also studied. The results showed that NCz2 Fig. Recently, bay-annulated indigo BAI , an old natural dye, was also studied as the electron-deficient building block.

As a side note, BAI may be a potential electron-deficient unit for high-performance polymer semiconductors. As shown in Fig. But their OFET performance still needs to be improved.

Subsequently, Wang et al. Such polymers did not show promising OFET performance, but the charge polarity of the polymers was proved to be influenced as the polymers PseS Table 5 and PseN Table 5 exhibit ambipolar properties while PSN Table 5 showed p-channel charge transporting behaviour.

Thiadizoloquinoxaline TQ , as another structure containing thiadiazole, was also investigated. Compared to the BBT acceptor, TQ acceptors have more sites to be alkylated, which will influence the solubility, structure, and packing of the corresponding polymers.

In , a phenyl-flanked benzodipyrrolidone BPP in Fig. Similarly, Li and co-workers reported polymers consisting of a kind of aromatic lactam unit — pyrimido[4,5- g ]quinazoline-4,9-dione PQ. Osaka and co-workers firstly incorporated the quinacridone unit into polymers for OFETs.

Among them, PQTE exhibited the highest hole mobility of 0. Following the above-mentioned fluorothiophene studies, difluorothiophene was also used as the building block for fluorinated conjugated polymers.

In , in order to explore the effect of fluorination of the co-monomer on the charge carrier mobility, optical properties, and crystallinity of different aryl-flanked DPP based polymers, Mueller et al.

They found that the crystallinity of the DPP-based polymers could be improved by fluorination irrespective of the different flanking aryl units. This conclusion was also proved by Gao et al.

This can be explained by the fact that the LUMO level of polymer semiconductors can be reduced by fluorination contributing to easier electron injection from the electrode in OFET devices.

Therefore, the influence of fluorination on DPP-based polymers still needs to be deeply studied. Prior to difluorothiophene as the fluorinated building block for polymer semiconductors, a fluorinated phenyl unit was also incorporated into the DPP-based polymer backbone.

In , Park et al. The results showed that the diverse fluorination substitution positions on diphenylethene caused a different OFET performance of the polymers because of the distinct intra- and intermolecular interactions and backbone conformations.

There are also many other non-covalent interactions existing in polymers. The above-mentioned fluorination process belongs to the charge donor fluorination. Besides, charge acceptor fluorination has also been reported.

Compared to the charge donor fluorination, it may be more difficult to fluorinate the charge acceptors in terms of their complicated chemical structures. Fluorinated IID-based polymers were investigated in The electron mobility of the IID-based polymers was improved from 0.

Characterization by grazing incident X-ray diffraction GIXRD and tapping-mode atomic force microscopy AFM also revealed the different interchain interactions and stronger crystalline tendencies caused by fluorination of the IID core.

Additionally, there are also some donor fluorinations reported for IID-based polymers. The compound of formula VIII is reacted with a suitably substituted compound of formula IX , a known compound or compound prepared by known methods; in a suitably selected organic solvent such as DCM, THF, chloroform, and the like, to yield the corresponding compound of formula X.

The compound of formula X is reacted with benzyl-trimethyl-ammonium tribromide, a known compound; in a suitably selected organic solvent such as DCM, 1,2-dimethoxyethane, acetonitrile, and the like, to yield the corresponding compound of formula XI.

The compound of formula XI is de-protected according to known methods; to yield the corresponding compound of formula Ia. The compound of formula XIV is reacted with a suitably substituted compound of formula V , wherein PG 1 is a suitably selected nitrogen protecting group such as Boc, CBz, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling system such as HOBt in combination with EDCI, and the like; in the presence of a suitably selected organic base such as TEA, DIPEA, pyridine, and the like; in a suitably selected organic solvent such as DCM, DMF, and the like; to yield the corresponding compound of formula XV.

The compound of formula XV is de-protected according to known methods to yield the corresponding compound of formula Ib. Accordingly, a suitably substituted compound of formula II , wherein LG 1 is a suitably selected leaving group such as bromo, chloro, and the like, a known compound or compound prepared by known methods, is reacted with a suitably selected source of chlorine such as oxalyl chloride, thionyl chloride, and the like; in the presence of a catalytic amount of DMF; in a suitably selected solvent such as DCM, THF, and the like; to yield the corresponding compound of formula III.

The compound of formula XIX is de-protected according to known methods to yield the corresponding compound of formula Ic. One skilled in the art will recognize that compounds of formula Ic wherein R 1 is selected from the group consisting of C alkyl, optionally substituted phenyl, 5 to 6 membered heteroaryl and benzo[d][1,3]dioxolyl, may alternatively be prepared by reacting as described in Scheme 5, below.

Accordingly, a suitably substituted compound of formula XIXa , a compound of formula XIX wherein a is 1 and R 1 is bromo, prepared for example as described in Scheme 4 above, is reacted with a suitably substituted boronic acid compound of formula XXX , wherein R 12 is selected from the group consisting of C alkyl, optionally substituted phenyl, 5 to 6 membered heteroaryl and benzo[d][1,3]dioxolyl, a known compound or compound prepared by known methods; in the presence of a suitably selected coupling agent such as Pd PPh 3 4 , Pd OAc 2 , Pd dppf Cl 2 , and the like; in the presence of a suitably selected inorganic base such as K 2 CO 3 , and the like; in a suitably selected solvent or mixture thereof such as 1,4-dioxane, water, a mixture of THF and water, and the like; to yield the corresponding compound of formula XIXb.

The compound of formula XIXb is de-protected according to known methods, for example, as described in Scheme 4 above, to yield the corresponding compound of formula Id.

Accordingly, a suitably substituted compound of formula XX , wherein A 1 is C alkyl, preferably methyl or ethyl, and wherein LG 2 is a suitably selected leaving group such as bromo, chloro, and the like, a known compound or compound prepared by known methods, is reacted as herein described, to yield the corresponding compound of formula XXI , wherein PG 1 is a suitably selected nitrogen protecting group such as Boc, CBz, and the like.

For example, the compound of formula XX may be reacted with a suitably substituted compound of formula VI , de-protected and then reacted with a suitably substituted compound of formula V , according to the process outlined in Scheme 2 above.

Alternatively, the compound of formula XX may be reacted with a suitably substituted compound of formula XVI , de-protected and then reacted with a suitably substituted compound of formula V , according to the process outlined in Scheme 4 above.

The compound of formula XXI is reacted with a suitably selected base such as NaOH, LiOH, and the like; in a suitably selected organic solvent such as methanol, ethanol, and the like; to yield the corresponding compound of formula XXII.

The compound of formula XXIII is de-protected according to known methods, to yield the corresponding compound of formula Ie. Accordingly, a suitably substituted compound of formula XX , wherein A 1 is C alkyl, preferably methyl or ethyl, and wherein LG 2 is a suitably selected leaving group such as bromo, chloro, and the like, a known compound or compound prepared by known methods, is reacted with a compound of formula XVI , wherein PG 3 is a suitably selected nitrogen protecting group such as Boc, CBz, and the like, a known compound or compound prepared by known methods; in the presence of a suitably selected inorganic base such as K 2 CO 3 , Cs 2 CO 3 , and the like; in a suitably selected organic solvent such as acetonitrile, DMF, and the like; to yield the corresponding compound of formula XXIV.

The compound of formula XXV is then de-protected according to known methods, reacted with a suitably substituted compound of formula V , as described in Scheme 4 above, to yield the corresponding compound of formula XXVI.

The compound of formula XXVI is then de-protected according to known methods, to yield the corresponding compound of formula If , a compound of formula I wherein R 1 is hydroxymethyl.

The compound of formula XXIX is de-protected according to known methods, to yield the corresponding compound of formula Ig. The present invention further comprises pharmaceutical compositions containing one or more compounds of formula I with a pharmaceutically acceptable carrier.

Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.

The carrier may take a wide variety of forms depending upon the desired route of administration e. Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.

Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.

Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives. To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.

In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.

Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.

If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.

Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.

The pharmaceutical compositions herein will contain, per unit dosage unit, e. The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed.

The use of either daily administration or post-periodic dosing may be employed. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.

Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.

This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.

For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.

A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The methods of treating described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.

The pharmaceutical composition may contain between about 0. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.

Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules each including immediate release, timed release and sustained release formulations , granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.

Forms useful for parenteral administration include sterile solutions, emulsions and suspensions. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.

To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.

Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.

For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

To prepare a pharmaceutical composition of the present invention, a compound of formula I as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration e.

Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients , published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders mediated by DPP-1 is required.

The daily dosage of the products may be varied over a wide range from 0. For oral administration, the compositions are preferably provided in the form of tablets containing about 0.

An effective amount of the drug is ordinarily supplied at a dosage level of from about 0. Preferably, the range is from about 0. More preferably, from about 0. The compounds may be administered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition.

In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

For example, Methot, N. The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed as having been isolated as a residue. To an ice cold mixture of Ntrifluoroacetamido-L-butanoic acid 1. The organic layer was dried over sodium sulfate, filtered and concentrated.

To a heterogenous mixture of S -benzyl 2- 2- 2,2,2-trifluoroacetamido butanamido ethylcarbamate 1. The resulting mixture was stirred overnight at room temperature. The resulting mixture was stirred at room temperature for 1 h, then treated with benzyltrimethylammonium tribromide The resulting mixture was then stirred overnight.

The reaction was quenched with aqueous sodium bicarbonate and the mixture extracted into methylene chloride. The organic layer was dried over sodium sulfate, then filtered and concentrated to yield a residue which was purified by normal phase column chromatography, eluting with The resulting mixture was extracted into chloroform.

The organic layer was dried over sodium sulfate, filtered and concentrated to yield a residue. The residue was purified by preparative thin layer chromatography, eluting with a Acidification of the free base in chloroform, with 1 N hydrogen chloride in diethyl ether yielded the corresponding di-hydrochloride salt as a moisture-sensitive solid.

To a solution of S —N- 2-aminoethyl 2,2,2-trifluoroacetamido butanamide A solution of R —N- 2- 3- 4-methoxyphenyl thioureido ethyl 2,2,2-trifluoroacetamido butanamide The reaction was then quenched with aqueous sodium bicarbonate and extracted into methylene chloride.

To an ice cold solution of S —N- 2- 6-methoxybenzo[d]thiazolylamino ethyl 2,2,2-trifluoroacetamido butanamide mg, 0. After 1d, additional 3N aqueous sodium hydroxide solution 0.

The organic layer was dried over sodium sulfate, filtered and concentrated to a residue. Acidification of the free base in chloroform, with 1 N hydrogen chloride in diethyl ether yielded the corresponding di-hydrochloride salt as an off-white solid.

The solid mass was dissolved in chloroform, and the resulting solution was washed with aqueous sodium bicarbonate then dried, filtered and concentrated to a yield a residue.

A white separated solid was collected by filtration, washed with diethyl ether and dried in vacuum oven overnight at room temperature to yield the hydrochloride salt of N1- benzo[d]thiazolyl ethane-1,2-diamine as an off-white amorphous solid.

The resulting mixture was stirred overnight at room temperature, then was diluted with dichloromethane, washed with water, dried over sodium sulfate, filtered and concentrated to yield a flaky solid.

S -tert-butyl 1- 2- benzo[d]thiazolylamino ethylamino oxo thiophenyl propanylcarbamate The resulting mixture became homogenous, then a solid separated as the stirring continued for 4 h. The solid was collected by filtration, washed with 1,4-dioxane, then dried in a vacuum oven overnight at room temperature, to yield the title compound as its corresponding hydrochloride salt, as a white solid.

A mixture of 2-chlorobenzoxazole 0. The focus of operations in the period continued to be on underground development rather than mining of ore, so processing was limited in the quarter.

Total gold production was ounces from ongoing test work and refinement of the process plant. Diamond drilling during the quarter was focussed on stope delineation with no resource drilling undertaken.

Unit costs in the first quarter were skewed by the plant maintenance shut down, which reduced output and increased costs. Rising prices for fuel and blasting consumables, along with adverse exchange rate movements, also contributed to a rise in costs.

For the full year , the company now expects to produce in excess of , ounces, with production boosted by the merger with Equigold, subject to completion as scheduled in June. Production from Lihir Island and Ballarat remains on track to reach between ,, ounces, including 40,, ounces from Ballarat.

The Bonikro operations of Equigold are scheduled to commence production in July, and will produce around 60,, ounces this year, while Mt Rawdon production over the period from June to December is expected to contribute approximately 50, ounces.

Unit costs are forecast to decline during the remainder of the year, assisted by increased production rates, but are likely to be slightly higher than initial expectations due to rising diesel and HFO prices and continued weakness of the US dollar.

The ongoing transformation of the company is continuing to gather momentum and I look forward to reporting a successful completion of the Equigold merger and further operational progress during the remainder of the year.

Material movements in the quarter totalled Mining was affected by record rainfall in January which hampered haul road and production face conditions. Shovel availability in the quarter was also lower than expected, with one of the five shovels out of production for seven weeks.

Two replacement shovels, scheduled for delivery in , have been brought forward, with the first of those to be brought into production in the second half of the current year.

The focus of mining activity was on the continued development of the Lienetz pit. The bulk of ore continued to come from Phase 6 with preliminary access to Phase 8 ore late in the quarter following waste stripping.

Increased autoclave throughput and the addition of the flotation grinding circuit have moved throughput pressures earlier in the production line, placing additional demands on the crushing circuit.

This led to increased maintenance on the crusher and associated infrastructure during the quarter, reductions in crushed ore stockpiles and lower volumes of ore crushed and processed.

Crusher throughput is expected to increase following the commissioning of the Abon sizer in the second quarter to more effectively process softer ores. Ore crushed and milled in the quarter was 1.

The feed to the autoclaves was kt at 5. Ongoing drilling at Lihir Island continued to produce encouraging results and may lead to an increase in the current resource estimate.

Significant assay results received from holes targeting an area east-northeast of planned mining development are shown in the following plan. These intercepts were returned from drill holes located outside of the existing resource.

The drilling results define a broadly horizontal zone of gold mineralisation, varying in true thickness from 50 to metres. Additional drilling is to be completed this year.

Progress on mine development continued with metres of development completed during the quarter, including a record month of metres in March. The focus of operations continues to be on the development of underground declines and ventilation infrastructure to facilitate the start of ore production in the fourth quarter.

Mining progress continued in the two Prince declines in the southern zone and the Woah Hawp and Sovereign declines in the central zone of the field. Additional development work continued on the ventilation infrastructure including the Golden Point shaft which was at a depth of 78 metres at quarter end.

The shaft is expected to be completed by year end, reaching a depth of more than metres.