Dpp1 5 28853ru 03 07 2011 – 6 7 – ar


valid until 2018/1/23

Dpp1 5 28853ru 03 07 2011

Dpp1 5 28853ru 03 07 2011

Dpp1 5 28853ru 03 07 2011

Dpp1 5 28853ru 03 07 2011

Dpp1 5 28853ru 03 07 2011

16.03.2018 – The length and composition of the primer depends on many parameters, including, for example, the temperature at which the annealing reaction is conducted, proximity of the probe binding site to that of the primer, relative concentrations of the primer and probe and the particular nucleic acid composition of the probe. Sobrero P, Valverde C Evidences of autoregulation of hfq expression in.

Naiad dpp1 5 28853ru 03 07 2011 qui veut

Dpp1 5 28853ru 03 07 2011

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1. 8Exogenous translational elements and initiation codons can be of various origins, both natural and synthetic. 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.
2. 6 Riboregulation stands for RNA-based control of gene expression. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.http://softik.org/a-tube-catcher-latest-2013-old-versionupdate-working-exclusive/ http://softik.org/a-view-bot-make-money-2000-views-an-hour/Too high or too low levels of fats in the bloodstream, especially cholesterol, can cause long-term problems.

3. 2 For example, the subject may be deemed at risk of developing a disorder, disease or condition and therefore in need of prevention or preventive treatment as a consequence of the subject’s medical history, including, but not limited to, family history, pre-disposition, co-existing comorbid disorders or conditions, genetic testing, and the like. Regions of genomic alteration can be narrowed further using loss of heterozygosity analysis LOHin which disease DNA is analyzed and compared with normal DNA for the loss of a heterozygous polymorphic marker. http://softik.org/xiaomi-mi5-english-essays/Some of these will only bear minimal homology to the nucleotide sequence of the known and naturally occurring DPPl. Determining the ability of the test compound to modulate the activity of DPPl can be accomplished, for example, by determining the ability of DPP i to bind to or interact with a target molecule.

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Dpp1 5 28853ru 03 07 2011

4. 7 In yet another aspect of the invention, a DPPl -like polypeptide can be used as a “bait protein” in a two-hybrid assay or three-hybrid assay [Szabo, ; U.Dpp1 5 28853ru 03 07 2011This is to appraise the entire student of The polytechnic, Ibadan

5. 6 More detailed discussion on such a structure will be displayed in the later content.

6. 2 Very severe hypothyroidism is called myxedema. The absence of Hfq results in deficient growth in.

7. 8 Chronic pancreatitis is a longstanding inflammation of the pancreas. Sinorhizobium meliloti bluB is necessary for production of 5,6-dimethylbenzi.

Dpp1 5 28853ru 03 07 2011 windows bits

This application claims priority from U. The present invention is directed to novel substituted benzothiazole and benzoxazole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by DPP COPD consists of chronic obstructive bronchitis, with obstruction of small airways, and emphysema, with enlargement of air spaces and destruction of lung parenchyma, loss of lung elasticity, and closure of small airways.

In COPD patients, there were increased numbers of neutrophils, cytotoxic T lymphocytes and macrophages in bronchoalveolar lavage BAL airways and lung parenchyma. The presence of these inflammatory cells is correlated well with severity of airway obstruction dpp1 alveolar wall destruction.

It has been shown that neutrophil elastase; cathepsin G and proteinase 3 can produce emphysema and mucus hypersecretion in lab animals. In COPD the protease-antiprotease balance appears to be tipped in favor of increased proteolysis due to increase in polymorphonuclear neutrophil PMN -derived proteases, cathepsins and matrix metalloproteases MMPs.

Therefore, a drug that inhibits all or most of the relevant proteases mentioned above is expected to be effective in the treatment of COPD. DPP-1 MW kd 2011 composed of a dimer of disulfide-linked heavy and light chains, both from a single protein precursor.

DPP-1 mRNA is highly expressed in tissues such as lung, spleen, kidney and liver; in inflammatory cells such as PMN, cytotoxic T lymphocytes, alveolar macrophages and mast cells.

The biological function of DPP-1 is to convert inactive proenzymes into active enzyme by removing a dipeptide from N-terminal. Additional therapeutic indications for a DPP-1 inhibitor are asthma, rhinitis, and rheumatoid arthritis.

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.

The present invention is further directed to processes for the preparation of the compounds of formula I. The present invention is further directed to a product prepared according to the process described herein.

Illustrative of the invention is dpp1 pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared 28853ru to the process described herein.

An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.

Illustrating the invention is a process for making a pharmaceutical composition comprising mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating a disorder mediated by DPP-1 cathepsin C 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 comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: In another example, the present invention is directed to a compound as described herein for use in a methods 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 compounds of formula I of the present invention are inhibitors of DPP-1, useful in the treatment of disorders, diseases and conditions mediated by DPP-1 cathepsin Cincluding, but not limited to, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, 2011 abdominal 28853ru aneurism.

In an embodiment of the present invention a is 0. In another embodiment of the present invention a is 1. In another embodiment of the present invention, R 1 is selected from the group consisting of 6- bromo6- carboxy6- hydroxymethyl6- methoxy6- benzo[d][1,3]dioxolyl6- pyridyl6- 4-methylphenyl6- 3,4-dimethoxyphenyl6- 3,4-difluorophenyl6- 4-trifluoromethyl-phenyl6- 4-hydroxyphenyl6- 2-fluorophenyl6- 3,5-dichlorophenyl6- 3,4-dimethoxyphenyl-amino-carbonyl6- cyclopentyl-amino-carbonyl6- 4-fluorophenyl-amino-carbonyl6- n-butyl-amino-carbonyl6- methoxy-n-propyl-amino-carbonyl6- dimethylamino-carbonyl6- 4-ethoxyphenyl-amino-carbonyl6- n-propylamino-carbonyl6- cyclohexyl-amino-carbonyl6- 3-methoxy-benzyl-amino-carbonyl and 6- cyclopentyl-amino-methyl.

In another embodiment of the present invention, R 1 is selected from the group consisting of 6- bromo6- hydroxymethyl6- benzo[d][1,3]dioxolyl6- pyridyl6- 4-methylphenyl6- 3,4-dimethoxyphenyl6- 3,4-difluorophenyl6- 4-trifluoromethyl-phenyl6- 4-hydroxyphenyl6- 2-fluorophenyl6- 3,5-dichlorophenyl6- 3,4-dimethoxyphenyl-amino-carbonyl6- cyclopentyl-amino-carbonyl6- 4-fluorophenyl-amino-carbonyl6- n-butyl-amino-carbonyl6- methoxy-n-propyl-amino-carbonyl6- dimethylamino-carbonyl6- 4-ethoxyphenyl-amino-carbonyl6- n-propylamino-carbonyl6- cyclohexyl-amino-carbonyl6- 3-methoxy-benzyl-amino-carbonyl and 6- cyclopentyl-amino-methyl.

In another embodiment of the present invention, R 1 is selected from the group consisting of 6- hydroxymethyl6- benzo[d][1,3]dioxolyl6- pyridyl6- 3,4-dimethoxyphenyl6- 3,4-difluorophenyl6- 4-hydroxyphenyl6- 2-fluorophenyl6- 3,4-dimethoxyphenyl-amino-carbonyl6- cyclopentyl-amino-carbonyl6- 4-fluorophenyl-amino-carbonyl6- n-butyl-amino-carbonyland 6- cyclopentyl-amino-methyl.

In another embodiment of the present invention, R 1 is selected from the group consisting of 2011 benzo[d][1,3]dioxolyl6- 20116- 4-hydroxyphenyl and 6- 3,4-dimethoxyphenyl-amino-carbonyl.

In an embodiment of the present invention, X is O. In another embodiment of the present invention, X is S. In an embodiment of the present invention, R 2 is selected from the group consisting of C alkyl, C alkynyl, —CH 2 -thienyl and —CH 2 -furyl.

In another embodiment of the present invention, R 2 is selected from the group consisting of C alkyl, C alkynyl, —CH 2 -thienyl and —CH 2 -furyl. In another embodiment of the present invention, R 2 is selected from the group consisting of ethyl, n-propynyl, —CH 2 – thienyl—CH 2 – thienyl and —CH 2 – furyl.

In another embodiment of the present invention, R 2 is selected from the group consisting of —CH 2 – thienyl and —CH 2 – furyl. In another embodiment of the present invention, R 2 is —CH 2 – thienyl.

Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein i. In another embodiment of the present invention is any single compound or subset of compounds selected from the representative compounds listed in Tables 1 and 2, below.

Representative compounds of the present invention are as listed in Tables 1 to 2, below. One skilled in the art will recognize that in the recitation of the bonding position of the R 1 a substituent group s to the.

For example, the notation 6- 3,4-dimethoxy-phenyl-amino-carbonyl shall denoted a 3,4-dimethoxy-phenyl-amino-carbonyl substituent, bound through the carbonyl portion, and bound at the 6-position of the.

For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and 28853ru. Preferably, the halogenated or fluorinated alkyl is —CF 3.

For example, C alkenyl radicals include ethenyl, n-propenyl, n-butenyl, and the like. For example, C alkynyl radicals include ethynyl, n-propynyl, n-butynyl, and the like. For dpp1, alkoxy radicals include methoxy, 28853ru, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, and the like.

Suitably examples include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and t-butoxy. Preferably, the halogenated or fluorinated alkoxy is —OCF 3. The 5 to 6 membered heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, and the like.

Preferred heteroaryl groups include, but are not limited to, furyl, thienyl, imidazolyl, thiazolyl, pyridyl and pyrimidinyl. Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers.

Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water i.

Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.

In an embodiment, the compound of formula I is prepared as an isolated form. In an embodiment, the compound of formula I is present as a substantially pure compound.

In an embodiment, the compound of formula I is present in a form which is substantially free of corresponding salt form s. One skilled in the art will recognize that wherein the present invention is directed to methods of prevention, a subject in need of thereof i.

Further, 2011 subject in need thereof may additionally be a subject preferably a mammal, more preferably a human who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition.

For example, the subject may be deemed at risk of developing a disorder, disease or condition and therefore in need of prevention or preventive treatment as a consequence of the subject’s medical history, including, but not limited to, family history, pre-disposition, co-existing comorbid disorders or conditions, genetic testing, and the like.

One skilled in the art will recognize that disorders mediated by DPP-1 include, but are not limited to. One skilled in the art will recognize that, where not otherwise specified, the reaction step s is performed under suitable conditions, according to known methods, to provide the desired product.

For example wherein two steps of a process recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.

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.

To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any range therein.

Examples of suitable solvents, bases, reaction temperatures, and other reaction parameters and components are provided in the detailed descriptions which follows herein. One skilled in the art will recognize that the listing of said examples is not intended, and should not be construed, as limiting in any way the invention set forth in the claims which follow thereafter.

Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like. Other suitable nitrogen protecting groups may be found in texts such as T. Other suitable oxygen protecting groups may be found in texts such as T.

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.

Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography.

The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.

Alternatively, the compounds may be resolved using a chiral HPLC column. The enantiomeric excess may be calculated as follows. The enantiomeric excess may alternatively be calculated from the specific rotations of the desired enantiomer and the prepared mixture as follows:.

This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistryed. McOmie, Plenum Press, ; and T. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e. Thus, representative pharmaceutically acceptable salts include, but are not limited to, the following: Representative acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: Representative bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the 28853ru The present invention includes within its scope prodrugs of the compounds of this invention.

In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Accordingly, a suitably substituted compound of formula Vwherein PG 1 is a suitably selected nitrogen protecting group such as —C O CF 3Boc, CBz, and the like, a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula IVwherein PG 0 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 EDC, 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 VII.

The compound of formula VII is selectively de-protected according to known methods; to yield the corresponding compound of formula VIII. The compound of formula VIII is reacted with a suitably substituted compound of formula IXa 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 dpp1 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 Vwherein 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 IIwherein 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 dpp1 yield the corresponding compound of formula Ic.

Xbox 360 dpp1 5 28853ru 03 07 2011 que hay comer

In strainthe absence of hfq generates a. Other examples of Thyroiditis are silent lymphocytic thyroiditis, Hashimoto’s thyroiditis, or subacute granulomatous thyroiditis. The reasons for this discrepancy are. The control elements or regulatory sequences are those non-translated regions of the vector – enhancers, promoters, 5′ and 3′ untranslated regions — which interact with host cellular proteins to carry out transcription and translation. 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. Any recognized modeling method may be used, including parameterized models specific to particular biopolymers such as proteins or nucleic acids, molecular dynamics models based on computing molecular motions, statistical mechanics models based on thermal ensembles, or combined models.

Full dpp1 5 28853ru 03 07 2011 juegos

Ibadan — The decision of the management of The Polytechnic Ibadan to re-open the institution after over two months strike is causing confusion among leadership of trade unions in all the six Oyo State owned tertiary institutions.

Workers in the six institutions namely; The Polytechnic Ibadan, Ibadan: DPP and PT is still on till futher notice Coke center South Campus: Royal Shawama canteen , orisun hostel.

This is to inform interested candidates that the long awaited HND form is out. Interested applicants can now proceed by visiting the school websites to obtain the form.

Local Government Studies Marketing. However, We heard your voices and the stress you are going through concerning your course form and we Now these are what we discovered and solution we agreed on with the management; 1.

The course form makes it difficult for them to complete their registration which will affect their result processing. This could lead to data loss The resulting homogenous mixture was stirred for 3 h, then concentrated to a solid.

The solid was dissolved in dichloromethane 20 mL , the resulting solution was cooled in an ice bath, then treated with diisopropylethylamine 0. The resulting mixture was stirred overnight at room temperature, then diluted with dichloromethane, washed with water, washed with brine, dried over sodium sulfate, filtered and concentrated to yield 2-bromo-N- 3,4-dimethoxyphenyl benzo[d]thiazolecarboxamide as a brown solid.

A mixture of 2-bromo-N- 3,4-dimethoxyphenyl benzo[d]thiazolecarboxamide The organic layer was washed with water, dried sodium sulfate , filtered and concentrated in vacuo.

The resulting mixture was stirred for 2 h and a solid separated from the solution. The solid was collected by filtration, washed with 1,4-dioxane, then dried in vacuum oven for 2d at room temperature to yield the hydrochloride salt of N- 3,4-dimethoxyphenyl 2- methylamino ethylamino benzo[d]thiazolecarboxamide as a yellow solid.

N- 3,4-dimethoxyphenyl 2- methylamino ethylamino benzo[d]thiazolecarboxamide After 18 h, water was added and a solid separated, which solid was collected by filtration. The solid was then washed with additional water and dried under house vacuum.

S -tert-Butyl 1- 2- 6- 3,4-dimethoxyphenylcarbamoyl benzo[d]thiazolylamino ethyl methyl amino oxo thiophenyl propanylcarbamate The free base was dissolved in chloroform 3 mL and treated with 1N hydrogen chloride in diethyl ether 0.

The separated solid was covered with diethyl ether, collected by filtration and dried in vacuum oven to yield the title compound as an off-white solid. After 18 h, the resulting mixture was diluted with chloroform and washed with water.

S -tert-butyl 1- 4- benzo[d]oxazolyl piperazinyl oxo thiophenyl propanylcarbamate The resulting mixture was stirred at room temperature for 3 h, then additional 4N HCl in 1,4-dioxane 1 mL was added and the resulting mixture stirred for 18 h.

The resulting solid was collected by decantation, washed with 1,4-dioxane, and purified by recrystallization from an isopropanol-diethyl ether mixture to yield the title compound as an off-white solid.

The resulting mixture was diluted with water and the solid separated from the solution. The resulting homogenous mixture was stirred for 30 min, then diluted with diethyl ether and cooled in ice bath.

The resulting solid was collected by filtration and dried in vacuum oven at room temperature to yield N- 3,4-dimethoxyphenyl piperazinyl benzo[d]thiazolecarboxamide as a khaki colored amorphous solid.

N- 3,4-dimethoxyphenyl piperazinyl benzo[d]thiazolecarboxamide After 18 h, water was added and a solid separated, which was collected by filtration. The S -tert-butyl 1- 4- 6- 3,4-dimethoxyphenylcarbamoyl benzo[d]thiazolyl piperazinyl oxobutanylcarbamate The resulting heterogenous mixture was concentrated under high vacuum, then covered with diethyl ether and placed under high vacuum for 2d to yield the title compound as a pale yellow powder.

N- 3,4-dimethoxyphenyl piperazinyl benzo[d]thiazolecarboxamide 1. S -tert-butyl 1- 4- 6- 3,4-dimethoxyphenylcarbamoyl benzo[d]thiazolyl piperazinyl oxo thiophenyl propanylcarbamate 0.

The resulting mixture was stirred at room temperature overnight. The resulting solid was filtered and treated with 4M HCl in 1,4-dioxane 2 ml , again stirring overnight.

The solid was filtered, dissolved in dichloromethane and washed with saturated NaHCO 3 to yield the title compound as its corresponding free base. The free base residue 0.

Then, 2M trimethylsilyl diazomethane 2. The resulting mixture was warmed to room temperature and stirred at room temperature for 2 hrs. The resulting mixture was concentrated in vacuo to yield methyl 2-bromobenzo[d]thiazolecarboxylate.

The resulting mixture was then cooled to room temperature, concentrated in vacuo to approximately 2 ml, diluted with water and extracted with ethyl acetate. The resulting mixture was concentrated in vacuo, the resulting residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate to yield methyl 2- piperazinyl benzo[d]thiazolecarboxylate.

Methyl 2- piperazinyl benzo[d]thiazolecarboxylate 0. S -methyl 2- 4- 2- tert-butoxycarbonylamino thiophenyl propanoyl piperazinyl benzo[d]thiazolecarboxylate 0. The organic layer was dried MgSO 4 and concentrated in vacuo to yield S 4- 2- tert-butoxycarbonylamino thiophenyl propanoyl piperazinyl benzo[d]thiazolecarboxylic acid.

S 4- 2- tert-Butoxycarbonylamino thiophenyl propanoyl piperazinyl benzo[d]thiazolecarboxylic acid 0. The following compounds were similarly prepared according to the process described in Example 9 above, by selecting and substituting a suitably substituted reagent for the cyclopentylamine in STEP E.

To the resulting deep green solution was added tert-butylnitrite 7. The resulting yellow solution was concentrated to yield ethyl 2-bromobenzo[d]thiazolecarboxylate as a yellow solid.

The ethyl 2-bromobenzo[d]thiazolecarboxylate The resulting mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The ethyl 2- 4- tert-butoxycarbonyl piperazinyl benzo[d]thiazolecarboxylate 1.

The resulting mixture was stirred overnight at room temperature, then heated to reflux for 24 hours. Saturated aqueous sodium bicarbonate was added and the resulting mixture was extracted with ethyl acetate.

The resulting solution was concentrated to yield tert-butyl 4- 6- hydroxymethyl benzo[d]thiazolyl piperazinecarboxylate as a white solid 1. The tert-butyl 4- 6- hydroxymethyl benzo[d]thiazolyl piperazinecarboxylate 1.

After four hours, the resulting mixture was concentrated to yield 2- piperazinyl benzo[d]thiazolyl methanol as a yellow oil 0. BocAlanine- 2-thienyl -OH 0. The S -tert-butyl 1- 4- 6- hydroxymethyl benzo[d]thiazolyl piperazinyl oxo thiophenyl propanylcarbamate 83 mg was dissolved in dry 1,4-dioxane 3 mL and HCl 4N in 1,4-dioxane, 1 mL was added.

The resulting solution was stirred overnight at room temperature, then concentrated to a white solid. The solid was chromatographed S -tert-butyl 1- 4- 6- hydroxymethyl benzo[d]thiazolyl piperazinyl oxo thiophenyl propanylcarbamate 0.

The resulting mixture was diluted with saturated aqueous sodium bicarbonate and then extracted with DCM. S -tert-Butyl 1- 4- 6-formylbenzo[d]thiazolyl piperazinyl oxo thiophenyl propanylcarbamate 45 mg , cyclopentylamine 12 mg , and sodium triacetoxyborohydride 29 mg were combined in DCM 1 mL , and the resulting mixture stirred at room temperature overnight, then heated to reflux for 24 hours.

S -tert-Butyl 1- 4- 6- cyclopentylamino methyl benzo[d]thiazolyl piperazinyl oxo thiophenyl propanylcarbamate 20 mg was dissolved in dry 1,4-dioxane 2 ml and HCl 4N in 1,4-dioxane.

The resulting mixture was stirred overnight at room temperature, then concentrated and chromatographed The resulting white precipitate was collected and dried to yield the title compound.

BocAlanine- 2-thienyl -OH 1. The resulting mixture was stirred for 15 min at room temperature, then 6-bromo piperazinyl benzo[d]thiazole 1. The resulting mixture was stirred at room temperature overnight, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate.

The combined organic extracts were washed twice with brine and concentrated to yield a brown oil. S -tert-Butyl 1- 4- 6-bromobenzo[d]thiazolyl piperazinyl oxo thiophenyl propanylcarbamate 80 mg , 4- trifluoromethyl phenylboronic acid 33 mg , palladium tetrakistriphenylphosphine 8 mg , and potassium carbonate 54 mg were combined in 1,4-dioxane 5 mL and water 1 mL.

The S -tert-butyl 1-oxo thiophenyl 4- 6- 4- trifluoromethyl phenyl benzo[d]thiazolyl piperazinyl propanylcarbamate 96 mg was dissolved in dry 1,4-dioxane 3 mL and then HCl 4N in 1,4-dioxane, 1 mL was added.

The resulting mixture was stirred at room temperature overnight, then concentrated and chromatographed The resulting white precipitate was collected by filtration to yield the title compound.

The following compounds were similarly prepared according to the process described in Example 12 above, by selecting and substituting a suitably substituted reagent for the boronic acid in STEP C.

The amount of amino-methylcoumarin released is proportional to the DPP-1 activity, and the reaction is monitored kinetically with a Molecular Devices plate reader using black well plates. All compounds were tested under room temperature conditions.

Additions to a well black Costar plates were as follows: Fluorescent reactions were monitored kinetically at nm excitation, nm emission on a Molecular Devices Spectramax XPS reader. The Softmax Pro software of the reader determined the initial velocity of the selected data the first minutes of the reaction , and the best linear regression fit of the initial kinetic data.

Final assay conditions were 0. Initial velocity rates were plotted vs. Representative compounds of the present invention were tested according to the procedure as described above, with results as listed in Table 3, below.

Where a compound was tested according to the above procedure multiple times, the average value is listed in Table 3, below. As a specific embodiment of an oral composition, mg of the Compound 3, prepared as in Example 8, is formulated with sufficient finely divided lactose to provide a total amount of to mg to fill a size 0 hard gel capsule.

A SumoBrain Solutions Company. Search Expert Search Quick Search. The present invention is directed to substituted benzothiazole and benzoxazole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by DPP Click for automatic bibliography generation.

A compound as in claim 4, wherein a is an integer from 0 to 1; R 1 is selected from the group consisting of 6- bromo , 6- hydroxymethyl , 6- benzo[d][1,3]dioxolyl , 6- pyridyl , 6- 4-methylphenyl , 6- 3,4-dimethoxyphenyl , 6- 3,4-difluorophenyl , 6- 4-trifluoromethyl-phenyl , 6- 4-hydroxyphenyl , 6- 2-fluorophenyl , 6- 3,5-dichlorophenyl , 6- 3,4-dimethoxyphenyl-amino-carbonyl , 6- cyclopentyl-amino-carbonyl , 6- 4-fluorophenyl-amino-carbonyl , 6- n-butyl-amino-carbonyl , 6- methoxy-n-propyl-amino-carbonyl , 6- dimethylamino-carbonyl , 6- 4-ethoxyphenyl-amino-carbonyl , 6- n-propylamino-carbonyl , 6- cyclohexyl-amino-carbonyl , 6- 3-methoxy-benzyl-amino-carbonyl and 6- cyclopentyl-amino-methyl ; X is selected from the group consisting of O and S; L is selected from the group consisting of —NH—CH 2 CH 2 —NH—, —NH—CH 2 CH 2 —N CH 3 — and R 2 is selected from the group consisting of —CH 2 – thienyl and —CH 2 – furyl ; or a pharmaceutically acceptable salt thereof.

A compound as in claim 5, wherein a is an integer from 0 to 1; R 1 is selected from the group consisting of 6- hydroxymethyl , 6- benzo[d][1,3]dioxolyl , 6- pyridyl , 6- 3,4-dimethoxyphenyl , 6- 3,4-difluorophenyl , 6- 4-hydroxyphenyl , 6- 2-fluorophenyl , 6- 3,4-dimethoxyphenyl-amino-carbonyl , 6- cyclopentyl-amino-carbonyl , 6- 4-fluorophenyl-amino-carbonyl , 6- n-butyl-amino-carbonyl , and 6- cyclopentyl-amino-methyl ; X is selected from the group consisting of O and S; L is selected from the group consisting of —NH—CH 2 CH 2 —NH—, —NH—CH 2 CH 2 —N CH 3 — and R 2 is —CH 2 – thienyl ; or a pharmaceutically acceptable salt thereof.

A compound as in claim 6, wherein a is 1; R 1 is selected from the group consisting of 6- benzo[d][1,3]dioxolyl , 6- pyridyl , 6- 4-hydroxyphenyl and 6- 3,4-dimethoxyphenyl-amino-carbonyl ; X is S; L is selected from the group consisting of —NH—CH 2 CH 2 —N CH 3 — and R 2 is —CH 2 – thienyl ; or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier. A method of treating a disorder mediated by DPP-1 comprising administering to a subject in need thereof a therapeutically effective amount of a compound as in claim 1.

The method of claim 11, wherein the disorder mediated by DPP-1 is selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism.

A method of treating rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, or abdominal aortic aneurism in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of claim 8.

A method of 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 comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1.

The use of a compound as in claim 1 for the preparation of a medicament for treating: The use of a compound as in claim 1, 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.

In another embodiment of the present invention, R 1 is selected from the group consisting of 6- benzo[d][1,3]dioxolyl , 6- pyridyl , 6- 4-hydroxyphenyl and 6- 3,4-dimethoxyphenyl-amino-carbonyl ; In an embodiment of the present invention, X is O.

One skilled in the art will recognize that in the recitation of the bonding position of the R 1 a substituent group s to the core of the compounds of formula I including in Tables 1 and 2, below , the position of R 1 a substituent group s shall be denoted according to the following numbering scheme: For example, the notation 6- 3,4-dimethoxy-phenyl-amino-carbonyl shall denoted a 3,4-dimethoxy-phenyl-amino-carbonyl substituent, bound through the carbonyl portion, and bound at the 6-position of the core.

One skilled in the art will recognize that disorders mediated by DPP-1 include, but are not limited to a disorders of the respiratory tract: The enantiomeric excess may alternatively be calculated from the specific rotations of the desired enantiomer and the prepared mixture as follows: Compounds of formula I wherein L is may be prepared according to the process outlined in Scheme 4, below.

Example 11 Compound 21 S amino 4- 6- cyclopentylamino methyl benzo[d]thiazolyl piperazinyl thiophenyl propanone STEP A: Example 12 Compound 14 S amino thiophenyl 4- 6- 4- trifluoromethyl phenyl benzo[d]thiazolyl piperazinyl propanone STEP A: Method of determining a dosage of anti-oxidant for an individual.

Stabilized and preserved ketotifen ophth almic compositions. Arrows point to the growth stage in which cells were. The overlap of positively Hfq-controlled. A remarkable finding was that of the phage protein p, as one.

However, neither p nor other phage. So, this mobile element could be specific of S. The cobalamine-dependent ribonucleotide reductase NrdJ. SMc , directly involved in the biosynthesis of cobalamine.

As the biosynthesis of cobalamine is essential for the symbiosis. The SMc protein was quantified among the strongest. SMc encodes a hypothetical protein with six DUF Interestingly, SMc was found.

Structural proteins of the S. In the insoluble fraction. In agreement with our observations,. These results suggest a. In turn, the reduced motility of hfq mutant cells derived.

SMc , 3 proteins shared with Torres-Quesada et al. Thus, our quantitative proteomic analysis. As observed for proteins positively regulated by Hfq, the degree. N-labeled proteins in this study. It cannot be discarded that some of the observed changes in the.

A Representative Venn diagram of identified. B Functional distribution of positively Hfq-regulated proteins. However, for the two. AniA and FrcR , we found that also one of the proteins under.

SMc [51] were upregulated ca. Hfq-dependent riboregulation of mRNAs encoding transcriptional. Several components of ABC transport systems possibly involved. Table S2 , confirming the strong influence of Hfq on the flow of.

These findings point to the existence of. Hfq-dependent sRNAs in S. GcvB and RybB homolog genes seem to be confined to. However, neither Dpp, Opp or Aap components have been.

Hfq-dependent riboregulation imposed to multiple oligopeptide. In order to get an in vivo correlation with the observed. This herbicidal and antibiotic. Strain 20PS01 showed an increased sensitivity to Bialaphos.

Most probably, the increased sensitivity to. Bialaphos could be explained by the overexpression of oligopep-. In addition, the hfq mutant. As for Bialaphos, this.

It is worth pointing out that. In this related a -proteobacterium, a number of spontaneous. Strikingly, 12 independent spontaneous mutants that regained. On the other hand, our analysis identified and quantified a.

Among these, only PotF SMc has been. None of these proteins or putative polyamine. Altogether, our quantitative proteomic analysis revealed a. On the other hand, the.

SMc remained unaltered in the hfq mutant. Other enzymes with the same biological function,. Nevertheless, this deficiency would be complemented. The nitrogen assimilatory activity of glutamine.

The GS activity in complex. TY medium was not affected by the hfq deletion Table 1. Despite the fact that GlnAI levels remained. The accumulation of these proteins were.

The hfq mutant presented a higher. The accumulation of this ABC transport system would. In order to discard an increased sensitivity of the hfq mutant to FU rather than a more pronounced accumulation of the chemical,.

Among the differentially expressed proteins identified in the hfq. Notably, the putative iron-storage bacterioferritin. Bfr or SMc of S. Bfr was downregulated in. The reasons for this discrepancy are.

Bacterioferritins have an important role in the. The intracellular iron content of the D hfq strain was. This 9-fold increment in the cellular iron content could be. Bialaphos and sodium glufosinate sensitivity assay.

In both cases, bacterial growth was estimated by OD. N , wild type strain ; , D hfq. Data represent the growth measured for each S. The experiment was repeated. The chemical structure of both chemicals is shown within each panel.

Glutamine synthetase activity of an S. Different letters indicate statistically significant differences. Similar results were reported for S. Thus, the higher sensitivity to oxidative stress in the.

Figures 3 and 4 , we cannot rule out that the higher sensitivity of. However, the observed phenotypes Figures 3, 4, 5. Considering that the iron concentration in the growth medium.

Under iron sufficient conditions,. Thus, we studied the production of secreted iron-chelating. As expected, both strains responded. However, in the absence of hfq , more.

A Schematic representation of the chromosomal S. The arrows indicate possible transcription start sites J. B Bacterial growth was. Values represent the relative growth of S.

The experiment was repeated twice with similar results. The chemical structure of the uracil.