Showing posts with label sweden. Show all posts
Showing posts with label sweden. Show all posts

Thursday 2 April 2015

Rosa canina for osteoarthritis

Rosiflex contains a unique natural supplement that is good for joint health. If you are looking forward to a natural way to minimize your joint pain and stiffness, then Rosiflex is the ideal choice for you. Rosiflex is for anyone who wants healthy, flexible and mobile joints for a better quality of life. The unique natural ingredient in Rosiflex has been clinically proven to soothe the inflamed joints and improve joint comfort and flexibility.
What is Rosiflex?
Rosiflex is a Unique Dietary Supplement containing 100% Rosehip powder, made from a species of wild rose, Rosa canina. Rosiflex is available in capsule form with each capsule containing 750 mg (of imported) rosehip powder. Rosehip powder has been shown to decrease joint pain, improve joint health and increase mobility and flexibility in arthritic patients, particularly osteoarthritic patients.

The speciality of Rosiflex is as given below:
  • European supplement now brought to Indian arthritic patients
  • Huge success internationally
  • Effective within 3 weeks
  • Good pain relief
  • Reduces the need for regular pain killers
  • Very Safe, being a herbal supplement
  • Dosage: 2 capsules thrice daily for the initial 3 weeks followed by maintenance dose of 2 capsules twice daily
  • Rosa canina
    Divlja ruza cvijet 270508.jpg
    Photograph showing Rosa canina flowers.
    Scientific classification
    Kingdom:Plantae
    (unranked):Angiosperms
    (unranked):Eudicots
    (unranked):Rosids
    Order:Rosales
    Family:Rosaceae
    Genus:Rosa
    Species:R. canina
    Binomial name
    Rosa canina
    L.
    Synonyms
    See text

History:
Click here for a larger image. ROSE HIPS
Rose Hips (also called rose haws) are the pomaceous fruit of the rose plant.  Roses are a group of herbaceous shrubs found in temperate regions throughout both hemispheres and grown in sunny areas or light shade and thrive in well-drained, slightly acid soil.  Probably cultivated first in ancient Persia and carried to Greece and Rome, there are now hundreds of species of this beautiful flower cultivated throughout the world that occupy a vital place in medicine, as well as cosmetics, perfumes, soaps and foods.  The leaves of Rosa canina were once even used as a substitute for tea.  The botanical genus, Rosa, is derived from the Greek, roden, meaning "red" and the Latin, ruber, also meaning "ruby" or "red," as apparently, the Roses of the ancient Mediterranean region were deep crimson, giving birth to the legend that the flowers sprang from the blood of Adonis.
Roses have a long tradition of medicinal use.  The ancient Romans used Rosa canina (or Dog Rose) for the bites of rabid dogs, and in the first century A.D., the Roman, Pliny, recorded thirty-two different disorders that responded well to Rose preparations.  An oriental species (Rosa laevigata) was mentioned in Chinese medical literature about A.D. 470, and in China, Rose Hips are still used for chronic diarrhea with stomach weakness.
It is typically red to orange but may be dark purple to black in some species.  In Ayurvedic medicine, Roses have long been considered "cooling" to the body and a tonic for the mind, and Native Americans used Rose Hips to treat muscle cramps.  In 1652, the esteemed British herbalist, Nicholas Culpeper, prescribed them for "consumptive persons," for "tickling rheums," to "break the stone" (kidneys) and to help digestion.
Long used for medicinal purposes in Great Britain, Rose Hips remained listed in the official British Pharmacopœia well into the 1930s, and were considered an overall cooling tonic, an astringent, a great help for sore throats and a source of the essential vitamin C.  During World War II, there was a shortage of citrus fruit in England, and the British government organized the harvesting of all the Rose Hips in England as a substitute for vitamin C.  This illuminated the importance of Rose Hips as a superior source of the vitamin and began its worldwide popularity.  Rose Hips have a reported sixty times the amount of vitamin C than citrus fruit, and we now know how absolutely essential vitamin C is to the maintenance of good health and the prevention of many diseases.
Rose Hips contain one of the highest measures of vitamin C (about 1700-2000 mgs. per 100 g. in the dried product) than is known in other herbs.  Rose Hips are the fruits of the Rose, the ripe seed receptacles that remain after the petals are removed, and they contain many vitamins and other beneficial supplements, including lycopene, essential fatty acids, beta-carotene, bioflavonoids, pectin, sugar, resin, wax, malates, citrates and other salts, tannin, malic and citrus acids, magnesium, calcium, iron, manganese, sulfur, phosphorus, potassium, selenium, zinc and vitamins A, B-1, B-2, B-3, B-5, C, D, E and K.
Beneficial Uses:
Probably the greatest known use of Rose Hips is as an extraordinary and powerful source of vitamin C, which is most beneficial for the prevention and treatment of infection and a great many common diseases, including the common cold, flu and pneumonia.  It is said to prevent ailments before they happen by using a prophylactic dosage on a daily basis.  Vitamin C is necessary for every cell in our bodies and without it, we would not be able to sustain life.
Natural vitamin C and bioflavonoids are combined in nature, and for efficacy, it is vital that they be used together. Rose Hips are rich in both, and together they help to strengthen body tissues and build and maintain a healthy vascular system and are said to heal and prevent damage to fragile capillaries.  The combination is also thought to enhance the body's ability to absorb vitamin C in those who have difficulty absorbing it.
Rose Hips, with its abundance of vitamin C, are useful in treating infections of all kinds and have been used for centuries for the relief of diarrhea and dysentery.  It is considered to be a cleansing agent and may be helpful for temporary bladder problems, gallbladder dysfunction, kidney health, general debility and exhaustion.
Current research indicates that large doses of vitamin C in Rose Hips could be helpful in enhancing our immune systems, which may be valuable in warding off infectious invaders and serious malignant disease.
Rose Hips are said to have mild laxative and diuretic properties.
Rosa canina, commonly known as the dog-rose,[1] is a variable climbing wild rose species native to Europe, northwest Africa and western Asia.
It is a deciduous shrub normally ranging in height from 1–5 m, though sometimes it can scramble higher into the crowns of taller trees. Its stems are covered with small, sharp, hooked prickles, which aid it in climbing. The leaves are pinnate, with 5-7 leaflets. The flowers are usually pale pink, but can vary between a deep pink and white. They are 4–6 cm diameter with five petals, and mature into an oval 1.5–2 cm red-orange fruit, or hip.
dried-rose-hipsIt’s that time of year again and the hedgerows are heaving with fruit. But with most people intent on collecting juicy blackberries, the vibrantly coloured and perhaps mystifying rose-hip is often overlooked. Maybe it’s because they are a suspicious red colour or maybe it’s because they’re a fruit that’s never seen in supermarkets. Whatever the reason, the conclusion is the same: there’s more to collect for yourself!
Rose-hips are the fruit of the rose bush and in the summer are found as a swollen green part of the stem just underneath the flower. Every rose left uncut will eventually produce a hip but some will appear in the summer and others later in the autumn depending on species. To my knowledge all rose hips are edible, though some varieties have better flavour than others.
Blessed with a delicate fruity taste and rich in vitamins A, B and C, Rose-hips can be used to make an assortment of products including jellies, syrups, teas, wine and even cosmetics. Both the fruit and the seeds are edible but you should not eat rose-hips whole due to irritating hairs which are found inside the berries. These hairs must be removed either by filtering during the cooking process.
The best variety for making edible products is the hip of the common wild rose, also known as the Dog Rose, Latin name Rosa Canina. It produces small, firm, deep-red hips that are rich in flavour and easy to find and harvest. They are available in the autumn but it’s said the best time to harvest them is directly after a frost. Being that birds favour other foods over these hard seed-laden hips, you can often find them hanging onto bare branches in the darkest days of winter. If you choose to use them to make edible products please know that it’s not necessary to separate the seeds from the red fruit as both have their own nutritious values. But of course beware the hairs mentioned previously and make sure they are excluded from your end product.
Dog-Rose-Hips

Synonyms

From DNA analysis using amplified fragment length polymorphisms of wild-rose samples from a transect across Europe (900 samples from section Caninae, and 200 from other sections), it has been suggested that the following named species are best considered as part of a single Rosa canina species complex, and are therefore synonyms of R. canina:[2]
  • R. balsamica Besser
  • R. caesia Sm.
  • R. corymbifera Borkh.
  • R. dumalis Bechst.
  • R. montana Chaix
  • R. stylosa Desv.
  • R. subcanina (Christ) Vuk.
  • R. subcollina (Christ) Vuk.
  • R. × irregularis Déségl. & Guillon

Cultivation and uses


A botanical illustration showing the various stages of growth by Otto Wilhelm Thomé
The plant is high in certain antioxidants. The fruit is noted for its high vitamin C level and is used to make syrup, tea and marmalade. It has been grown or encouraged in the wild for the production of vitamin C, from its fruit (often as rose-hip syrup), especially during conditions of scarcity or during wartime. The species has also been introduced to other temperate latitudes. During World War II in the United States Rosa canina was planted in victory gardens, and can still be found growing throughout the United States, including roadsides, and in wet, sandy areas up and down coastlines. In Bulgaria, where it grows in abundance, the hips are used to make a sweet wine, as well as tea. In the traditional Austrian medicine Rosa canina fruits have been used internally as tea for treatment of viral infections and disorders of the kidneys and urinary tract.[3]
Forms of this plant are sometimes used as stocks for the grafting or budding of cultivated varieties. The wild plant is planted as a nurse or cover crop, or stabilising plant in land reclamation and specialised landscaping schemes.
Numerous cultivars have been named, though few are common in cultivation. The cultivar Rosa canina 'Assisiensis' is the only dog rose without prickles. The hips are used as a flavouring in Cockta, a soft drink made in Slovenia.

Canina meiosis


A tall, climbing Rosa canina shrub

Rose hips

Rose bedeguar gall on a dog rose
The dog roses, the Canina section of the genus Rosa (20-30 species and subspecies, which occur mostly in Northern and Central Europe), have an unusual kind of meiosis that is sometimes called permanent odd polyploidy, although it can occur with even polyploidy (e.g. in tetraploids or hexaploids). Regardless of ploidy level, only seven bivalents are formed leaving the other chromosomes as univalents. Univalents are included in egg cells, but not in pollen.[4][5] Similar processes occur in some other organisms.[6] Dogroses are most commonly pentaploid, i.e. five times the base number of seven chromosomes for the genus Rosa, but may be tetraploid or hexaploid as well.

Names and etymology

The botanical name is derived from the common names 'dog rose' or similar in several European languages, including classical Latin and ancient (Hellenistic period) Greek.
It is sometimes considered that the word 'dog' has a disparaging meaning in this context, indicating 'worthless' (by comparison with cultivated garden roses) (Vedel & Lange 1960). However it also known that it was used in the eighteenth and nineteenth centuries to treat the bite of rabid dogs, hence the name "dog rose" may result from this[7] (though it seems just as plausible that the name gave rise to the treatment).
Other old folk names include dogberry and witches' briar.[citation needed]

Invasive species

Dog rose is an invasive species in the high country of New Zealand. It was recognised as displacing native vegetation as early as 1895[8] although the Department of Conservation does not consider it to be a conservation threat.[9]

Dog rose in culture

The dog rose was the stylized rose of medieval European heraldry, and is still used today.[citation needed] It is also the county flower of Hampshire.[10] Legend states the Thousand-year Rose or Hildesheim Rose, that climbs against a wall of Hildesheim Cathedral dates back to the establishment of the diocese in 815.[11]

Rose hip, rose hip and seed and rose hip seed, all were negatively monographed by the German Commission E due to insufficient evidence of effects and effectiveness. Therefore a comprehensive review of the literature was conducted to summarize the pharmacological and clinical effects of Rosa canina L. to reevaluate its usefulness in traditional medicine. For various preparations of rose hip and rose hip and seed, antioxidative and antiinflammatory effects have been demonstrated. Lipophilic constituents are involved in those mechanisms of action. The proprietary rose hip and seed powder Litozin has been employed successfully in a number of exploratory studies in patients suffering from osteoarthritis, rheumatoid arthritis and low back pain. However, the sizes of the clinical effects for the different indications need to be determined to assure clinical significance. There is also a rationale behind the use of Litozin as part of a hypocaloric diet based on the rose hip probiotic, stool regulating and smooth muscle-relaxing actions, as well as the rose hip seed lipid-lowering, antiobese and antiulcerogenic effects. Further research is needed to clarify the importance of the reported promising experimental effects in clinical use and to characterize the optimum rose hip seed oil preparation for topical use in the treatment of skin diseases.
Rosiflex Discovery

Rosiflex Discovery

The Rosiflex™ story began in the early 1990s, when Erik Hansen, a farmer from Langeland, Denmark, discovered, quite by chance that rosehips from the Rosa Canina plant appeared to help soothe his aching joints.
Encouraged by this realisation, he developed the first of his rosehip powders. Made from rosehips grown on his own farm, he sold the powder to friends and neighbours after telling them of his own positive experiences.
The response from these early customers was so positive that Erik, and his son Torbjorn, decided to seek scientific verification of what they had found. They contacted scientists at the local hospital to see if they could find what it was in the rosehip that was producing the positive joint-health benefits being reported.
At first, the scientists were sceptical about the claimed benefits of the rosehip fruit - more commonly associated with teas and marmalades than with potential joint-health benefits. They did however agree to begin some scientific studies.
As the results of the testing began to emerge, the researchers became more and more convinced about the Langeland rosehip powder. Since then, several well designed scientific studies involving a couple of hundred people have been undertaken and published in recognised scientific journals.
 

Anti-inflammatory action of Rose hip

Rose hip is a typical daily food supplement traditionally used for its vitamin C content and other active principles to treat several discomforts: respiratory disorders, infectious diseases, gastrointestinal and urinary system illnesses and prophylaxis of vitamin C deficiencies. Rose hips have been eaten as jam or drunken as fruit tea for centuries. Therefore the separated Rose hip peels have always been regarded as everyday food.
In the last ten years it was scientifically documented, that the daily use of food containing rose hip fruits was positive to treat inflammatory joint diseases, in particular osteoarthritis. Several human studies with rose hip powder showed pain reducing properties and could also reduce symptoms such stiffness or even the need for additional medication.
However, the daily amount of 5 g over a period of 12 weeks showed moderate beneficial effects and low compliance demonstrating what the limits of a treatment with rose hip powder are.
Rose hip fruit skin powder contains remarkable active principles able to inhibit pro-inflammatory mediators and oxidative substances as well as enzymes responsible for the degradation of the organic matrix of joints and bones. A marked action on the inhibition of different cytokines has been observed as the interleukin 1β (IL-1β), the interleukin 6 (IL-6) and the alpha tumoral necrosis factor (TNF- α).
However herbal drug powders are usually not as stable and uniform as extracts. Using purification techniques and water as extraction solvent Finzelberg get a new extract, which compared with the rose hip drug powder is 7 fold stronger in their anti-inflammatory activity.

References

  1. ^ "BSBI List 2007" (xls). Botanical Society of Britain and Ireland. Retrieved 2014-10-17.
  2. ^ De Riek, Jan; De Cock, Katrien; Smulders, Marinus J.M.; Nybom, Hilde (2013). "AFLP-based population structure analysis as a means to validate the complex taxonomy of dogroses (Rosa section Caninae)". Molecular Phylogenetics and Evolution 67 (3): 547–59. doi:10.1016/j.ympev.2013.02.024. PMID 23499615.
  3. ^ Vogl, Sylvia; Picker, Paolo; Mihaly-Bison, Judit; Fakhrudin, Nanang; Atanasov, Atanas G.; Heiss, Elke H.; Wawrosch, Christoph; Reznicek, Gottfried; Dirsch, Verena M.; Saukel, Johannes; Kopp, Brigitte (2013). "Ethnopharmacological in vitro studies on Austria's folk medicine—An unexplored lore in vitro anti-inflammatory activities of 71 Austrian traditional herbal drugs". Journal of Ethnopharmacology 149 (3): 750–71. doi:10.1016/j.jep.2013.06.007. PMC 3791396. PMID 23770053.
  4. ^ Täckholm, Gunnar (1922) Zytologische Studien über die Gattung Rosa. Acta Horti Bergiani 7, 97-381.
  5. ^ Lim, K Y; Werlemark, G; Matyasek, R; Bringloe, J B; Sieber, V; El Mokadem, H; Meynet, J; Hemming, J; Leitch, A R; Roberts, A V (2005). "Evolutionary implications of permanent odd polyploidy in the stable sexual, pentaploid of Rosa canina L". Heredity 94 (5): 501–6. doi:10.1038/sj.hdy.6800648. PMID 15770234.
  6. ^ Stock, M.; Ustinova, J.; Betto-Colliard, C.; Schartl, M.; Moritz, C.; Perrin, N. (2011). "Simultaneous Mendelian and clonal genome transmission in a sexually reproducing, all-triploid vertebrate". Proceedings of the Royal Society B: Biological Sciences 279 (1732): 1293. doi:10.1098/rspb.2011.1738.
  7. ^ Howard, Michael. Traditional Folk Remedies (Century, 1987); p133
  8. ^ Kirk, T (1895). "The Displacement of Species in New Zealand". Transactions of the New Zealand Institute 1895 (Wellington: Royal Society of New Zealand) 28. Retrieved 2009-04-17.
  9. ^ Owen, S. J. (1997). Ecological weeds on conservation land in New Zealand: a database. Wellington: Department of Conservation.
  10. ^ "County Flowers | Wild plants". Plantlife. Retrieved 2012-02-04.
  11. ^ Lucy Gordan. "Hildesheim’s Medieval Church Treasures at the Met". Inside the Vatican. Archived from the original on 30 April 2014. Retrieved 30 April 2014.

Further reading

  • Flora Europaea: Rosa canina
  • Blamey, M. & Grey-Wilson, C. (1989). Flora of Britain and Northern Europe. Hodder & Stoughton. ISBN 0-340-40170-2.
  • Vedel, H. & Lange, J. (1960). Trees and bushes. Metheun, London.
  • Graham G.S. & Primavesi A.L. (1993). Roses of Great Britain and Ireland. B.S.B.I. Handbook No. 7. Botanical Society of the British Isles, London.

External links

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Contraindications:
As a natural diuretic, Rose Hips Herbal Supplement may increase the efficacy of prescription diuretics and should not be used at the same time.   Make sure your doctor knows if you are taking a blood thinner, such as Coumadin®.
Disclaimer:
The information presented herein by this post is intended for educational purposes only. These statements have not been evaluated by the FDA and are not intended to diagnose, cure, treat or prevent disease. Individual results may vary, and before using any supplements, it is always advisable to consult with your own health care provider.







SWEDEN
A golden medallion with an embossed image of Alfred Nobel facing left in profile. To the left of the man is the text
A black and white photo of a bearded man in his fifties sitting in a chair.
Alfred Nobel had the unpleasant surprise of reading his own obituary, titled The merchant of death is dead, in a French newspaper.
Map of sweden europe
Nyköping (Sweden)-houses.
Fjallbacka, a colorful fishing Village along the west coast of Sweden
Knights Island, Stockholm, Sweden
Stockholm, Sweden
Sweden Stockholm
Europe Örby Änger – Sweden
Despite the cold weather, public came and enjoyed different activities. The famous chef, Paul Svensson who works in one of the fanciest and most famous …

Tuesday 17 March 2015

GSK 2793660, Trying to crack the structure

GSK 2793660, Trying to crack the structure

WP_000289COMPD A
WP_000290COMPD B
CCOMPD C
DCOMPD D
Figure imgf000036_0001A
OR
Figure imgf000037_0001 B
or
Figure imgf000028_0001C
OR
Figure imgf000028_0002D
OUT OF 4 , ONE OF THEM IS GSK 2793660…………… EITHER A OR B OR C OR D,
EMAIL ME AT amcrasto@gmail.com
GSK 2793660
DATA FOR A
HCL SALT CAS 1613458-78-8
BASE CAS 1613458-70-0
C20 H27 N3 O3 . Cl H
MW OF BASE…..357.45
4-amino-N-[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten-l- yl]tetrahydr -2H-pyran-4-carboxamide hydrochloride
2H-​Pyran-​4-​carboxamide, 4-​amino-​N-​[(1S,​2E)​-​4-​(2,​3-​dihydro-​1H-​indol-​1-​yl)​-​1-​ethyl-​4-​oxo-​2-​buten-​1-​yl]​tetrahydro-​, hydrochloride (1:1)
DATA FOR B
1613458-79-9 HCL SALT
1613458-71-1 BASE
C22 H31 N3 O3 . Cl H
MW 385.50 OF BASE
4-amino-N-[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-(2-methylpropyl)-4-oxo-2-buten- l-yl]tetrahydro-2H-pyran-4-carboxamide hydrochloride 
4-Amino-N-[(2E,4S)-1-(2,3-dihydro-1H-indol-1-yl)-6-methyl-1-oxohept-2-en-4-yl]tetrahydro-2H-pyran-4-carboxamide hydrochloride
DATA FOR C
1-Amino-N-[(3S)-1-(3-cyano-4′-fluorobiphenyl-4-yl)pyrrolidin-3-yl]cyclohexanecarboxamide hydrochloride
l-amino-N-[(3S)-l-(3-cyano-4′-fluoro-4-biphenylyl)-3- pyrrolidin l] cyclohexanecarboxamide hydrochloride
C24 H27 F N4 O . Cl H,  MW 442.957
CAS OF BASE 1394001-73-0
CAS OF HCL 1394001-71-8
DATA FOR D
l-amino-N-[(3S)-l-(3-cyano-4′-fluoro-4-biphenylyl)-3- pyrrolidin l] cyclohexanecarboxamide hydrochloride
CAS OF BASE 1394001-74-1
CAS OF HCL 1394001-72-9
Cathepsin C inhibitors for treating cystic fibrosis, non-cystic fibrosis bronchiectasis, and ANCA-associated vasculitis
Bronchiectasis
Dipeptidyl peptidase I inhibitor
This study is the first administration of GSK2793660 to humans and will evaluate the safety, tolerability, PK and PD of single oral ascending doses of GSK2793660, and of repeat oral doses of GSK2793660 in healthy subjects. The study will comprise two parts (Part A and Part B). Part A will consist of two cohorts of subjects, each taking part in a three-way cross over study, with ascending doses of GSK2793660 and placebo. Available safety, PK and PD data will be reviewed before each dose escalation. This will be followed by a food-effect arm in the cohort that received what is deemed to be the target clinical dose. Part B is planned to consist of up to two cohorts of subjects, each taking part in one 14 day repeat dose study period. Subjects will be dosed on Day 1 and then on Days 3-15. It is planned that two doses will be evaluated. The dose(s) to be tested will be selected based on safety, PK, and PD from Part A. The study is intended to provide sufficient confidence in the safety profile of the molecule and information on target engagement to allow progression to further studies………..https://clinicaltrials.gov/ct2/show/NCT02058407
Cathepsin C inhibitors for treating cystic fibrosis, non-cystic fibrosis bronchiectasis, and ANCA-associated vasculitis
Cathepsins are a family of enzymes included in the papain superfamily of cysteine proteases. Cathepsins B, C, F, H, K, L, S, V, and X have been described in the scientific literature. Cathepsin C is also known in the literature as Dipeptidyl Peptidase I or “DPPI.”
A number of recently published studies have begun to describe the role cathepsin C plays in certain inflammatory processes. See e.g. Adkison et al., The Journal of Clinical Investigation 109:363-371 (2002); Tran et al., Archives of Biochemistry and Biophysics 403 : 160-170 (2002); Thiele et al., The Journal of Immunology 158: 5200-5210 (1997);
Bidere et al., The Journal of Biological Chemistry 277: 32339-32347 (2002); Mabee et al., The Journal of Immunology 160: 5880-5885 (1998); McGuire et al., The Journal of
Biological Chemistry, 268: 2458-2467 (1993); and Paris et al., FEBS Letters 369: 326-330 (1995). From these studies, it appears that cathepsin C is co-expressed in granules of neutrophils and other leukocytes with certain serine proteases and cathepsin C functions to process the pro-forms of the serine proteases to active forms. Serine proteases are released from the granules of leukocytes recruited to sites of inflammation. Once activated, these proteases have a number of functions including degradation of various extracellular matrix components, which together can propagate tissue damage and chronic inflammation.
Studies in both cathepsin C deficient mice, and the human cathepsin C deficiency
Papillon-Lefevre syndrome clearly demonstrate that cathepsin C is required for the
activation of the neutrophil serine proteases in azurophilic granules such as neutrophil elastase (NE), cathepsin G, and proteinase 3. See Pham, C. T. et al., J. Immunol. 173 :
7277-7281 (2004).
A number of respiratory diseases are associated with an overabundant
acculumation of neutrophils and the presence of increased levels of at least some
neutrophil serine proteases. These enzymes are believed to play a role in the pathology of several respiratory diseases, such as Chronic Obstructive Pulmonary Disease (“COPD”), cystic fibrosis (CF), and non-cystic fibrosis (non-CF) bronchiectasis. Each of these diseases is associated with increased levels of E in particular, and E at least is considered to play a role in the progression of disease. See Ranes, J. and Stoller, J. K., Semin. Respir. Crit. Care Med 26: 154-166 (2005); Saget, S. D. et al., Am. J. Resp. Crit. Care Med. 186: 857-865 (2012); Tsang, K. W. et al., Chest 117: 420-426 (2000).
Additional roles of the other proteases is emerging. See Hartl, D. et al., Nature Med. 13 : 1423-1430 (2007); Korkmaz, B. et al., Pharm. Rev. 62: 726-759 (2010).
Cigarette smoking is a significant risk factor for developing COPD. Exposure to cigarette smoke and other noxious particles and gases may result in chronic inflammation of the lung. In response to such exposure, inflammatory cells such as CD8+ T cells, macrophages, and neutrophils are recruited to the area. These recruited inflammatory cells release proteases, which are believed to play a major role in the disease etiology by a number of mechanisms. Proteases released from recruited cells include the serine proteases NE as above; granzymes A and B, released from cytotoxic T cells or natural killer cells; and chymases, released from mast cells. Cathepsin C appears to be involved in activating all of these enzymes to some extent.
A number of studies with cathepsin C deficient mice have suggested roles for cathepsin C in disease models. Cathepsin C knockout mice are resistant to lung airspace enlargement and inflammatory cell infiltration in both cigarette smoke and ozone exposure models of COPD. See Guay et al., Current Topics in Medicinal Chemistry, 2010, 10, 708- 716; See also Podolin et al. (2008), Inflammation Research, 57(Suppl 2) S104.
In a model of rheumatoid arthritis (“RA”), another chronic inflammatory disease where cathepsin C may play a role, neutrophils are recruited to the site of joint
inflammation and release cathepsin G, NE, and proteinase 3, which are believed to be responsible in part for cartilage destruction associated with RA (Hu, Y. and Pham, C. T. Arthritis Rheum. 52: 2553-2558 (2005); Zen, K. et al, Blood 117:4885-4894 (2011)). Other models where cathepsin C may play a role include osteoarthritis, asthma, Multiple Sclerosis, and Anti-Neutrophil Cytoplasmic Autoantibody (ANCA)-related diseases (e.g. ANCA-associated vasculitis). See e.g. Matsui, K., Yuyama, N., Akaiwa, M., Yoshida, N. L., Maeda, M., Sugita, Y., Izuhara, K., Gene 293(1-2): 1-7 (2002); Wolters, P. J., Laig- Webster, M., Caughey, G. H., American Journal of Respiratory Cell & Molecular Biology 22(2): 183-90 (2000); Schreiber et al., J. Am. Soc. Nephrol. 23 :470-482 (2012). Cathepsin C has been demonstrated to have a role in neutrophil migration in the development of aortic aneurysms by a mechanism which has not been clearly elucidated (Pagano, M. B. et al., PNAS 104: 2855-2860 (2007)).
One approach to treating these conditions is to inhibit the activity of the serine proteases involved in the inflammatory process, especially NE activity. See e.g.,
Ohbayashi, Expert Opin. Investig. Drugs 11(7): 965-980 (2002); Shapiro, Am. J. Respir. Cell Mol. Biol. 26: 266-268 (2002). Indeed, a potent and selective inhibitor of NE was found to improve lung function in patients with bronchiectasis (Stockley, R. et al. Respir. Med. 107, 524-533 (2013)). In light of the role cathepsin C plays in activating certain serine proteases, especially NE, it is desirable to prepare compounds that inhibit its activity, which thereby inhibit serine protease activity. Thus, there is a need to identify compounds that inhibit cathepsin C, which can be used in the treatment of a variety of conditions mediated by cathepsin C.
There are additional activities of cathepsin C that may also be related to disease etiology. Cathepsin C is highly expressed in the lung epithelium where it may play a role in the processing of other enzymes not yet identified. Cathepsin C has also been reported to cleave kallikrein-4, which is believed to play a role in dental enamel maturation (Tye, C. E. et al. J. Dental Res. 88: 323-327 (2009)). Finally, cathepsin C is itself released from cells and may play a direct role in the degradation of matrix proteins.
DATA FOR A
WO 2014091443
Figure imgf000004_0001
synthesis
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000030_0002
Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000036_0001
Intermediate 1
1,1-dimethylethyl ((l -l-{[methyl(methyloxy)amino]carbonyl}propyl)carbamate
Figure imgf000029_0001
To a solution of (2,S)-2-({[(l,l-dimethylethyl)oxy]carbonyl}amino)butanoic acid (2.50 g, 12.3 mmol) in THF (15.0 mL) was added Ι,Γ-carbonyldiimidazole (2.39 g, 14.8 mmol) portionwise over about 10 min. After stirring 30 min at RT, a solution of Ν,Ο- dimethylhydroxylamine hydrochloride (1.32 g, 13.5 mmol) and DIPEA (2.36 mL, 13.5 mmol) in DMF (4.0 mL) was added. The reaction mixture was stirred for 2 h at RT, followed by concentration in vacuo. The residue was diluted with EtOAc (50 mL) and washed with 1 M aq. HC1 (2 x 20 mL), saturated aq. NaHC03 (2 x 20 mL), and brine (20 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound (2.60 g, 88%) as a clear, colorless oil. LC-MS m/z 247 (M+H)+, 0.94 min (ret time).
Intermediate 2
1,1-dimethylethyl [(lS -l-formylpropyl] carbamate
Figure imgf000030_0001
To a solution of L1AIH4 (0.453 g, 11.9 mmol) in Et20 (20 mL) at 0 °C was added dropwise a solution of 1, 1-dimethylethyl ((l,S)-l-{[methyl(methyloxy)amino]carbonyl}- propyl)carbamate (2.67 g, 10.8 mmol) in Et20 (15 mL). The reaction mixture was stirred for 30 min at 0 °C and quenched with EtOAc (6.5 mL) followed by 5% aq. potassium bisulfate (6.5 mL). The reaction mixture was washed with 1 M aq. HC1 (3 x 10 mL), saturated aq. NaHC03 (3 x 10 mL), and brine (10 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound as a clear, colorless oil.
Intermediate 3
methyl (2E V)-4-({ [(1 , l-dimethylethyl)oxy] car bonyl} amino)-2-hexenoate
Figure imgf000030_0002
To a stirred solution of methyl (triphenylphosphoranylidene) acetate (4.35 g, 13.0 mmol) in Et20 (25 mL) at RT was added a solution of Intermediate 2 in Et20 (15 mL). The reaction mixture was stirred at RT overnight. The solid was removed by filtration and the solution was concentrated in vacuo. Purification via flash column chromatography (0-50% EtOAc/hexanes) afforded the title compound (1.44 g, 55% over two steps) as a clear, colorless oil. LC-MS m/z 244 (M+H)+, 0.98 min (ret time). Intermediate 4
(2E,4S)-4-({[(l,l-dimethylethyl)oxy]carbonyl}amino)-2-hexenoic acid
Figure imgf000031_0001
Li OH (2.95 g, 123 mmol) was added to a solution of methyl (2£, S 4-({[(1, 1- dimethylethyl)oxy]carbonyl}amino)-2-hexenoate (6 g, 24.66 mmol) in THF (50 mL), MeOH (10.00 mL), and water (50.0 mL). The reaction was stirred overnight at RT. After 18.5 h, the reaction mixture was concentrated under reduced pressure to remove the THF and MeOH. Water (40 mL) was added, and aqueous mixture was adjusted to pH = 3 with 6 M aq. HC1, as measured by pH paper. EtOAc (80 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over Na2S04, concentrated under reduced pressure, and dried under high vacuum, giving 6.09 g of the title compound. LC-MS m/z 230 (M+H)+, 0.77 min (ret time).
Intermediate 5
1,1-dimethylethyl [(lS,2E)-4-(2,3-dihydro-li -indol-l-yl)-l-ethyl-4-oxo-2-buten-l- yl] carbamate
Figure imgf000031_0002
A solution of 50 wt% *T3P in EtOAc (22.00 mL, 37.0 mmol) was added dropwise via addition funnel to a solution of (2£,,4,S)-4-({[(l, l-dimethylethyl)oxy]carbonyl}- amino)-2-hexenoic acid (5.65 g, 24.64 mmol), 2,3-dihydro-lH-indole (2.76 mL, 24.64 mmol), and Et3N (11 mL, 79 mmol) in CH2C12 (90 mL) at 0 °C (bath temp). The ice bath was removed, and the reaction was stirred at RT. After 30 min, the reaction was quenched by dropwise addition of saturated aq. NaHC03 (50 mL). The layers were separated, and the reaction was washed with 10% citric acid (1 x 50 mL). The organic layer was concentrated under a stream of nitrogen, and the residue was purified by flash column chromatography, giving 7.21 g (89%) of the title compound. LC-MS m/z 331 (M+H)+, 1.05 (ret time). Intermediate 6
[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten-l-yl]amine
trifluoroacetate
Figure imgf000032_0001
TFA (25 mL, 324 mmol) was added to a solution of 1, 1-dimethylethyl [(1^,2£)-4- (2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten-l-yl]carbamate (7.21 g, 21.82 mmol) in CH2C12(25 mL). The reaction was stirred at RT. After 3.5 h, CH2C12 (200 mL) was added, and the reaction was concentrated under reduced pressure and dried under high vacuum. LC-MS m/z 231 (M+H)+, 0.69 (ret time).
Intermediate 7
1,1-dimethylethyl [4-({[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten- l-yl]amino carbonyl)tetrahydro-2H-pyran-4-yl]carbamate
Figure imgf000032_0002
A solution of 50 wt% UT3P in EtOAc (1.3 mL, 2.184 mmol) was added dropwise to a solution of [(l,S’,2£)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten-l-yl]amine trifluoroacetate (500 mg, 1.452 mmol), 4-((tert-butoxycarbonyl)amino)tetrahydro-2H- pyran-4-carboxylic acid (356 mg, 1.452 mmol), and Et3N (1 mL, 7.21 mmol) in CH2C12 (5 mL) at 0 °C (bath temp). The ice bath was removed, and the reaction was stirred at RT. After 1 h 20 min, the reaction mixture was washed with saturated aq. NaHC03 (1 x 5 mL) and 10% citric acid (1 x 5 mL). The organic layer was concentrated under a stream of nitrogen, and the residue was purified by flash column chromatography, giving 251 mg (38%) of the title compound. LC-MS m/z 458 (M+H)+, 0.96 (ret time).
Example 1
4-amino-N-[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten-l- yl]tetrahydr -2H-pyran-4-carboxamide hydrochloride
Figure imgf000036_0001
A solution of concentrated aq. HCI (0.23 mL, 2.76 mmol) was added to a solution of 1,1-dimethylethyl [4-({[(l^,2£)-4-(2,3-dihydro-lH-indol-l-yl)-l-ethyl-4-oxo-2-buten- l-yl]amino}carbonyl)tetrahydro-2H-pyran-4-yl]carbamate (251 mg, 0.549 mmol) in isopropanol (2.5 mL). The reaction flask was fitted with an air condenser, and the reaction mixture was heated to 65 °C (bath temp) for 1 h 45 min. The solvent was evaporated under reduced pressure. Water (5 mL) was added to the residue, and the mixture was concentrated under reduced pressure at 65 °C. Water (2 mL) was added to the residue, and the mixture was lyophilized, giving 193.3 mg (89%) of the title compound. LC-MS m/z 358 (M+H)+, 0.68 (ret time).
1H MR (400 MHz, METHANOL-^) δ ppm 8.14 (br. s., 1 H); 7.25 (d, J=7.03 Hz, 1 H); 7.18 (t, J=7.53 Hz, 1 H); 7.02 – 7.09 (m, 1 H); 6.83 (dd, J=15.18, 6.65 Hz, 1 H); 6.49 (d, 7=14.8 Hz, 1 H); 4.56 (d, 7=7.28 Hz, 1 H); 4.22 (br. s., 2 H); 3.95 (d, 7=7.53 Hz, 1 H); 3.88 – 3.94 (m, 1 H); 3.71 – 3.78 (m, 2 H); 3.23 (br. s., 2 H); 2.39 – 2.46 (m, 2 H); 1.79 – 1.86 (m, 2 H); 1.75 (s, 1 H); 1.72 (d, 7=8.28 Hz, 1 H); 1.00 (t, 7=7.40 Hz, 3 H)
DATA FOR B
4-Amino-N-[(2E,4S)-1-(2,3-dihydro-1H-indol-1-yl)-6-methyl-1-oxohept-2-en-4-yl]tetrahydro-2H-pyran-4-carboxamide hydrochloride
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000034_0002
Figure imgf000034_0003
Figure imgf000035_0001
Figure imgf000035_0002
Figure imgf000037_0001
Intermediate 8
N -{[(l,l-dimethylet leucinamide
Figure imgf000033_0001
To a solution ofN-(tert-butoxycarbonyl)-L-leucine (3.00 g, 13.0 mmol) in THF (25.0 mL) was added Ι,Γ-carbonyldiimidazole (2.52 g, 15.6 mmol) portionwise over about 10 min. After stirring 1 h at RT, a solution of N,O-dimethylhydroxylamine hydrochloride (1.39 g, 14.3 mmol) and DIPEA (2.49 mL, 14.3 mmol) in DMF (6.0 mL) was added. The reaction mixture was stirred for 2.5 h at RT, followed by concentration in vacuo. The residue was diluted with EtOAc (50 mL) and washed with 1 M aq. HCl (2 x 20 mL), saturated aq. NaHC03 (2 x 20 mL), and brine (20 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound (2.34 g, 66%) as a clear, colorless oil. LC-MS m/z 275 (M+H)+, 1.17 min (ret time).
Intermediate 9
1,1-dimethylethyl [(lS -l-formyl-3-methylbutyl]carbamate
Figure imgf000033_0002
To a solution of L1AIH4 (0.356 g, 9.38 mmol) in Et20 (20 mL) at 0 °C was added dropwise a solution ofN2-{[(l, l-dimethylethyl)oxy]carbonyl}-N1-methyl-N1-(methyloxy)-L- leucinamide (2.34 g, 8.53 mmol) in Et20 (15 mL). The reaction mixture was stirred for 30 min at 0 °C and quenched with EtOAc (6 mL) followed by 5% aq. potassium bisulfate (6 mL). The reaction mixture was washed with 1 M aq. HCl (2 x 10 mL), saturated aq. NaHC03 (2 x 10 mL), and brine (10 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to afford the title compound as a clear, colorless oil. Intermediate 10
methyl (2E 4S)-4-({[(l,l-dimethylethyl)oxy]carbonyl}amino)-6-methyl-2-heptenoate
Figure imgf000034_0001
To a stirred solution of methyl (triphenylphosphoranylidene) acetate (3.42 g, 10.2 mmol) in Et20 (25 mL) at RT was added a solution of Intermediate 9 in Et20 (15 mL). The reaction mixture was stirred for 15 h at RT. The solid was removed by filtration and the solution was concentrated in vacuo. Purification via flash column chromatography (0-50% EtOAc/hexanes) afforded the title compound (1.74 g, 75% over two steps) as a clear, colorless oil. LC-MS m/z 272 (M+H)+, 1.22 min (ret time).
Intermediate 11
(2E,4S)-4-({[(l,l-dimethylethyl)oxy]carbonyl}amino)-6-methyl-2-heptenoic acid
Figure imgf000034_0002
To a solution of methyl (2£,,4,S)-4-({[(l,l-dimethylethyl)oxy]carbonyl}amino)-6- methyl-2-heptenoate (5.00 g, 18.43 mmol) in THF (15 mL), MeOH (15.0 mL), and water (15 mL) was added Li OH (2.206 g, 92.00 mmol). After stirring for 2 h at RT, the reaction mixture was concentrated in vacuo. The reaction mixture was acidified with 6 M aq. HC1 to pH = 5 and then extracted with EtOAc. The organic layer was washed with water, dried over Na2SC”4, filtered, and concentrated in vacuo to afford the title compound (4.7 g, 99%) as a white semi-solid. LC-MS m/z 158 (M+H-Boc)+, 0.94 min (ret time).
Intermediate 12
1,1-dimethylethyl [(lS,2E)-4-(2,3-dihydro-li -indol-l-yl)-l-(2-methylpropyl)-4-oxo-2- buten-l-yl]carbamate
Figure imgf000034_0003
To a solution of (2£,,4,S)-4-({[(l,l-dimethylethyl)oxy]carbonyl}amino)-6-methyl-2- heptenoic acid (4.70 g, 18.26 mmol) in DMF (30.0 mL) were added BOP reagent (8.08 g, 18.26 mmol) and DIPEA (6.38 mL, 36.5 mmol). After stirring at RT for 5 min, 2,3-dihydro- lH-indole (2.053 mL, 18.26 mmol) was added and stirring continued overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered, concentrated in vacuo and purified by flash column chromatography (0-20% EtOAc/hexanes) to afford the title compound (4.83 g, 74%) as a white solid. LC-MS m/z 359 (M+H)+, 1.18 min (ret time).
Intermediate 13
[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-(2-methylpropyl)-4-oxo-2-buten-l-yl]amine trifluoroacetate
Figure imgf000035_0001
To a solution of 1, 1-dimethylethyl [(l^,2£)-4-(2,3-dihydro-lH-indol-l-yl)-l-(2- methylpropyl)-4-oxo-2-buten-l-yl]carbamate (3.21 g, 8.95 mmol) in CH2C12 (10.0 mL) was added TFA (10 mL, 130 mmol). The reaction mixture was stirred for 17.5 h at RT and then concentrated under reduced pressure and dried under high vacuum to afford the title compound. LC-MS m/z 259 (M+H)+, 0.76 min (ret time).
Intermediate 14
1,1-dimethylethyl [4-({[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-(2-methylpropyl)-4- oxo-2-buten-l- l]amino}carbonyl)tetrahydro-2H- ran-4-yl]carbamate
Figure imgf000035_0002
A solution of 50 wt% ¾P in EtOAc (1.2 mL, 2.016 mmol) was added dropwise to a solution of [(15′,2JE)-4-(2,3-dihydro-lH-indol-l-yl)-l-(2-methylpropyl)-4-oxo-2- buten-l-yl]amine trifluoroacetate (500 mg, 1.343 mmol), 4-((tert- butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (329 mg, 1.343 mmol), and Et3N (0.93 mL, 6.71 mmol) in CH2C12 (5 mL) at 0 °C (bath temp). The ice bath was removed, and the reaction was stirred at RT. After 1 h 20 min, the reaction was washed with saturated aq. NaHC03 (1 x 5 mL) and 10% citric acid (1 x 5 mL). The organic layer was concentrated under a stream of nitrogen, and the residue was purified by flash column chromatography, giving 204 mg (31%) of the title compound. LC-MS m/z 486 (M+H)+, 1.07 min (ret time).
Example 2
4-amino-N-[(lS,2E)-4-(2,3-dihydro-lH-indol-l-yl)-l-(2-methylpropyl)-4-oxo-2-buten- l-yl]tetrahydro-2H-pyran-4-carboxamide hydrochloride
Figure imgf000037_0001
A solution of concentrated aq. HCI (0.22 mL, 2.64 mmol) was added to a solution of 1,1-dimethylethyl [4-({[(1^2JE)-4-(2,3-dihydro-lH-indol-l-yl)-l-(2-methylpropyl)-4- oxo-2-buten-l-yl]amino}carbonyl)tetrahydro-2H-pyran-4-yl]carbamate (251 mg, 0.517 mmol) in isopropanol (2.5 mL). The reaction flask was fitted with an air condenser, and the reaction mixture was heated to 65 °C (bath temp). After 1 h 45 min, the solvent was evaporated under reduced pressure at 60 °C. Water (5 mL) was added to the residue, and the mixture was concentrated under reduced pressure at 65 °C. Water (2 mL) was added to the residue, and the mixture was lyophilized, giving 130.6 mg (60%) of the title compound. LC-MS m/z 386 (M+H)+, 0.79 (ret time). 1H MR (400 MHz, METHANOL- d4) δ ppm 8.15 (d, J=7.03 Hz, 1 H); 7.25 (d, J=7.03 Hz, 1 H); 7.18 (t, J=7.65 Hz, 1 H); 7.06 (t, J=7.91 Hz, 1 H); 6.81 (dd, J=15.18, 6.40 Hz, 1 H); 6.49 (br. s., 1 H); 4.73 – 4.85 (m, 2 H); 4.21 (t, J=8.28 Hz, 2 H); 3.91 – 3.97 (m, 2 H); 3.70 – 3.77 (m, 2 H); 3.25 – 3.21 (m, 2 H); 2.35 – 2.48 (m, 2 H); 1.82 (d, J=14.31 Hz, 2 H); 1.63 – 1.71 (m, 2 H); 1.50 – 1.57 (m, 1 H); 0.98 (dd, J=11.92, 6.40 Hz, 6 H).
DATA FOR C
1-Amino-N-[(3S)-1-(3-cyano-4′-fluorobiphenyl-4-yl)pyrrolidin-3-yl]cyclohexanecarboxamide hydrochloride
Example 1
l-amino-N-[(3S)-l-(3-cyano-4′-fluoro-4-biphenylyl)-3- pyrrolidin l] cyclohexanecarboxamide hydrochloride
Figure imgf000028_0001
HCI salt
A solution of 1,1-dimethylethyl [l-({[(35)-l-(3-cyano-4′-fluoro-4-biphenylyl)-3- pyrrolidinyl]amino}carbonyl)cyclohexyl]carbamate (44 mg, 0.087 mmol) in HCI (4 M solution in 1,4-dioxane, 1.0 mL, 4.00 mmol) was stirred at RT for 1 h. The reaction mixture was diluted with Et20 (5 mL), and the mixture was filtered and washed with Et20 (2 x 2 mL). Residual solid was dissolved in MeOH and concentrated under a stream of nitrogen at 50 °C and dried under high vacuum. Water (2 mL) was added to the residue, and the mixture was lyophilized with a Genevac® HT-4X to afford the title compound (33.5 mg, 87%). LC-MS m/z 407 (M+H)+, 0.94 min (ret time). 1H NMR (400 MHz, METHANOL-^) δ ppm 7.65 – 7.72 (m, 2 H), 7.52 – 7.59 (m, 2 H), 7.10 – 7.17 (m, 2 H), 6.89 (d, J=8.53 Hz, 1 H), 4.50 – 4.58 (m, 1 H), 3.94 (dd, J=10.29, 6.53 Hz, 1 H), 3.80 (dt, J=9.41, 7.09 Hz, 1 H), 3.67-3.71 (m, 1 H), 3.64 (dd, J=10.29, 4.52 Hz, 1 H), 2.29 – 2.37 (m, 1 H), 2.04 – 2.16 (m, 3 H), 1.78 – 1.88 (m, 5 H), 1.45 – 1.62 (m, 3 H).
DATA FOR D
Example 2
4-amino- V-[(3S)-l-(3-cyano-4′-fluoro-4-biphenylyl)-3-pyrrolidinyl]tetrahydro-2H- pyr -4-carboxamide hydrochloride
Figure imgf000028_0002
HCI salt
A solution of 1,1-dimethylethyl [4-({[(35)-l-(3-cyano-4′-fluoro-4-biphenylyl)-3- pyrrolidinyl] amino }carbonyl)tetrahydro-2H-pyran-4-yl] carbamate (183 mg, 0.360 mmol) in HC1 (4 M solution in 1,4-dioxane, 2.0 mL, 8.00 mmol) was stirred at RT for 0.5 h. The reaction mixture was diluted with Et20 (10 mL), and the mixture was filtered and washed with Et20 (2 x 5 mL). Residual solid was dissolved in MeOH and concentrated under a stream of nitrogen at 50 °C and dried under high vacuum. Water (2 mL) was added to the residue, and the mixture was lyophilized with a Genevac® HT-4X to afford the title compound (122.8 mg, 77%). LC-MS m/z 409 (M+H)+, 0.87 min (ret time). 1H NMR (400 MHz, METHANOL-^) δ ppm 7.66 – 7.72 (m, 2 H), 7.53 – 7.60 (m, 2 H), 7.11 – 7.18 (m, 2 H), 6.89 (d, J=8.78 Hz, 1 H), 4.53 – 4.60 (m, 1 H), 3.87 – 3.97 (m, 3 H), 3.78 – 3.84 (m, 1 H), 3.64 – 3.76 (m, 4 H), 2.30 – 2.44 (m, 3 H), 2.11 – 2.19 (m, 1 H), 1.77 – 1.84 (m, 2 H).
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