Senior Fitness - Exercise and Nutrition for Aging Men and Women
FREE Article Feed for your website.
Home Ownership Magazine
Party Planning Information
Article Marketing Resources
Bio-Medical Research Article Database
Informative Articles on Life, Love and Happiness
Tutorials on Business to Writing
Famous Quotes from Famous People
Song Lyric Information
New US Patent Information
Comprehensive List of Content by Category
Online Auctions and Shopping Related Articles
Article Search
Most Recent Articles
 

Credit Card Facts
Category:
Finance / Investment  

Got Bills to Pay You ve got a Decision to Make
Category:
Business  

What to look for when getting a loan
Category:
Business  

Are UK Secured Loans a part of your financial portfolio
Category:
Business  

How things change
Category:
Marketing  

Eating Well While Traveling
Category:
Travel  

The never ending Spyware story
Category:
Computers  

Raise Your Income
Category:
Marketing  

Is There A Single Acne Cure That Will Work For Everyone
Category:
Health / Fitness  

Hypertension Determining If You Are At Risk
Category:
Health / Fitness  

Making Money With Niche Products
Category:
Marketing  

Euro Pound brief property Almeria Spain 2nd August 2006
Category:
Business  

The Best Way To Generate Free Targeted Website Traffic
Category:
Marketing  

Credit Cards Answers to the Approval Process
Category:
Finance / Investment  

Croydon Hotels Hotels in Croydon Cheap B and B Accommodation nea...
Category:
Travel  

Is Growing Saint George Utah The New Palm Springs
Category:
Travel  

Contact Lenses Have Come A Long Way To Give You Simple Hassle Fr...
Category:
Health / Fitness  

Why Secondary research is preferred for Market research Report
Category:
Business  

Traffic Generation Using Only Free Methods
Category:
Business  

Golf Fitness Tips Five Benefits Of Adding A Few Simple Exercises...
Category:
Sports  

Discover The Simple Method Of Fat Loss No One Else Will Tell You...
Category:
Health / Fitness  

Failure is Part of Success
Category:
Business  

Two Things You Do Not Know About LASIK Eye Surgery
Category:
Health / Fitness  

Tennis A sport your love handles hate
Category:
Sports  

Vitamins for Depression
Category:
Health / Fitness  

The Best Countertops Are Granite
Category:
Home And Family  

Life Insurance Should be Death Insurance but they d have a hard ...
Category:
Business  

The Fastest Way To Secure A Loan
Category:
Marketing  

What is better for carpet cleaning Steam cleaners or regular vac...
Category:
Home And Family  

Free Ebook Demonstrates Your Path To The Top Of The Search Engin...
Category:
Business  

Homoeopathy
Category:
Health / Fitness  

Cosmetic Surgery for Those in their 40s and Up
Category:
Health / Fitness  

Flax Seed a source for omega 3 fatty acids
Category:
Health / Fitness  

How do negative affirmations affect my life
Category:
Marketing  

Cheap Airfares Ways To Secure It
Category:
Finance / Investment  

When the Cardiologist says you have heart disease part 2
Category:
Health / Fitness  

Virtual Economy in MMORPGs
Category:
Business  

Bedding Basics What s Inside Your Bed
Category:
Home And Family  

Top Ten Secrets to Saving Big Money in the Airline Flights
Category:
Finance / Investment  

CRM 101 The Basics of Customer Relationship Management
Category:
Business  

Baby Shower Fun Activities
Category:
Home And Family  

Beach front Vacation Homes
Category:
Travel  

Protecting Yourself During Your European Jaunt
Category:
Finance / Investment  

Finding Sales Leads For Your Cleaning Business
Category:
Business  

FIFA
Category:
Sports  

When Early Signs of Menopause Strike Women
Category:
Health / Fitness  

Stop Losing Money and Get into an Investment Opportunity
Category:
Business  

Some tips about analysis of the advance of the site
Category:
Marketing  

ACRX Donates Free Rx Cards To YWCA Of Greater Toledo
Category:
Business  

Tips On How To Choose Winning Stock
Category:
Business  

Collection Of Classical Music Cd
Category:
Entertainment / Television  

Dry chemical carpet cleaning for your carpet
Category:
Home And Family  

Parents You can become financially successful
Category:
Finance / Investment  

How to remove stains from your carpet
Category:
Home And Family  

Getting the Best Natural Skin Care for Your Money
Category:
Health / Fitness  

What not to do when negotiating your Surrey lease
Category:
Business  

Easy Way to Increase Your Online Income
Category:
Business  

On Page SEO in five easy steps
Category:
Marketing  

Creating a Business Plan
Category:
Business  

What are MLM Leads
Category:
Business  

Happy Relationships
Category:
Home And Family  

Take Control Of Your Home Heating Oil Costs This Winter
Category:
Home And Family  

Your Own Com
Category:
Business  

Support is key to success for any company
Category:
Business  

An Overview of Unsecured Loans
Category:
Business  

Is Internet Marketing Dead
Category:
Marketing  

Night of the Living Debt How Re Aged Bills Can Hurt You
Category:
Finance / Investment  

Design is Key to Trade Show Exhibit Success
Category:
Marketing  

Best Practices For Website Directory Submissions
Category:
Marketing  

4 Questions You Need to Answer Before You Tear Down the Walls
Category:
Home And Family  

Do Blood Types Really Matter
Category:
Entertainment / Television  

Ideal Web Hosting WebHostingInsider
Category:
Computers  

Spiti The Hidden Valley Part I
Category:
Travel  

Dynamic Product Search
Category:
Business  

Can You Afford To Live On Organic Food
Category:
Health / Fitness

Calcium receptor active molecules and method for preparing same Number:7,084,167 from the United States Patent and Trademark Office (PTO) owispatent

Home    Author Login    Submit Article    Article Search    Add Your Link    Edit Your Link    Contact Us    Advertising    Disclaimer

   

 
Web LinkGrinder.com

Top Breaking News
     Greek, Cypriot Leaders Resume Unification Talks in Nicosia by Nathan Morley
     Indonesia Tobacco Sales Grow, Raising Health Fears
     South Korea Allows Top Defector to Travel Overseas by VOA News

Title: Calcium receptor active molecules and method for preparing same

Abstract: The invention concerns compounds of general formula (I) wherein: the group X represents a --NR4, --CH.dbd.N or --CHR5-NR4-group; the group Y represents an oxygen or sulphur atom or a NR, --CR5, --CHR5-, --CR5=CR6- or --CHR5-CHR6 group provided that when group X represents the --CH.dbd.N-- or --CHR5-NR4-group, group Y represents an oxygen or a sulphur atom or a Nr, --CR5 or --CHR group; the group R represents a hydrogen atom or an alkyl, aryl or aralkyl group; the groups R1, R5 and R6, identical or different, represent each a hydrogen or halogen atom or an alkyl or alkoxy group; the group R2 represents a hydrogen atom or an alkyl group; the group R3 represents an aryl group; and the group R4 represents a hydrogen atom, an alkyl, aryl, aralkyl, alkylsulphonamide, arylsulphonamide or aralkylsulphonamide group; and their salt with a pharmaceutically acceptable acid, in the form of a racemic mixture and their optically pure isomer. The invention also concerns their preparation, pharmaceutical compositions containing them and their use as CaSR activity modulator and as medicine for preferably treating diseases or physiological disorders involving the intervention of CaSR activity modulation. ##STR00001##

Patent Number: 7,084,167 Issued on 08/01/2006 to Ruat,   et al.


Inventors: Ruat; Martial (Bourg la Reine, FR); Dodd; Robert (Paris, FR); Faure; Heee (Gif-sur-Yvette, FR); Dauban; Philippe Marcel (Bures-sur-Yvette, FR); Kessler; Albane (Paris, FR); Potier; Pierre Jean-Paul (Paris, FR)
Assignee: Centre National de la Rechereche Scientifique (CNRS) (Cedex, FR)
Appl. No.: 10/296,288
Filed: May 23, 2001
PCT Filed: May 23, 2001
PCT No.: PCT/FR01/01599
371(c)(1),(2),(4) Date: April 24, 2003
PCT Pub. No.: WO01/90069
PCT Pub. Date: November 29, 2001


Foreign Application Priority Data

May 24, 2000 [FR] 00 06619

Current U.S. Class: 514/415 ; 514/418; 548/484; 548/491; 548/504
Current International Class: A61K 31/404 (20060101); A61K 31/4045 (20060101); C07D 209/04 (20060101); C07D 209/10 (20060101)


References Cited [Referenced By]

U.S. Patent Documents
3906099 September 1975 Morrison et al.
Foreign Patent Documents
542696 Apr., 1985 ES
2010406 Jan., 1989 ES
WO 93/04373 Mar., 1993 WO
WO 96/12697 May., 1996 WO
WO 96/23789 Aug., 1996 WO
WO 00/21910 Apr., 2000 WO
WO 00/32578 Jun., 2000 WO
WO 00/35864 Jun., 2000 WO
WO 01/34562 May., 2002 WO

Other References

Cruces, et al., "Acetylenic and Allenic Derivatives of 2-(1-methylindolyl)methylamine As Selective Inhibitors of the Monoamine Oxidases A and B," Farmaco, Edizione Scientifica, vol. 43, Iss. 7-8, p. 567-73 (1988). cited by examiner .
Cherqaoui et al.; Structure-selectivity relationship of MAO inhibitors using neural networks; Models in Chemistry 135 (1-2), pp. 79-91 (1998). cited by other .
Ferry et al.; Effects of divalent cations and of a calcimimetic on adrenocorticotropic hormone release in pituitary cells, Biochem. and Biophys. Res. Comm. 238, pp. 866-873 (1997). cited by other .
Nemeth et al.; Calcimimetic compounds: a direct approach to controlling plasma levels of parathyroid hormone in hyperparathyroidism, TEM, vol. 10, No. 9, pp. 66-71 (1999). cited by other .
Ye et al.; Amyloid-62 proteins activate CA.sup.2+ permeable channels through calcium-sensing receptors, J. Neuroscience Res. 47:547-554 (1997). cited by other .
Antonsen et al.; A cacimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure; Kidney International, 53:223-227 (1998). cited by other .
Wada et al.; NPS R-568 halts or reverses osteitis fibrosa I uremic rats; Kidney International 53:448-453 (1998). cited by other .
Wada et al.; The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency; INIST CNRS 2977-2983 (2002). cited by other .
Silverberg et al.; Short-term inhibition of parathyroid hormone secretion by a calcium receptor agonist in patients with primary hyperparathyroidism, New England Journal of Medicine, 1506-1510 (1997). cited by other .
Brown et al.; The extracellular calcium-sensing receptor: Its role in health and disease; Annu. Rev. Med. 49:15-29 (1998). cited by other .
Brown et al.; Cloning and characterization of an extracellular CA2+ sensing receptor from bovine parathyroid; Nature 366:575-580 (1993). cite- d by other .
Nemeth et al.; Calcimimetics with potent and selective activity on the parathyroid calcium receptor, PNAS 95:4040-4045 (1998). cited by other .
Pollak et al.; Autosomal dominant hypocalcaemia caused by a CA2+ sensing receptor gene mutation, Nature Genetics, 8:303-307 (1994). cited by other .
Ruat et al.; Calcium sensing receptor: Molecular cloning in rat and localization to nerve terminals; PNAS 92:3161-3165 (1995). cited by other .
Ruat et al.;Cloned and expressed rat CA2+ sensing receptor; J. Biol. Chem., 271:5972-5975 (1996). cited by other .
Pollak et al.; Mutations in the human CA2+ sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, Cell, 75:1297-1303 (1993). cited by other .
Chattopadhyay et al.; The calcium-sension receptor: A window into the physiology and pathophysiology of mineral ion metabolism; Endocrine 17(4):289-307 (1996). cited by other .
Gavela et al.; Preparacion de derivados acetilenicos y alenicos de 2-indolilmetilaminas y resultdos preliminaries de su estudio como inhibidores selectivos para las monoaminooxidasaas AYB; 82:129-120 (1986). cited by other .
Nogradi, Thomas; Untersuchungen uber rauwolfia-alkaloid-modelle II; 2-substituierte indole, tetrahydrocarbolin und hexadehydro-yohimban-derivate; Monatshefte fur Chemie. Bd. 88(6) 1088-1094 (1957). cited by other .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161450 (1987). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161408 (1996). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161449 (1986). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161453 (1996). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161448 (1998). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161454 (1998). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161455 (1986). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161456 (1985). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161451 (1958). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161457 (1958). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161464 (1989). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161465 (1989). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161452 (1978). cited by oth- er .
6001 Chemical Abstracts, Columbus, Ohio; XP-002161458 (1978). cited by oth- er.

Primary Examiner: Saeed; Kamal A.
Assistant Examiner: Freistein; Andrew B.
Attorney, Agent or Firm: Foley & Lardner LLP

Claims



The invention claimed is:

1. A compound of the following formula I: ##STR00040## in which: the group X represents a group ##STR00041## the group Y represents a group ##STR00042## the groups R1 and R5, which may be identical or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy group, the group R2 represents a hydrogen atom or an alkyl group, the group R3 represents an aryl group, and the group R4 represents a hydrogen atom or an alkyl, aryl, aralkyl, alkylsulfonamide, arylsulfonamide or aralkylsulfonamide group, and its salt with a pharmaceutically acceptable acid, in the form of a racemic mixture or of its optically pure isomer, and with the exception of compounds, which have the following formulae: ##STR00043##

2. The compound of claim 1, wherein the compound is represented by the following formula III: ##STR00044## and its salt with a pharmaceutically acceptable acid, in the form of a racemic mixture or of its optically pure isomer.

3. The compound of claim 1, wherein the compound is represented by the following formula IV: ##STR00045## and its salt with a pharmaceutically acceptable acid.

4. A method for preparing the compound of claim 1, comprising reducing an amide of the following formula V: ##STR00046## in which: the group X represents a group ##STR00047## the group Y represents a group ##STR00048## the groups R1 and R5, which may be identical or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy group, the group R2 represents a hydrogen atom or an alkyl group, the group R3 represents an aryl group, and the group R4 represents a hydrogen atom or an alkyl, aryl, aralkyl, alkylsulfonamide, arylsulfonamide or aralkylsulfonamide group, and with the exception of the compounds, which have the following formula: ##STR00049##

5. The method of claim 4, wherein the method further comprises reacting: (A) an acyl chloride of the following formula VI: ##STR00050## in which: the group X represents a group ##STR00051## the group Y represents a group ##STR00052## the groups R1 and R5, which may be identical or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy group, and the group R4 represents a hydrogen atom or an alkyl, aryl, aralkyl, alkylsulfonamide, arylsulfonamide or aralkylsulfonamide group, with (B) an amine of the following formula VII: ##STR00053## in which: the group R2 represents a hydrogen atom or an alkyl group, and the group R3 represents an aryl group; so as to obtain the amide of general formula V, wherein the following groups are substituted or unsubstituted: alkyl, alkoxy, aryl, aralkyl, alkylsulfonamide, arylsulfonamide, and aralkylsulfonamide.

6. The method of claim 5, wherein the method further comprises reacting a carboxylic acid of the following formula VIII: ##STR00054## in which: the group X represents a group ##STR00055## the group Y represents a group ##STR00056## the groups R1 and R5, which may be identical or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy group, and the group R4 represents a hydrogen atom or an alkyl, aryl, aralkyl, alkylsulfonamide, arylsulfonamide or aralkylsulfonamide group; with a thionyl chloride; so as to obtain acyl chloride of the formula VI, wherein the following groups are substituted or unsubstituted: alkyl, alkoxy, aryl, aralkyl, alkylsulfonamide, arylsulfonamide, and aralkylsulfonamide.

7. A pharmaceutical composition comprising: (A) a compound of the following formula I: ##STR00057## in which: the group X represents a group ##STR00058## the group Y represents a group ##STR00059## the groups R1 and R5, which may be identical or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy group, the group R2 represents a hydrogen atom or an alkyl group, the group R3 represents an aryl group; and the group R4represents a hydrogen atom or an alkyl, aryl, aralkyl, alkylsulfonamide, arylsulfonamide or aralkylsulfonamide group, wherein the following groups are substituted or unsubstituted: alkyl, alkoxy, aryl, aralkyl, alkylsulfonamide, arylsulfonamide, and aralkylsulfonamide; and (B) a suitable pharmaceutical carrier.

8. A pharmaceutical composition comprising the compound of claim 2 and a suitable pharmaceutical carrier.

9. A pharmaceutical composition comprising the compound of claim 3 and a suitable pharmaceutical carrier.
Description



This application is a 371 of PCT/FR01/01599, filed May 23, 2001 and claims priority to French Patent Application No. 00/06619, filed May 24, 2000.

The present invention relates to compounds having calcimimetic activity. It in particular relates to a novel class of amino compounds, to the preparation thereof, to the pharmaceutical compositions comprising them and to the use thereof as a modulator of the activity of (Ca.sup.2+).sub.e and (Mg.sup.2+).sub.e ion receptors or CaSR, for Calcium Sensing Receptor, and as a medicinal product preferably intended for the treatment of physiological disorders or diseases involving modulation of CaSR activity.

The calcimimetic activity corresponds to the ability to produce or induce biological responses observed through variations in the concentration of extracellular calcium ions (Ca.sup.2+).sub.e and extracellular magnesium ions (Mg.sup.2+).sub.e.

(Ca.sup.2+).sub.e and (Mg.sup.2+).sub.e ions play a major role in the body since they regulate calcium homeostasis on which the vital functions of the body depend. Thus, hypercalcemia, that is to say conditions in which (Ca.sup.2+).sub.e ions are below the mean threshold, have a major effect on many functions, such as cardiac, renal or intestinal functions. They deeply affect the central nervous system (Chattopadhyay et al. Endocr. Review, 1998).

CaSRs are proteins which are sensitive to (Ca.sup.2+).sub.e and (Mg.sup.2+).sub.e ions, and are present in the parathyroid and thyroid glands, the kidney, the intestine, the lungs, bone cells, the brain, the spinal cord, the pituitary gland, the stomach and keratinocytes (Brown et al, Nature, 1993; Ruat et al, Proc. Natl. Acad. Sci., USA, 1995; Brown et al, Ann. Rev. Med., 1998). These proteins are encoded by a single gene isolated from various animal species. They belong to the family of G protein-coupled receptors with seven transmembrane domains, and exhibit structural homologies with metabotropic glutamate receptors, GABA.sub.R receptors, and hypothetical pheromone and taste receptors. Activating or inhibitory mutations of the genes in humans are responsible for extremely serious genetic diseases which cause hypocalcemia or hypercalcemia (Pollack et al, Cell, 1993; Pollack et al, Nature Genetic, 1994; Brown et al, Ann. Rev. Med., 1998). The functions associated with the expression of these proteins in tissues are not yet all known and are the subject of a very great deal of research activity, particularly with regard to the CaSRs present in the parathyroid and thyroid glands, the kidney, the intestine, the spinal cord, the brain and bone cells.

In the parathyroid gland, the CaSRs modulate the secretion of parathyroid hormone (PTH), which is the main regulator of calcium homeostasis: an increase in (Ca.sup.2+).sub.e ions in the serum will activate the CaSRs present on the cells of the parathyroid gland and decrease secretion of the PTH hormone.

The complementary DNA encoding rat CaSR has been isolated from a rat striatum cDNA library (Ruat et al, Proc. Natl. Acad. Sci., 1995). This receptor is identical, in terms of its amino acid sequence, to that expressed in the other tissues. Transfected Chinese hamster ovary (CHO) cells expressing rat CaSR (CHO(CaSR)) have been characterized and the chemical signals (second messengers) induced by activation of this receptor have been analyzed. Thus, a biochemical test for measuring the accumulation of tritiated inositol phosphates, [.sup.3H]IPs, in response to activation of the receptor has been developed (Ruat et al, J. Biol. Chem., 1996; Ferry et al, Biochem. Biophys. Res. Common., 1997).

It has been shown that Ca.sup.2+ and Mg.sup.2+ ions, but also Ba.sup.2+ ions, within millimolar concentration ranges, stimulate CaSRs. Activation of CaSRs might be induced in the brain by .beta.-amyloid peptides, which are involved in neurodegenerative diseases such as Alzheimer's disease (Ye et al, J. Neurosci. Res., 1997).

Disturbance of CaSR activity is associated with biological disorders such as primary and secondary hyperparathyroidism, osteoporosis, cardiovascular, gastrointestinal, endocrine and neurodegenerative diseases, or certain cancers in which (Ca.sup.2+).sub.e ions are abnormally high.

Secondary hyperparathyroidism is observed in chronic renal failure and is characterized by hyperplasia of the parathyroid glands and an increase in circulating PTH. The renal failure is also accompanied by renal osteodystrophy, which is characterized by bone disorders with a very considerable or poor renewal of the bone mass (osteitis fibrosa, osteomalacia).

Osteoporosis is a multifactor disease which depends in particular on age and sex. While menopausal women are very greatly affected, osteoporosis is increasingly proving to be a problem in elderly men, and, for the moment, no really satisfactory treatments exist. Its social cost may become even heavier in the years to come, particularly in our European society where life expectancy is becoming longer. Osteoporosis is currently treated with estrogens, calcitonin or biphosphonates which prevent bone resorption without stimulating bone growth. More recent data demonstrate that intermittent increases in PTH or in derivatives thereof are effective in the treatment of osteoporosis and make it possible to remodel bone by stimulating bone formation (Whitfield et al., 1999). This new therapeutic approach for treatment of osteoporosis appears to be very advantageous, although major problems are associated with the use of PTH hormone, such as the route of injection, but also the appearance of tumors, observed recently during clinical trials in humans. Intermittent secretion of endogenous PTH can be obtained by blocking the calcium receptor. The blocking of PTH secretion with CaSR agonists may be followed by a rapid increase in PTH (rebound effect), which is then beneficial in the treatment of osteoporosis.

The search for selective ligands for CaSRs has led the company NPS to develop two main types of family of organic compounds, namely polyamines such as NPS 019 (3), and arylalkylamines, the most well known representative of which, to date, is NPS-R-568 (2).

The compound NPS-R-568 (2), an allosteric ligand of the CaSR, belongs to the first family of small size (M<600) organic molecules which interact with this receptor. This arylalkylamine has developed from the structure of Fendilin (1), a potent activator of the CaSR of the parathyroid gland.

##STR00002##

The agent NPS-R-568 reduces or eliminates osteitis fibrosa in rats (Wada et al, Kidney International, 1998) and reduces PTH concentrations in patients (men) suffering from chronic renal failure (Antansen et al, Kidney International, 1998). This compound has been successfully used orally to lower concentrations of PTH and of free serum Ca.sup.2+ ions in menopausal women suffering from primary hyperparathyroidism (Silverborg et al, New Engl. J. Med., 1997). In another study, the compound NPS-R-568 made it possible to reduce by between 20 50% the cell proliferation observed in the parathyroid gland in a rat model reproducing chronic renal failure (Wada et al, J. Clin. Invest., 1997). These studies demonstrate that a calcimimetic compound which is active with respect to the calcium receptor present on the parathyroid gland may be considered to be an advantageous therapeutic tool for treating certain forms of primary and secondary hyperparathyroidism.

During clinical trials (phase I II), the company NPS Pharmaceutical observed a low bioavailability of the compound NPS-R-568 and also varying clinical effects, depending on the individuals, which might result from polymorphism of the gene encoding the CaSR in humans (Nemeth et al, Trends Endoc. Metab, 1999). In addition, during experimental trials in rats, the compound NPS R-467, a compound with a structure similar to NPS-R-568, proved to be more selective with respect to the receptors of the parathyroid compared with those of the thyroid gland. This selectivity can be explained by tissue-related differences, which suggest that calcimimetic molecules specific for a tissue may be synthesized and may be of considerable clinical importance.

In parallel, the preparation and the calcimimetic activity of arylalkyl-1,2-diamines having the general structure described below (4), and among which the compound PHD 321 (5) constitutes one of the most active products, have been reported.

##STR00003##

The complete lack of clinically available calcimimetic molecules, and the problems encountered in phase I II for the first generation calcimimetics underline the need to find novel calcimimetic molecules.

In this invention, the molecules synthesized have advantages compared with the compound NPS-R-568 and with the compound NPS 019 since their structure reveals several sites of interaction with the CaSR or with its transduction system.

The present invention therefore relates to the compounds of the following general formula I:

##STR00004## in which:

the group X represents a group --NR4, --CH.dbd.N-- or --CHR5-NR4-,

the group Y represents an oxygen or sulfur atom or a group --CR5, --CHR5, --CR5=CR6-, --CHR5-CHR6- or NR, on the condition that, when the group X represents the group --CH.dbd.N-- or --CHR5-NR4-, the group Y represents an oxygen or sulfur atom or the group NR, --CR5 or --CHR5,

the group R represents a hydrogen atom or an alkyl, aryl or aralkyl group,

the groups R1, R5 and R6, which may be identical or different, each represents a hydrogen or halogen atom or an alkyl or alkoxy group,

the group R2 represents a hydrogen atom or an alkyl group,

the group R3 represents an aryl group,

and the group R4 represents a hydrogen atom, or an alkyl, aryl, aralkyl, alkylsulfonamide, arylsulfonamide or aralkylsulfonamide group,

and their salt with a pharmaceutically acceptable acid.

Advantageously, the compounds according to the invention are represented by the following general formula II:

##STR00005## in which:

the groups R1 and R5, which may be identical or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy group,

the group R2 represents a hydrogen atom or an alkyl group,

the group R3 represents an aryl group,

and the group R4 represents a hydrogen atom or an alkyl, aryl, aralkyl, alkylsulfonamide, arylsulfonamide or aralkylsulfonamide group.

Even more advantageously, the group R3 represents a phenyl or naphthyl group which may or may not be substituted.

Examples of advantageous compounds according to the invention are those having the formula III:

##STR00006##

For the purpose of the invention, the term "pharmaceutically acceptable acid" is intended to mean any nontoxic acid, including organic and inorganic acids. Such acids include acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric and para-toluenesulfonic acid. Hydrochloric acid is particularly preferred.

For the purpose of the present invention, the term "alkyl group" is intended to mean any linear or branched, substituted or unsubstituted, C.sub.1 C.sub.6 alkyl group, in particular a methyl group.

For the purpose of the present invention, the term "alkoxy group" is intended to mean any alkoxy group having 1 to 6 linear or branched, substituted or unsubstituted, carbon atoms, in particular the group OCH.sub.3.

For the purpose of the present invention, the term "aryl group" is intended to mean one or more aromatic rings having 5 to 8 carbon atoms, which may be joined or fused, and substituted or unsubstituted. In particular, the aryl groups may be phenyl or naphthyl groups and the substituents may be halogen atoms, alkoxy groups as defined above, alkyl groups as defined above or a nitro group.

For the purpose of the present invention, the term "aralkyl group" is intended to mean any aryl group as defined above, linked via an alkyl group as defined above. In particular, an aralkyl group is a benzyl group.

For the purpose of the present invention, the term "alkylsulfonamide group" is intended to mean any alkyl group as defined above, linked via a sulfonamide group.

For the purpose of the present invention, the term "arylsulfonamide group" is intended to mean any aryl group as defined above, linked via a sulfonamide group. In particular, an arylsulfonamide group is the group;

##STR00007##

For the purpose of the present invention, the term "aralkylsulfonamide group" is intended to mean any aralkyl group as defined above, linked via a sulfonamide group.

The compounds according to the invention all possess an asymmetric center and can therefore exist in the form of optical isomers. The present invention also comprises these isomers, either separately or as a mixture.

The present invention also relates to the method of preparing these compounds.

This method in particular comprises the steps of:

a) transformation of the carboxylic acid of the following general formula VIII:

##STR00008## in which:

the group X represents a group --NR4, --CH.dbd.N-- or --CHR5-NR4-,

the group Y represents an oxygen or sulfur atom or a group NR, --CR5, --CHR5, --CR5=CR6- or --CHR5-CHR6-, on the condition that, when the group X represents the group --CH.dbd.N-- or --CHR5-NR4-, the group Y represents an oxygen or sulfur atom or a group NR, --CR5 or --CHR5,

the group R represents a hydrogen atom or an alkyl, aryl or aralkyl group,

the groups R1, R5 and R6, which may be identical or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy group,

and the group R4 represents a hydrogen atom or an alkyl, aryl, aralkyl, alkylsulfonamide, arylsulfonamide or aralkylsultonamide group,

into acyl chloride of the following general formula VI:

##STR00009## in which:

the group X represents a group --NR4, --CH.dbd.N-- or --CHR5-NR4-,

the group Y represents an oxygen or sulfur atom or a group NR, --CR5, --CHR5, --CR5=CR6- or --CHR5-CHR6-, on the condition that, when the group X represents the group --CH.dbd.N-- or --CHR5-NR4-, the group Y represents an oxygen or sulfur atom or a group NR, --CR5 or --CHR5,

the group R represents a hydrogen atom or an alkyl, aryl or aralkyl group,

the groups R1, R5 and R6, which may be identical or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy group,

and the group R4 represents a hydrogen atom or an alkyl, aryl, aralkyl, alkylsulfonamide, arylsulfonamide or aralkylsulfonamide group, advantageously by reaction with a thionyl chloride.

b) reaction between the acyl chloride of general formula VI and an amine of the following general formula VII:

##STR00010## in which:

the group R2 represents a hydrogen atom or an alkyl group,

and the group R3 represents an aryl group,

so as to obtain the amide of the following general formula V:

##STR00011## in which:

the group X represents a group --NR4, --CH.dbd.N-- or --CHR5-NR4-,

the group Y represents an oxygen or sulfur atom or a group NR, --CR5, --CHR5, --CR5=CR6- or --CHR5-CHR6-, on the condition that, when the group X represents the group --CH.dbd.N-- or --CHR5-NR4-, the group Y represents an oxygen or sulfur atom or a group NR, --CR5 or --CHR5,

the group R represents a hydrogen atom or an alkyl, aryl or aralkyl group,

the groups R1, R5 and R6, which may be identical or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy group,

the group R2 represents a hydrogen atom or an alkyl group,

the group R3 represents an aryl group,

and the group R4 represents a hydrogen atom or an alkyl, aryl, aralkyl, alkylsaufonamide, arylsulfonamide or aralkylsulfonamide group.

c) Reduction of the amide of general formula V, advantageously with LiAlH.sub.4, in a compound of general formula I.

The carboxylic acids of general formula VIII and the amines of general formula VII are readily available commercially.

The simplicity of this synthesis and its very good yield make it possible to introduce a large variety of substituents R, R1, R2, R3, R4, R5 and R6 onto the compound of general formula I.

The use, in the method of synthesis, of an optically pure isomer of the amine of general formula VII allows the synthesis of an optically pure compound of general formula I.

The present invention also relates to the amides of the following general formula V:

##STR00012## in which:

the group X represents a group --NR4, --CH.dbd.N-- or --CHR5-NR4-,

the group Y represents an oxygen or sulfur atom or a group NR, --CR5, --CHR5, --CR5=CR6- or --CHR5-CHR6-, on the condition that, when the group X represents the group --CH.dbd.N-- or --CHR5-NR4-, the group Y represents an oxygen or sulfur atom or a group NR, --CR5 or --CHR5,

the group R represents a hydrogen atom or an alkyl, aryl or aralkyl group,

the groups R1, R5 and R6, which may be identical or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy group,

the group R2 represents a hydrogen atom or an alkyl group,

the group R3 represents an aryl group,

and the group R4 represents a hydrogen atom or an alkyl, aryl, aralkyl, alkylsulfonamide, arylsulfonamide or aralkylsulfonamide group,

and their salts with a pharmaceutically acceptable acid.

These amides are a reaction intermediate of the synthesis of the compound of general formula I.

The amides according to the invention all have an asymmetric center and may therefore exist in the form of optical isomers. The present invention also comprises the isomers, either separately or as a mixture.

The present invention also relates to the pharmaceutical compositions comprising, as active principle, one of the compounds defined above, and a suitable excipient. These compositions can be formulated for administration to mammals, including humans. The dosage varies depending on the treatment and depending on the condition in question. These compositions are prepared so as to be administrable by the digestive or parenteral route.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active ingredient can be administered in unit forms for administration, mixed with conventional pharmaceutical carriers, to animals or to humans. Suitable unit forms for administration comprise the forms for oral administration, such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, the forms for sublingual and buccal administration, the forms for subcutaneous, intramuscular, intravenous, intranasal or intraoccular administration and the forms for rectal administration.

When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. The tablets may be coated with sucrose or with other suitable materials, or they may be treated in such a way that they have a prolonged or delayed activity and they continuously release a predetermined amount of active principle.

A preparation in gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.

A preparation in the form of a syrup or an elixir may contain the active ingredient together with a sweetener, an antiseptic, and also a taste enhancer and a suitable coloring agent.

The water-dispersible powders or granules may contain the active ingredient mixed with dispersing agents or wetting agents, or suspending agents, and with flavor correctors or sweeteners.

For rectal administration, suppositories are used which are prepared with binders which melt at rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral, intranasal or intraoccular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and/or wetting agents are used.

The active principle may also be formulated in the form of microcapsules, optionally with one or more carrier additives.

The present invention also relates to the use of these compounds, and of the pharmaceutical compositions comprising them, as a modulator of CaSR activity.

The CaSR can be found in the parathyroid gland, the thyroid, bone cells, the stomach, the lung, the kidney, pituitary gland, the brain, the hypothalamus, the olfactory areas or the hippocampus.

The compounds according to the present invention are preferably more selective, in their use, with respect to the receptors of the parathyroid compared with those of the thyroid gland.

The compounds according to the invention, and the pharmaceutical compositions comprising them, may be used as a medicinal product, in particular for the treatment of physiological disorders or diseases associated with disturbances of CaSR activity. Even more particularly, these physiological disorders or diseases of the type including primary or secondary hyperparathyroidism, osteoporosis, cardiovascular, gastrointestinal, endocrine or neurodegenerative diseases or certain cancers in which (Ca.sup.2+).sub.e ions are abnormally high. The secondary hyperparathyroidism is more particularly observed in chronic renal failure.

The following example of synthesis of compounds according to the invention is given by way of nonlimiting illustration of the invention.

Synthesis of (R)-N-[1-(1-naphthyl)ethyl]indole-2-carboxamide

7 equivalents of thionyl chloride (0.760 ml; 10.5 mmol) and 0.020 ml of N,N-dimethylformamide (DMF) are successively added, at ambient temperature, under argon, to a solution of indole-2-carboxylic acid (242 mg; 1.5 mmol) in 10 ml of chloroform. After stirring overnight at 30.degree. C., the mixture is evaporated to dryness to give a corresponding acid chloride in the form of an oily yellow residue. The latter is dissolved in 10 ml of chloroform and then 1.5 equivalents of triethylamine (0.315 ml; 2.25 mmol) and 1.5 equivalents of (R)-1-(1-naphthyl)ethylamine (0.360 ml; 2.25 mmol) are added. The solution is stirred for 2 hours at ambient temperature before being concentrated and then purified on a silica column (eluant: heptane/ethyl acetate: 4/1). 340 mg (1.08 mmol; 72%) of the amide are isolated in the form of a yellow solid.

Mass spectrometry (ES): m/z: 315 [M+H].sup.+

Synthesis of (R)-N-[(indole-2-yl)methyl]-N-[1-(1-naphthyl)ethyl]amine.HCl (PHD 337-R)

A solution of aluminum chloride, AlCl.sub.3 (213 mg; 1.6 mmol), in 4 ml of distilled tetrahydrofuran (THF) is added, at ambient temperature, under argon, to a solution of lithium aluminum hydride, LiAlH.sub.4 (60 mg; 1.6 mmol), in 2 ml of distilled THF. The solution is stirred for 45 minutes at ambient temperature before introducing the amide (252 mg; 0.80 mmol) in steps. The reaction medium is then heated to 60.degree. C. After 6 hours of reaction, a further two equivalents of LiAlH.sub.4 (60 mg; 1.6 mmol) are added. The reaction is left overnight at 60.degree. C. and then, after cooling, the medium is hydrolyzed by slowly adding aqueous 10% THF. The mixture is then treated with a molar sodium hydroxide solution before being extracted 3 times with ethyl ether. The organic phase is dried over sodium sulfate, evaporated and purified on a silica column (eluant: heptane/ethyl acetate: 60/10). 200 mg (0.66 mmol; 83%) of a yellow oil are isolated. The free amine is then transformed into its hydrochloride by treatment in chloroform with a saturated solution of hydrochloric acid in methanol.

Melting point: 204.degree. C.

Mass spectrometry (ES): m/z: 301 [M+H].sup.+

Optical rotation: [.alpha.].sup.20 .sub.D=+25.0.degree. (c 0.4, CHCl.sub.3)

Activity on Transfected Cells Expressing the [Ca.sup.2+].sub.e Ion Sensing Receptor

The calcimimetic activity of the compounds was estimated by measuring the accumulation of tritiated inositol phosphates, induced by 10 .mu.M of each of the compounds in the presence of 2 mM of Ca.sup.2+, in CHO(CaSR) cells (Ferry et al, Biochem Biophys Res Commun, 1997).

This activation was compared with that induced by the compound NPS-R-568, a reference calcimimetic used at a concentration of 10 .mu.M (Table 1) (Ferry et al, Biochem Biophys Res Commun, 1997; Nemeth et al, Proc Natl Acad Sci USA, 1997).

The compounds PHD 337, PHD 337R and PHD 356, used at a concentration of 10 .mu.M, exhibit an activity ranging from 90 to 100% of that obtained with 10 mM of Ca.sup.2+, comparable to that of the compound NPS-R-568 at the same concentration (Table 1). It should be noted (Table 2) that the compounds PHD 337 and PHD 337R or the compound PHD 356 at 1 .mu.M exhibit an activity which is 50% greater than that of calcium (10 mM), whereas the compound PHD 363 is less active at this same concentration, suggesting that the group R1 on the phenyl ring has an important role.

TABLE-US-00001 TABLE 1 Accumulation of tritiated inositol phosphates in CHO (CaSR) cells, induced by the PHD/AK compounds and by the calcimimetic compound NPS-R-568 Empirical Accumulation of formula- (.sup.3H)-IP % of Molar mass the 10 mM Ca.sup.2+ Compound- (melting response .+-. (10 .mu.M) point) Structure S.E. NPS R-568 C.sub.18H.sub.22ClNO.HCl340,29 ##STR00013## 106 .+-. 15 PHD 337 C.sub.21H.sub.20N.sub.2.2HCl373,32 ##STR00014## 103 .+-. 6 PHD 337-R C.sub.21H.sub.20N.sub.2.2HCl373,32 ##STR00015## 117 .+-. 5 PHD 337-S C.sub.21H.sub.20N.sub.2.2HCl373,32 ##STR00016## 32 .+-. 5 PHD 356 C.sub.29H.sub.20N.sub.2O.2HCl353,29 ##STR00017## 105 .+-. 15 PHD 359 C.sub.22H.sub.22N.sub.2O.2HCl403,34 ##STR00018## 55 .+-. 5 PHD 361 C.sub.21H.sub.19FN.sub.2.2HCl391,32 ##STR00019## 87 .+-. 7 PHD 363 C.sub.21H.sub.19CN.sub.2.2HCl407,77 ##STR00020## 60 .+-. 1 PHD 368 C.sub.21H.sub.22N.sub.2.2HCl375,34 ##STR00021## 77 .+-. 1 PHD 338 C.sub.29H.sub.28N.sub.2O.sub.4S.2HCl537,08 ##STR00022## 54 .+-. 5 AK 43 C.sub.22H.sub.22N.sub.2.2HCl350,89 ##STR00023## 79 .+-. 13

The calcimimetic activity of the PHD/AK compounds is compared with that of a reference compound, NPS-R-568, used at the same concentration and under the same experimental conditions. This activity is expressed as a percentage of the activity of 10 mM of Ca.sup.2+. The means.+-.standard errors of the means of 2 to 5 independent manipulations are indicated. The experiments were carried out in the presence of 2 mM of Ca.sup.2+.

TABLE-US-00002 TABLE 2 Accumulation of tritiated inositol phosphates in CHO (CaSR) cells, induced by the PHD compounds at 1 .mu.M Empirical Accumulation of formula- (.sup.3H)-IP % of Molar mass the 10 mM Ca.sup.2+ Compound- (melting response .+-. (10 .mu.M) point) Structure S.E. PHD 337 C.sub.21H.sub.20N.sub.2.2HCl373,32 ##STR00024## 69 .+-. 9 PHD 337-R C.sub.21H.sub.20N.sub.2.2HCl373,32 ##STR00025## 73 .+-. 10 PHD 337-S C.sub.31H.sub.20N.sub.2.2HCl373,32 ##STR00026## 3 .+-. 2 PHD 356 C.sub.29H.sub.20N.sub.2O.2HCl353,29 ##STR00027## 76 .+-. 1 PHD 363 C.sub.21H.sub.19ClN.sub.2.2HCl407,77 ##STR00028## 6 .+-. 3

4.2 Specificity of the Activity of These Molecules

The PHD molecules, used at a concentration of 10 .mu.M, produce little or no accumulation of [.sup.3H]IP in control CHO(WT.sup.+) cells, which suggests their specificity of action with respect to the CaSR (Table 3). The CHO(WT.sup.+) cells were transfected with the plasmid alone and do not express the CaSR.

The accumulation of tritiated inositol phosphates is expressed as a percentage of the basal level observed in the presence of 2 mM Ca.sup.2+ (100%) in CHO (WT.sup.+) or CHO(CaSR) cells.

TABLE-US-00003 TABLE 3 Accumulation of tritiated inisotol phosphates in the CHO (CaSR) and CHO (WT*) cells, induced by the PHD/AK compounds and the calcimimetic compound NPS-R-568 Accumulation of (.sup.1H)-IP % of Compound- basal level (10 .mu.M) Structure CHO (WT*) CHO (CaSR) NPS R-568 ##STR00029## 110 .+-. 9 454 .+-. 33 PHD 337 ##STR00030## 147 .+-. 14 444 .+-. 101 PHD 337-R ##STR00031## 130 .+-. 9 588 .+-. 129 PHD 337-S ##STR00032## 132 .+-. 1 225 .+-. 7 PHD 356 ##STR00033## 151 .+-. 7 482 .+-. 58 PHD 359 ##STR00034## 117 .+-. 8 303 .+-. 42 PHD 361 ##STR00035## 133 .+-. 3 420 .+-. 70 PHD 363 ##STR00036## 125 .+-. 12 325 .+-. 67 PHD 368 ##STR00037## 126 .+-. 6 388 .+-. 85 PHD 338 ##STR00038## 111 .+-. 10 202 .+-. 9 AK 43 ##STR00039## 109 .+-. 2 401 .+-. 16

*


Free Web Sudoku Puzzles.
Solve with your browser.
1   5   8 6 2    
9         1   5  
        5        
3         9 8 6  
                 
  9 4 2         3
        6        
  7   8         5
    2 4 7   9   8
What is it?



Add Your Site · Terms Of Service · Privacy Policy


DISCLAIMER
Linkgrinder is a free service that searches the Internet and indexes all files found so that you may search quickly and easily for shared files. These files are created and made available individually by users whose identity we are not aware of and who we have no control over. In essence we function like a search engine tool; these files ARE NOT STORED OR SERVED BY OUR NETWORK. We are not responsible for any materials obtained by using our service. We do not monitor any of the contents of these files. These files may contain viruses, illegal materials, materials inappropriate for minors, offensive files and the like. BY USING OUR SERVICE, YOU ASSUME FULL RESPONSIBILITY FOR DOWNLOADING THESE MATERIALS AND WILL INDEMNIFY US FOR ANY DAMAGES THAT MAY BE INCURRED.

For More Specific Information VIEW OUR TERMS OF SERVICE.

Thank you and Enjoy!