EP2201007A1 - Cannabinoid-rezeptorliganden - Google Patents

Cannabinoid-rezeptorliganden

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Publication number
EP2201007A1
EP2201007A1 EP08858116A EP08858116A EP2201007A1 EP 2201007 A1 EP2201007 A1 EP 2201007A1 EP 08858116 A EP08858116 A EP 08858116A EP 08858116 A EP08858116 A EP 08858116A EP 2201007 A1 EP2201007 A1 EP 2201007A1
Authority
EP
European Patent Office
Prior art keywords
thiazol
pyran
tert
tetrahydro
radical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08858116A
Other languages
English (en)
French (fr)
Inventor
Jérémiah HARNETT
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ipsen Pharma SAS
Original Assignee
Ipsen Pharma SAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ipsen Pharma SAS filed Critical Ipsen Pharma SAS
Publication of EP2201007A1 publication Critical patent/EP2201007A1/de
Withdrawn legal-status Critical Current

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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions

  • the present application relates to novel derivatives of 4-phenyl-1,3-azoles. These products have good affinity for certain cannabinoid receptor subtypes, particularly CB2 receptors. They are particularly useful for treating disease states and diseases in which one or more cannabinoid receptors are involved.
  • the invention also relates to pharmaceutical compositions containing said products and their use for the preparation of a medicament.
  • Cannabinoids found in Indian cannabis are
  • Cannabinoids are known to have effects on the central nervous system and / or the cardiovascular system. These effects include impaired memory, euphoria, and sedation. Cannabinoids also increase heart rate and alter systemic blood pressure. Peripheral effects related to bronchial constriction, immunomodulation and inflammation were also observed. More recently, cannabinoids have been shown to modulate cellular and humoral immune responses and have anti-inflammatory properties.
  • CB1 and CB2 cannabinoid receptors
  • CB1 is expressed predominantly in the central nervous system
  • CB2 is expressed in peripheral tissues, mainly in the immune system.
  • These two receptors are members of the G-protein coupled receptor family and their inhibition is related to the activity of adenylate cyclase.
  • compounds capable of selectively modulating the activity of cannabinoid receptors that is to say, selective products of a particular receptor subtype.
  • the problem to be solved by the invention is to provide products having an affinity for cannabinoid receptors and more particularly selective products of the CB2 receptor subtype.
  • the invention also provides the use of the compounds of general formula (I) for the treatment and prevention of disease states and diseases associated with cannabinoid receptor activity such as, but not limited to, cell proliferation disorders such as cancer, immune disorders and autoimmune diseases, allergic diseases, inflammation, pain, eye diseases, lung diseases, osteoporosis, gastrointestinal disorders, neurodegenerative diseases, cardiovascular diseases.
  • cell proliferation disorders such as cancer, immune disorders and autoimmune diseases, allergic diseases, inflammation, pain, eye diseases, lung diseases, osteoporosis, gastrointestinal disorders, neurodegenerative diseases, cardiovascular diseases.
  • diseases include, for example, the following diseases or conditions: disorders of the immune system, including autoimmune diseases: psoriasis, lupus erythematosus, connective tissue diseases or connective tissue diseases, Sj ⁇ gren's syndrome, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis , undifferentiated spondyloarthritis, Behcet's disease, hemolytic autoimmune anemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, transplant rejection, diseases affecting the plasma cell line; allergic diseases: delayed or immediate hypersensitivity, allergic rhinitis, contact dermatitis, allergic conjunctivitis; parasitic, viral or bacterial infectious diseases: AIDS, meningitis; amyloidosis, diseases affecting lineages of the lympho-hematopoietic system; chronic diseases of the liver of alcoholic, viral and toxic origin as well as stéato hepatitis of non-alcoholic origin and primary
  • A represents a radical -NR5R6, -CR5R6R7, or -OR5 with R5, R6, R7 independently representing a hydrogen atom, an alkyl or cycloalkyl radical;
  • A represents -NR5R6, with R5 and R6 forming together with the nitrogen atom to which they are attached a heterocycloalkyl;
  • A represents -CR5R6R7, with R5, R6 and R7 forming together with the carbon atom to which they are attached a cycloalkyl;
  • n an integer from 1 to 3 inclusive
  • B represents an oxygen atom, sulfur, a methylene radical or a radical -NR9-;
  • X represents an oxygen or sulfur atom
  • R4 represents a hydrogen atom or an alkyl radical
  • R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH 2 RH, -SR11, haloalkyl, -N (R9) 2 , -OR10;
  • R9 represents a hydrogen atom or an alkyl radical
  • R10 represents a hydrogen atom, an alkyl radical, or aryl optionally substituted with one or more identical or different radicals independently selected from halo, nitro, cyano, or alkoxy;
  • R 1 represents an aryl radical
  • alkyl when no more details are given, is meant a linear or branched alkyl radical containing from 1 to 8 carbon atoms, and preferably from 1 to 6 carbon atoms, even more preferably from 1 to 4 carbon atoms. carbon atoms.
  • linear or branched alkyl having from 1 to 6 carbon atoms is meant, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl and isohexyl radicals.
  • Haloalkyl means an alkyl radical as defined above, at least one of the hydrogen atoms is substituted by a halogen atom such as the -CF 3 radical.
  • Alkoxy when no further details are given, means an -O-alkyl radical in which the term alkyl is as defined above.
  • alkoxy represents a radical such as methoxy, ethoxy, propyloxy, isopropyloxy and very preferably the methoxy radical.
  • cycloalkyl when not given more details is meant a saturated carbocyclic radical having 3 to 7 carbon atoms such as for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • heterocycloalkyl or heterocyclic is meant in the sense of the present invention a non-aromatic cyclic radical comprising from 4 to 7 atoms, these atoms being chosen from carbon, nitrogen, oxygen or sulfur, or one of their combinations such as, for example, piperidine, pyrrolidine, azetidine, morpholine, thiomorpholine, piperazine and homopiperazine radicals.
  • piperazine means a radical
  • R8 represents a hydrogen atom or an alkyl radical.
  • R8 represents a hydrogen atom or an alkyl radical.
  • aryl an unsaturated carbocyclic system comprising at least one aromatic ring, preferably a radical chosen from phenyl, naphthyl and fluorenyl and very preferably a phenyl radical.
  • the subject of the invention is a compound of general formula (I) in which R 1, R 2, R 3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH 2 RH, -SR 11, haloalkyl N (R9) 2 , -OR10; R10 represents a hydrogen atom, an alkyl or phenyl radical optionally substituted with one or more identical or different radicals independently chosen from halo, nitro, cyano or alkoxy; and R11 represents a phenyl radical.
  • R 1, R 2, R 3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH 2 RH, -SR 11, haloalkyl N (R9) 2 , -OR10
  • R10 represents a hydrogen atom, an alkyl or phenyl radical optionally substituted with one or more identical or different radicals independently chosen from halo, nitro, cyano or alkoxy
  • R11 represents a phen
  • the subject of the invention is a compound of general formula (I) in which R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH 2 RH, -SR11, haloalkyl, -N (R9) 2 , -OR10; R10 represents a hydrogen atom, an alkyl or phenyl radical optionally substituted with one or more identical or different radicals independently chosen from halo, nitro, cyano, or methoxy; and R11 represents a phenyl radical.
  • R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH 2 RH, -SR11, haloalkyl, -N (R9) 2 , -OR10
  • R10 represents a hydrogen atom, an alkyl or phenyl radical optionally substituted with one or more identical or different radicals independently chosen from halo, nitro, cyano, or meth
  • the subject of the invention is a compound of general formula (I) in which X represents the sulfur atom.
  • the subject of the invention is a compound of general formula (I) in which X represents the oxygen atom.
  • the compound according to the invention has radicals R1, R2, R3 independently representing a hydrogen atom, a halogen atom, an alkyl radical or -OR10.
  • the compound according to the invention has radicals R1, R2, R3 which independently represent an alkyl radical or -OR10, in which R10 represents a hydrogen atom or an alkyl radical.
  • the compound according to the invention has a radical A which represents a radical -NR5R6 in which R5 and R6 independently represent a hydrogen atom or an alkyl radical.
  • the compound according to the invention has a radical A which represents -NR5R6 in which R5 and R6 together with the nitrogen atom to which they are attached form a heterocycloalkyl.
  • the compound according to the invention has a radical B which represents an oxygen or sulfur atom.
  • the compound according to the invention can correspond to the general formula (I) in which:
  • A independently represents a -NR5R6 radical, with R5, R6, independently representing a hydrogen atom, an alkyl or cycloalkyl radical; or A represents -NR5R6, with R5 and R6 forming together with the nitrogen atom to which they are attached a heterocycloalkyl;
  • n an integer from 1 to 3 inclusive
  • B represents an oxygen atom, sulfur, a methylene radical, or a radical -NR9;
  • X represents an oxygen or sulfur atom
  • R4 represents a hydrogen atom or an alkyl radical
  • R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -OR10;
  • R9 represents a hydrogen atom or an alkyl radical
  • R10 represents a hydrogen atom, an alkyl or aryl radical optionally substituted with one or more identical or different radicals independently chosen from halo, nitro, cyano or alkoxy;
  • the compound according to the invention can correspond to the general formula (I) in which:
  • A represents a radical -NR5R6, wherein R5 and R6 independently represent a hydrogen atom, an alkyl or cycloalkyl radical;
  • A represents -NR5R6, with R5 and R6 forming together with the nitrogen atom to which they are attached a heterocycloalkyl;
  • n an integer from 1 to 3 inclusive
  • B represents an oxygen atom, or sulfur
  • X represents an oxygen or sulfur atom
  • R4 represents a hydrogen atom or an alkyl radical
  • R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical, -CH 2 RH, -SR11, haloalkyl, -N (R9) 2 , -OR10;
  • R10 represents a hydrogen atom, alkyl, or an aryl radical optionally substituted with one or more identical or different radicals independently selected from halo, nitro, cyano, or alkoxy;
  • R11 represents an aryl radical; or a pharmaceutically acceptable salt thereof.
  • the compound according to the invention can correspond to the general formula (I) in which:
  • A represents a radical -NR5R6, wherein R5 and R6 independently represent a hydrogen atom, an alkyl or cycloalkyl radical;
  • A represents -NR5R6, with R5 and R6 forming together with the nitrogen atom to which they are attached a heterocycloalkyl;
  • n an integer from 1 to 3 inclusive
  • B represents an oxygen or sulfur atom
  • X represents an oxygen or sulfur atom
  • R4 represents a hydrogen atom or an alkyl radical
  • R1, R2, R3 independently represent a hydrogen atom, a halogen atom, an alkyl radical or -OR10;
  • R10 represents a hydrogen atom, alkyl, or an aryl radical optionally substituted with one or more identical or different radicals independently selected from halo, nitro, cyano, or alkoxy; or a pharmaceutically acceptable salt thereof.
  • the compound according to the invention is chosen from the following compounds or their salts:
  • the compound according to the invention is chosen from the following compounds or their salts:
  • the compounds according to the invention can be prepared according to the methods described below, of course, these methods are given for illustrative purposes and the skilled person can subject them to the variations that he judges useful, as well as to relates to the reagents that the conditions and techniques of the reactions.
  • ambient temperature indicates a temperature of between 20 ° C. and 25 ° C .; the yields of the reactions are indicated in molar percentage and the definition of the radicals is that given previously.
  • the different synthetic routes are envisaged and presented here according to the nature of the group A, which may be a substituted nitrogen atom -NR5R6, a substituted carbon atom -CR5R6R7 or a substituted oxygen atom - OR5.
  • the ketone derivatives (3) are converted into the corresponding ⁇ -haloketones of general formula (4) such as, for example, ⁇ -bromo-ketones by reaction with a halogenating agent such as, for example, CuBr 2 in ethyl acetate (J. Org Chem (1964), 29, 3459), or bromine (J. Het Chem (1988), 25, 337), or N-bromosuccinimide (J. Amer. Chem Soc. (1980), 102, 2838) in the presence of acetic acid in a solvent such as ethyl acetate or dichloromethane.
  • a halogenating agent such as, for example, CuBr 2 in ethyl acetate (J. Org Chem (1964), 29, 3459), or bromine (J. Het Chem (1988), 25, 337), or N-bromosuccinimide (J. Amer. Chem Soc. (1980), 102, 2838) in the presence of ace
  • the ketone derivatives (3) can also be converted into the corresponding ⁇ -halogenoketones of the general formula (4) by reaction with other halogenating agents such as HBr or Br 2 in ether or acetic acid (Bioorg Chem Chem Lett (1996), 6 (3), 253-258, J. Med Chem (1988), 31 (10), 1910-1918) or with the aid of a resin of bromation (J. Macromol Sci Chem (1977), A11, (3) 507-514).
  • Ketones (3) which are not commercially available are prepared from carboxylic acids (1) converted into Weinreb carboxamides (2) by reacting the carboxylic acids of general formula (1) with O, N-dimethylhydroxylamine hydrochloride in the presence of EDC and HOBT. Then the Weinreb carboxamides (2) are converted into ketones of general formula (3) by reaction with organometallic reagents R4-CH 2 -M, where M is a metal radical and in particular Li or MgCl or MgBr.
  • the compounds of general formula (6) comprising carboxamides (6a) and thiocarboxamides (6b) are prepared from amino acids (5) whose amino functions are protected by protective groups Gp1 and Gp2 such as Boc, Fmoc, CBZ , Bn.
  • Amino acids (5) are treated with ammonia-HOBT (NH 3 -HOBT, see experimental part) in a solvent such as DMF in the presence of BOP to form carboxamides (6a).
  • These carboxamides (6a) react with (P 2 S 5 J 2 or Lawesson's reagent in an organic solvent such as dioxane or benzene at a temperature preferably between room temperature and that of the reflux of the mixture to yield thiocarboxamides of general formula (6b).
  • the compounds of general formula (8) are prepared from the compounds of general formula (6).
  • the conditions differ according to the nature of the chain X.
  • the thiazoles of general formula (8) where X represents S are prepared from thiocarboxamides (6b), treated with ⁇ -haloketones (4) in an organic solvent such as acetone, ethanol or toluene at a temperature preferably between room temperature and that of the reflux of the mixture to yield thiazole compounds of general formula (8).
  • the oxazoles of general formula (8) wherein X is O are prepared from carboxamides (6a).
  • R 5 'and R 6' independently represent a hydrogen atom or an alkyl radical .
  • reductive amination such as sodium triacetoxyborohydride or sodium borohydride
  • a lower aliphatic alcohol such as methanol
  • molecular sieves the reaction temperature being between room temperature and that of the reflux of the mixture
  • the reductive amination can also be done by heating under a waves (Biotage® equipment) to form secondary (10) and / or tertiary amines (12) substituted with R5 'and / or R6' groups, it being understood that R5 'and R6' independently represent a hydrogen atom or a alkyl radical.
  • amines of general formula (13) and (14) according to scheme 2 are prepared from the halogenated derivatives (RS-HaI and R6-Hal where HaI is a halogen) to form secondary amines (13) and / or tertiary (14).
  • the amines of general formula (15) are prepared using dihaloalkyl (11) wherein B2 is NR8, NGp3, O, S or methylene.
  • the dihaloalkyl (11) and the compounds (9) react in a polar solvent such as, for example, ethanol in the presence of a base such as, for example, sodium bicarbonate, triethylamine, with or without sodium iodide, at a temperature of of reaction between the ambient temperature and that of the reflux of the mixture.
  • the reaction may also be carried out by heating under microwaves (equipment Biotage) at a temperature between 100 c C and 200 0 C for 4 to 60 minutes to complete heterocyclic general formula (15).
  • B2 represents a protected nitrogen atom NGp3
  • the compounds of general formula (15) are deprotected to give the corresponding amines of general formula (16) according to methods known to those skilled in the art, Gp3 may be CBZ, Boc, Fmoc or Bn.
  • compounds (16) are alkylated according to method i, ii or iii to yield compounds (17).
  • the protective groups (Gp1 and Gp2) can be deprotected selectively or non-selectively under conditions known to those skilled in the art to yield compounds of general formula ( 21); by channel 1 if R5, R6 and R9 are identical (see diagram 3), or by channels 2 or 3 if R5, R6 and R9 are not identical (see diagram 4).
  • Gp1 and Gp2 can be selected from CBZ, Boc, Fmoc, or Bn.
  • Gp1 and Gp2 are the Fmoc protective groups, they can be deprotected by an excess dimethylamine in an organic solvent such as, for example, tetrahydrofuran, at a reaction temperature between room temperature and 55 ° C.
  • Gp1 and Gp2 are Boc protecting groups they are deprotected by gaseous HCl bubbling in a solvent such as for example ethyl acetate to access the amines (20).
  • Gp1 is not identical to Gp2
  • the amino functions can be deprotected selectively under conditions known to those skilled in the art.
  • Gp1 represents a Fmoc group
  • Gp2 represents a Boc group
  • the Fmoc group is cleaved to release the amines (19) as free bases under basic conditions (for example dimethylamine in THF)
  • the Boc group is cleaved in acidic medium to lead to amines (20) or vice versa.
  • the amines (20) are then trialkylated by methods i, ii or Mi to form the compounds of general formula (21).
  • the compounds of general formula (27) are prepared according to the procedures described in scheme 4.
  • the protective groups Gp1 and Gp2 are cleaved selectively under conditions known to those skilled in the art.
  • Gp1 represents a group Fmoc
  • Gp2 represents a group Boc
  • the grouping Fmoc can be cleaved to liberate the amines (19) as free bases under basic conditions (eg dimethylamine in THF), to initiate pathway 2
  • the protecting group Gp2 can be selectively cleaved in an acid medium to form the amines (22) to initiate the pathway 3.
  • Figure 4 According to Route 2: After the selective deprotection of the compounds of the general formula (18), the primary amines (19) are alkylated by the methods i, ii, iii or iv described above to form the compounds (23). These compounds (23) are then deprotected to release secondary amines (25) which are in turn alkylated according to methods i, ii or iii to yield compounds (27).
  • the secondary amines (22) are alkylated by methods i, ii or iii to form the compounds of general formula (24).
  • the Gp1 group of the compounds (24) is then cleaved to form the primary amines (26) which are in turn alkylated by the methods i, ii, iii or iv to yield the compounds (27).
  • Compounds of general formula (30), including carboxamides (30a) where X is O and thiocarboxamides (30b) where X is S are prepared from carboxylic acids (28).
  • the dianion of the carboxylic acids (28) can be prepared by treatment with an excess of LDA (at least two eq.) At a temperature between 0 ° C and -78 ° C in tetrahydrofuran.
  • the amine (32a) is deprotected under standard conditions known to those skilled in the art, Gp2 being selected from the groups CBZ, Boc, Fmoc or Bn.
  • Gp2 being selected from the groups CBZ, Boc, Fmoc or Bn.
  • Gp2 is the Fmoc protecting group
  • it is deprotected by an excess of dimethylamine in a solvent such as tetrahydrofuran, at a reaction temperature between room temperature and 55 ° C to provide the compounds (33).
  • These compounds of general formula (33) may be alkylated according to procedures (i) ii) or (iii) to provide the compounds of general formula (34).
  • ketones of general formula (40) including carboxamides (40a) where X is O and thiocarboxamides (40b) where X is S are prepared from ketones of general formula (35) via trimethylsilyl ether cyanohydrins (36) .
  • the ketones (35) react with cyanotrimethylsilyl ether in the presence of a catalyst such as zinc iodide in an anhydrous solvent such as THF, to form the trimethylsilyl-ether cyanohydrins (36) which are not isolated but hydrolyzed by HCI solution to form the hydroxy acids (37).
  • the acids (37) are converted to ethyl or methyl esters and the hydroxyl group is alkylated by reaction with the halogenated derivatives R5-Hal (HaI being a halogen atom) in the presence of a base such as NaH in an anhydrous solvent such as than THF to form the compounds (38).
  • the esters obtained are then saponified by the action of a base such as for example LiOH in tetrahydrofuran to form the acids (39) which are subsequently converted into compounds of general formula (40), including carboxamides (40a) where X represents O and the thiocarboxamides (40b) where X represents S by the methods previously described for the compounds of general formula (6), as illustrated in scheme 1.
  • the compounds of general formula (40) are reacted with the halogenated derivatives of formula general (4) to yield compounds (42) by the previously described methods for compounds (8), as shown in Scheme 2.
  • the subject of the present invention is also a process for the preparation of a compound of general formula (I) as described above, characterized in that an ⁇ -haloketone of general formula (4) is reacted.
  • R1, R2, R3, R4, X, B, n, R5, R6 and R7 are as defined above;
  • R1, R2, R3, R4, X, B, n and R5 are as defined above;
  • R 1, R 2, R 3, R 4, X, B 1 n, R 5 and R 6 are as defined above and R 5 and / or R 6 is not hydrogen.
  • the present invention also relates to the compounds of general formula (I) as described above or a pharmaceutically acceptable salt of such a compound, as a drug.
  • the subject of the present invention is also pharmaceutical compositions comprising, as active ingredient, a compound of general formula (I) as described above or a pharmaceutically acceptable salt of such a compound, with at least one pharmaceutically acceptable excipient. acceptable.
  • the present invention also relates to the use of at least one compound of general formula (I) as described above, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing a disease or a disease.
  • disorder selected from the following diseases or disorders: cell proliferative disorders such as cancer, immune disorders and autoimmune diseases, allergic diseases, inflammation, pain, eye conditions, lung diseases, osteoporosis , gastrointestinal disorders, neurodegenerative diseases, cardiovascular diseases.
  • the subject of the present invention is also the use of the compounds of general formula (I) as described above or a pharmaceutically acceptable salt of such a compound, for preparing a medicament intended to treat or prevent cancers. .
  • the present invention also relates to the use of at least one compound of general formula (I) as described above, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating or preventing the cancer, characterized in that the cancers intended to be treated or prevented are chosen from cancers of the colon, rectum, stomach, lungs, pancreas, kidney, testes, breast, uterus, ovarian, prostate, skin, bones, spinal cord, neck, tongue, head as well as sarcomas, carcinomas, fibroadenomas, neuroblastomas, leukemias, melanomas .
  • the cancers intended to be treated or prevented are chosen from cancers of the colon, rectum, stomach, lungs, pancreas, kidney, testes, breast, uterus, ovarian, prostate, skin, bones, spinal cord, neck, tongue, head as well as sarcomas, carcinomas, fibroadenomas, neuroblastomas, leukemias, melanomas .
  • some of the compounds of general formula (I) can be in the form of enantiomers.
  • the present invention includes both enantiomeric forms and any combinations of these forms, including racemic "R, S" mixtures.
  • racemic "R, S” mixtures for the sake of simplicity, when no specific configuration is indicated in the structural formulas, it should be understood that the two enantiomeric forms and their mixtures are represented.
  • the compound of general formula (I) or its salt used according to the invention or the combination according to the invention may be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories.
  • the Suitable solid carriers may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose, and the like. sodium, polyvinylpyrrolidine and wax.
  • the compound of general formula (I) or its salt used according to the invention or the combination according to the invention may also be in liquid form, for example solutions, emulsions, suspensions or syrups.
  • suitable liquid carriers may be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
  • a compound of general formula (I) or its salt used according to the invention or the combination according to the invention may be carried out topically, orally, parenterally, by intramuscular injection, subcutaneously, etc.
  • the dose of a product according to the present invention varies according to the mode of administration, the age and the body weight of the subject to be treated as well as the state of the latter, and it will ultimately be decided by the attending physician or veterinarian. Such a quantity determined by the attending physician or veterinarian is referred to herein as a "therapeutically effective amount”.
  • the envisaged administration dose for a drug according to the invention is between 0.1 mg and 10 g depending on the type of active compound used.
  • Melting points were measured using a B ⁇ chi B-545 capillary device or a Leica VMHB kofler system.
  • the compounds are characterized by their molecular peak (MH +) determined by mass spectrometry (MS), using a simple quadrupole mass spectrometer (Micromass, Platform model) equipped with an electrospray source, used with a resolution of 0.8 da at 50% of valley.
  • MS mass spectrometry
  • the sodium hydride can also be changed to potassium carbonate and the solvent to DMF to provide the type I intermediates.
  • the product obtained is then extracted with ethyl acetate and water, and after decantation, the organic phase is washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous sodium chloride solution, dried on magnesium sulfate and filtered. The filtrate is concentrated to dryness to give a white solid, the solid is triturated with ethyl ether and filtered. The solid is washed with ether to provide the intermediate
  • Intermediate 1.4 (0.5 g, 1.3 mmol) and intermediate 1.2 (0.446 g, 1.3 mmol) are dissolved in acetone (20 ml) under an argon atmosphere and the mixture is then heated at 50 ° C. for 5 hours. hours and then left stirring at room temperature for 12 hours. Then it is taken up with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride.
  • Example 1 The product 1.6 of Example 1 (0.180 g, 0.447 mmol) is solubilized in DMSO (2 ml) and formaldehyde (72 ⁇ l, 0.894 mmol) is added thereto, followed by formic acid (47 ⁇ l, 0.894 mmol). .
  • the reaction mixture is heated under microwaves (Biotage® equipment) at 190 ° C. for 10 minutes. It is diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic phase is then washed with a saturated aqueous solution of sodium chloride. Then it is dried over magnesium sulfate. Filtered and then evaporated.
  • Example 3 is obtained in the form of a white solid after purification on a silica column (eluent: gradient of 10% to 40% of ethyl acetate in heptane) with a yield of 81.7%.
  • Example 4 is obtained in the form of a white solid with a yield of 86.8%.
  • Example 5 is obtained in the form of a yellow solid.
  • Example 6 is obtained in the form of a white solid.
  • step 1.3 3 - ⁇ [(9H-fluoren-9-ylmethoxy) carbonyl] amino ⁇ tetrahydrofuran-3-carboxylic acid replaces 4 - ⁇ [(9H-fluoren-9-ylmethoxy) carbonyl] amino ⁇ tetrahydro-2H-pyran-4-carboxylic acid in step 1.3 and 3,5-di-tert-butyl-4-hydroxy phenacyl bromide commercially available replaces intermediate 1.2 in step 1.5.
  • step 1.3 where commercially available 3,5-bis (trifluoromethyl) phenacyl bromide replaces intermediate 1.2 in step 1.5.
  • the expected final product is obtained in the form of a white solid.
  • intermediate 10.3 is obtained in the form of a light brown oil after purification on a silica column (eluent: sodium acetate). ethyl-heptane: 5-95) with a yield of 63%.
  • intermediate 10.4 is obtained in the form of a white foam after purification on a silica column (eluent: ethyl acetate heptane: 20-80) with a yield of 73%.
  • Example 10 is obtained in the form of a white crystalline solid after purification on a silica column (eluent ethyl acetate-heptane: 30-70) in quantitative yield.
  • Example 11 is obtained in the form of a pale yellow solid with a yield of 14%.
  • the experimental protocol used is the same as that described for Examples 1 and 2, in which 3,5-dimethyl-4-hydroxyacetophenone replaces 3,5-di-tert-butyl-4-hydroxyacetophenone.
  • the expected final product is obtained in the form of a white solid.
  • Example 15 is obtained in the form of a white solid with a yield of 12%.
  • 2-Bromo-1- (4-phenoxyphenyl) ethanone is prepared according to the method described above for Intermediate 1.2, where 4-phenoxyacetophenone replaces Intermediate 1.1.
  • ⁇ -Bromocetone is obtained as a red oil, and used directly in the next step.
  • Example 16 For the preparation of Example 16, the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting in step 1.5 and ⁇ -bromoketone 16.1 replacing intermediate 1.2. The expected final product is obtained in the form of a white solid.
  • Example 17 For the preparation of Example 17, the experimental protocol used is the same as that described for Example 2 in which Example 3 replaces Example 1, acetaldehyde replaces formaldehyde and the reaction mixture is heated under micro -ondes (Biotage® equipment) at 140 0 C for 4 minutes. The expected product in free base form is a pale yellow solid.
  • Example 3 (50 mg, 0.13 mmol) and paraformaldehyde (5 mg, 0.17 mmmol) is dissolved in methanol (1 mL) in a Biotage ® reaction tube and the molecular sieve (50 mg) followed by NaBH4 (10 mg, 0.26 mmol) are added.
  • the tube is sealed by a capsule, placed under microwave (Biotage ® ) and then heated with magnetic stirring at 120 ° C for 6 minutes.
  • the mixture is diluted with water and then extracted with ethyl acetate. After decantation, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then evaporated under vacuum.
  • the residue is purified on a silica column (eluent: 10% acetone in dichloromethane) and is salified directly.
  • the secondary amine (0.010 g, 0.025 mmol) is dissolved in ether (2 ml) and then HCl (0.1 ml, 1M in ether).
  • the solid formed is filtered and washed with ethyl ether and then dried under vacuum. A white solid is obtained with a yield of 21.1%.
  • Example 3 50 mg, 0.13 mmol and 1, 5-dibromopentane (201.4 mg, 0.876 mmmol) are dissolved in ethanol (1.5 mL) in a reaction tube Biotage ®.
  • Sodium bicarbonate 38 mg, 0.450 mmol is added and the tube is sealed with a capsule and heated under Biotage ® microwaves at 150 ° C for 15 minutes.
  • the mixture is diluted with water and then extracted with ethyl acetate. After decantation, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then evaporated under vacuum.
  • Example 21 For the preparation of Example 21, the experimental protocol used is the same as that described for Example 20 in which the bis (2-bromoethylether) (12 eq.) Replaces 1, 5-dibromopentane in the presence of an excess of sodium bicarbonate (14 eq.) - The reaction mixture is heated under microwaves (Biotage® equipment) at 160 ° C. for 45 minutes. The expected product is obtained in the form of a base, in the form of a white solid with a yield of 68.8%.
  • Example 22 For the preparation of Example 22, the experimental protocol used is the same as that described for Example 20 in which mechlorethamine (6 eq.) Replaces 1,5-dibromopentane. An excess of sodium bicarbonate is used (14 eq.), As well as triethylamine (6 eq.) And sodium iodide (12 eq.). The reaction mixture is heated under microwaves (Biotage® equipment) at 155 ° C. for 60 minutes. After treatment and purification on a silica column (eluent: 2% ethanol in dichloromethane), it is salified directly as in Example 20 and the expected product is obtained in the form of a white solid with a yield of 68.8%.
  • mechlorethamine (6 eq.) Replaces 1,5-dibromopentane.
  • An excess of sodium bicarbonate is used (14 eq.), As well as triethylamine (6 eq.) And sodium iodide (12 eq.).
  • step 1.4 The experimental protocol used is the same as that described for example 1 (step 1.4), intermediate 23.1 replacing intermediate 1.3.
  • the product 23.2 is obtained in the form of a white solid with a yield of 30%.
  • the di-isopropylethylamine (5.874 g, 0.058 mol) is dissolved in anhydrous THF (100 ml) at 0 ° C., then a solution of BuLi 1.6M in heptane (33 ml) is added dropwise and the mixture is stirred for 15 minutes. minutes.
  • the cyclopentanecarboxylic acid (2.738 g, 0.024 mol) in anhydrous THF is added at 0 ° C. and then stirred for 1 hour.
  • Iodoethane (3.928 g, 0.0252 mol) is added at -55 ° C. and then the mixture is allowed to rise to -100 ° C. for 12 hours.
  • reaction is cooled to -55 ° C and the reaction mixture is diluted with aqueous HCl (1N), extracted with ether. After decantation, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and then evaporated under vacuum. A red oil is obtained with a yield of 92%. The product is used directly in the next step.
  • Example 28 (4- ⁇ 4- [4- (Diethylamino) phenyl] -1,3-thiazol-2-yl ⁇ tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride
  • Example 29 For the preparation of Example 29, the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting in Step 1.5 where 1- (4-benzylphenyl) -2-bromoethanone replaces the intermediate 1.2 in step 1.5.
  • the expected final product is obtained in the form of a white solid.
  • 2- [4- (Bromoacetyl) phenoxy] -6-chlorobenzonitrile is prepared according to the method described for Intermediate 1.2, where 2- (4-acetylphenoxy) -6-chlorobenzene carbonitrile replaces Intermediate 1.1.
  • 2- [4- (Bromoacetyl) phenoxy] -6-chlorobenzonitrile is obtained in the form of a gray solid by crystallization from ether in quantitative yield.
  • Example 30 For the preparation of Example 30, the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting in Step 1.5 where 2- [4- (bromoacetyl) phenoxy] -6-chlorobenzonitrile replaces intermediate 1.2 in step 1.5.
  • the expected final product is obtained in the form of a yellow solid.
  • 2-Bromo-1- [2-chloro-4- (4-chlorophenoxy) phenyl] ethanone is prepared according to the method described for Intermediate 1.2 where 1- [2-chloro-4- (4-chlorophenoxy) phenyl] ethanone-1-one replaces intermediate 1.1.
  • 2-Bromo-1- [2-chloro-4- (4-chlorophenoxy) phenyl] ethanone is obtained as a yellow oil in quantitative yield, and is used directly in the next step.
  • Example 31 4- ⁇ 4- [2-Chloro-4- (4-chlorophenoxy) phenyl] -1,3-thiazol-2-yl ⁇ tetrahydro-2H-pyran-4-yl) dimethylamine hydrochloride (Example 31)
  • the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting at Step 1.5 where 2-bromo-1- [2-chloro-4- (4) -chlorophenoxy) phenyl] ethanone replaces intermediate 1.2 in step 1.5.
  • the expected final product is obtained in the form of a white solid.
  • 2-Bromo-1- [4- (4-nitrophenoxy) phenyl] ethanone is prepared according to the method described for Intermediate 1.2, where 4-acetyl-4'-nitrodiphenyl ether replaces Intermediate 1.1.
  • 2-Bromo-1- [4- (4-nitrophenoxy) phenyl] ethanone is obtained as a pale yellow solid with a yield of 53%.
  • Example 32 For the preparation of Example 32, the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting at step 1.5 where 2-bromo-1- [4- (4-nitrophenoxy) phenyl) ] ethanone replaces intermediate 1.2 in step 1.5.
  • the expected final product is obtained in the form of a pale yellow solid.
  • 2-Bromo-1- [4- (phenylthio) phenyl] ethanone is prepared according to the method described for Intermediate 1.2, where 4-acetyldiphenylsulfide replaces Intermediate 1.1.
  • 2-Bromo-1- [4- (phenylthio) phenyl] ethanone is obtained in the form of a yellow oil after purification on a silica column (eluent: ethyl acetate-heptane: 20-80) with a yield of 71% .
  • Example 33 For the preparation of Example 33, the experimental protocol used is the same as that described for Examples 1 and 2, the synthesis starting in Step 1.5 where 2-bromo-1- [4- (phenylthio) phenyl] ethanone replaces intermediate 1.2 in step 1.5. The expected final product is obtained in the form of a pale yellow solid.
  • Example 35 ⁇ 4- [4- (3,5-Di-tert-butyl-2-methoxyphenyl) -1,3-thiazol-2-yl] tetrahydro-2H-pyran-4-yl ⁇ dimethylamine hydrochloride
  • the experimental protocol used is the same as that described for Examples 1 and 2, in which 3,5-di-tert-butyl-2-methoxyacetophenone replaces 3,5-di-tert-butyl-4-hydroxyacetophenone.
  • the expected final product is obtained in the form of a light yellow solid.
  • the affinity of the compounds of the invention for CB2 human receptors is determined by measuring the inhibition of [ 3 H] -CP55940 binding to membrane preparations of transfected CHO-K1 cells.
  • CHO-K1 cells stably expressing human CB2 receptors are cultured in RPMI 1640 medium containing 10% fetal calf serum, 2 mM glutamine, 100 U / ml penicillin, 0.1 mg / ml streptomycin and 0.5 mg / ml G418.
  • the cells are collected with 0.5 mM EDTA and centrifuged at 500 g for 5 min at 4 ° C.
  • the pellet is resuspended in phosphate buffered saline (PBS) and centrifuged at 500 g for 5 min at 4 ° C.
  • PBS phosphate buffered saline
  • the pellet is resuspended in a 50 mM Tris buffer medium at pH 7.4 and centrifuged at 500 g for 5 min at 4 ° C.
  • the cells are lysed by sonication and centrifuged at 39,000 g for 10 min. at 4 ° C.
  • the pellet is resuspended in 50 mM Tris buffer medium at pH 7.4 and centrifuged at 50,000 g for 10 min at 4 ° C.
  • the membranes obtained in this latter pellet are stored at -80 ° C. vs.
  • the measurement of competitive inhibition of [ 3 H] -CP55940 binding to CB2 receptors is performed in duplicate using 96-well polypropylene plates.
  • the cell membranes (10 ⁇ g protein / well) are incubated with [ 3 H] -CP55940 (1 nM) for 60 min at 25 ° C. in a 50 mM Tris-HCl buffer medium, pH 7.4, comprising 0, 1% bovine serum albumin (BSA), 5 mM MgCl 2 , and 50 ⁇ g / ml bacitracin.
  • BSA bovine serum albumin
  • the bound [ 3 H] -CP55940 is separated from free [ 3 H] -CP55940 by filtration through GF / C fiberglass filter plates (Unifilter, Packard) preimpregnated with 0.1% polyethyleneimine (PEI). ), using a Filtermate 196 (Packard). The filters are washed with 50 mM Tris-HCl buffer, pH 7.4 at 0-4 ° C and the radioactivity present is determined using a counter (Packard Top Count).
  • the specific binding is obtained by subtracting the non-specific binding (determined in the presence of 0.1 ⁇ M of WIN55212-2 from the total binding).
  • the data are analyzed by computer-assisted nonlinear regression (MDL). For each test, a Cheng-Prusoff correction is made to convert the IC50 to a constant of inhibition Ki.
  • IC50 is a Cheng-Prusoff correction made to convert the IC50 to a constant of inhibition Ki.
  • [L] is the concentration of the radioligand used in the assay and Kd is the equilibrium radioligand dissociation constant.
  • the CB2 receptor agonist or antagonist activity of the compounds of the present invention was determined by measuring the cyclic AMP production by CHO-K1 cells transfected with the CB2 receptor. Measurement of intracellular cyclic AMP production via CB2 receptors:
  • CHO-K1 cells expressing cannabinoid CB2 receptors are cultured in 384-well plates in RPMI 1640 medium with 10% fetal calf serum and 0.5 mg / ml G418. The cells are washed twice with 50 ⁇ l of RPMI medium comprising 0.2% BSA and 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX).
  • IBMX 3-isobutyl-1-methylxanthine
  • the cells are incubated for 5 min at 37 ° C. in the presence of 0.5 mM of IBMX, then the stimulation of cyclic AMP production is obtained by adding 5 ⁇ M of Forskolin and inhibition is measured by adding the compound at concentrations of between 1 ⁇ M and 10 ⁇ M in duplicate for 20 min at 37 ° C.
  • the antagonistic effect of a compound is measured by inhibiting the inhibition of the production of Cyclic AMP induced by WIN55212-2 in the presence of 5 ⁇ M Forskolin, at concentrations of between 1 ⁇ M and 10 ⁇ M, in the presence of the test compound, at concentrations of between 1 nM and 10 ⁇ M, in duplicate for 20 min at 37 ° C.
  • the reaction medium is removed and 80 .mu.l of lysis buffer are added.
  • the level of intracellular cyclic AMP is measured by a competition test with fluorescent cyclic AMP (CatchPoint, Molecular Devices).
  • Examples 5, 14, 28, 29 and 33 have an affinity of between 1000 nM and 500 nM.
  • Examples 7, 8, 11, 13, 16, 17, 19, 21, 23, 25 and 32 have affinity between 500 nM and 100 nM.
  • Examples 2, 4, 6, 15, 18 and 20 have an affinity of even less than or equal to 100 nM.

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EP08858116A 2007-09-13 2008-09-11 Cannabinoid-rezeptorliganden Withdrawn EP2201007A1 (de)

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FR0706434A FR2921063B1 (fr) 2007-09-13 2007-09-13 Ligands des recepteurs cannabinoides
PCT/FR2008/001270 WO2009071753A1 (fr) 2007-09-13 2008-09-11 Derives de 4-phenyl-l, 3-thiazoles et de 4-phenyl-l, 3-oxazoles comme ligands des recepteurs cannabinoides

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US7183285B2 (en) * 2004-04-29 2007-02-27 Pharmix Corp. Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase
WO2006137658A1 (en) * 2005-06-20 2006-12-28 Dongbu Hitek Co., Ltd. New substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory acitivity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and pharmaceutical composition comprising the same
WO2007063928A1 (ja) * 2005-11-30 2007-06-07 Toray Industries, Inc. 新規な非環状アミンカルボキシアミド誘導体及びその塩
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