WO2007090733A1 - Nitrooxy derivatives suitable as alpha2 adrenergic receptor agonists - Google Patents

Nitrooxy derivatives suitable as alpha2 adrenergic receptor agonists Download PDF

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WO2007090733A1
WO2007090733A1 PCT/EP2007/050627 EP2007050627W WO2007090733A1 WO 2007090733 A1 WO2007090733 A1 WO 2007090733A1 EP 2007050627 W EP2007050627 W EP 2007050627W WO 2007090733 A1 WO2007090733 A1 WO 2007090733A1
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integer
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Nicoletta Almirante
Angela Monopoli
Stefano Biondi
Ennio Ongini
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Nicox S.A.
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
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Abstract

Alpha 2 adrenergic agonist nitrooxyderivatives of formula (I): A-(X0-ONO2)s(I) and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof, wherein: s is an integer equal to 1, 2 or 3; wherein A is a precursor of an alpha 2 adrenergic receptor agonists having wider pharmacological activity and enhanced tolerability. They can be employed for treating cardiovascular disease, in particular systemic hypertension, renal and chronic liver diseases, inflammatory processes and metabolic syndromes.

Description

NITROOXY DERIVATIVES SUITABLE AS ALPHA2 ADRENERGIC RECEPTOR AGONISTS
The present invention relates to α2 adrenergic receptor agonist derivatives. More particularly, the present invention relates to nitrooxy derivatives of α2 adrenergic receptor agonists, pharmaceutical compositions containing them and their use for the treatment of cardiovascular, renal and chronic liver diseases, inflammatory processes and metabolic syndromes.
With the α2 adrenergic receptor agonists or simply α2 adrenergic agonists, a class of compounds is intended, comprising as main components clonidine, moxonidine, guanabenz, guanfacine, rilmenidine, tiamenidine, methyl- DOPA, methyldopate and alpha-methylnoradrenaline . α2 adrenergic receptor agonists are used primarily for the treatment of hypertension, the antihypertensive activity is due mainly to the activation of α2 adrenergic receptors in the cardiovascular control centers of the central nervous system (CNS) ; such activation suppresses the outflow of sympathetic nervous system activity from the brain .
Now, it has been reported that α2 adrenergic receptor agonists have side-effects such as for example postural hypotension, bradycardia, gastrointestinal disturbances, dry mouth, sexual dysfunction, depression, anxiety, fatigue, nausea, sleep disturbances.
Object of the present invention is to provide novel derivatives of α2 adrenergic receptor agonists able not only to eliminate or at least reduce the side effects associated with their parent compounds, but also having an improved pharmacological activity. It has been so surprisingly found that a2 adrenergic receptor agonist nitrooxyderivatives have a significantly improved overall profile as compared to native compounds in terms both of wider pharmacological activity and enhanced tolerability .
In particular, it has been recognized that the α2 adrenergic receptor agonist nitrooxyderivatives of the present invention exhibit a strong anti-inflammatory, antithrombotic, analgesic and antiplatelet activity and can be furthermore employed for treating or preventing heart failure, myocardial infarction, ischemic stroke, atherosclerosis, systemic hypertension, hypertension associated with hyperlipidemia, pregnancy induced hypertension, chronic hypertension in pregnant women, pheochromocytoma, diabetic nephropathy, peripheral vascular diseases, left ventricular dysfunction, liver fibrosis, portal hypertension and metabolic syndromes.
Object of the present invention are, therefore, α2 adrenergic agonist nitrooxy derivatives of general formula (I) :
A-(X0-ONO2)s (D and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof, wherein : s is an integer equal to 1 or 2 or 3;
A is selected from the following groups:
Figure imgf000003_0001
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0003
Figure imgf000004_0004
Figure imgf000004_0005
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0003
wherein : Ni is -N-;
Nia is -NH, or -NH2;
N2 is -0, or -OH; with the proviso that at least one of Nia and N2, is a group, -NH, or -0 able to bind to Xo; X0 is equal to -Xi-Y- wherein Xi has the following meanings:
-C(O)-, -C(O)O-,
Figure imgf000005_0004
Y is a bivalent radical having the following meaning: a)
- straight or branched C1-C20 alkylene, preferably C1-C10, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO2 or T0, wherein T0 is
-OC(O) (Ci-Cio alkyl)-ONO2 or -0(Ci-Ci0 alkyl)-ONO2;
- cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T, wherein T is straight or branched alkyl with from 1 to 10 carbon atoms, preferably CH3; b)
Figure imgf000006_0001
C)
Figure imgf000006_0002
wherein n is an integer from 0 to 20, and n1 is an integer from 1 to 20; d)
Figure imgf000006_0003
wherein : n1 is as defined above and n2 is an integer from 0 to 2;
X2 = -OCO- or -COO- and R2 is H or CH3; e)
Figure imgf000007_0001
wherein : n1, n2,R2 and X2 are as defined above; Y1 is -CH2-CH2- or -CH=CH- (CH2) n 2-; f)
Figure imgf000007_0002
wherein : n1 and R2 are as defined above, R3 is H or -COCH3; with the proviso that when Y is selected from the bivalent radicals mentioned under b) -f) , the -ONO2 group is linked to a -(CH2In 1 group; g)
wherein X3 is -0- or -S-, n3 is an integer from 1 to 6, preferably from 1 to 4, R2 is as defined above; h)
Figure imgf000007_0004
wherein : n4 is an integer from 0 to 10; n5 is an integer from 1 to 10;
R4, R5, R6, R7 which can be the same or different each other, are H or straight or branched Ci-C4 alkyl, preferably R4, R5, R6, R7 are H; wherein the -ONO2 group is linked to
Figure imgf000008_0002
wherein n5 is as defined a ove;
Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from
Figure imgf000008_0001
The term "C1-C20 alkylene" as used herein refers to branched or straight chain C1-C20 hydrocarbon, preferably having from 1 to 10 carbon atoms such as methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene and the like. The term "Ci-Ci0 alkyl" as used herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like.
The term "cycloalkylene" as used herein refers to ring having from 5 to 7 carbon atoms including, but not limited to, cyclopentylene, cyclohexylene optionally substituted with side chains such as straight or branched (Ci-Cio) - alkyl, preferably CH3.
The term "heterocyclic" as used herein refers to saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, such as for example pyridine, pyrazine, pyrimidine, pyrrolidine, morpholine, imidazole and the like.
As stated above, the invention includes also the pharmaceutically acceptable salts of the compounds of formula (I) and stereoisomers thereof.
Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, triethylamine, dibenzylamine, piperidine and other acceptable organic amines .
The compounds according to the present invention, when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in an organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acids.
Examples of pharmaceutical acceptable organic acids are: oxalic, tartaric, maleic, succinic, citric acids. Examples of pharmaceutical acceptable inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids. Salts with nitric acid are preferred. The compounds of the invention which have one or more asymmetric carbon atoms can exist as optically pure enantiomers, pure diastereomers, enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures. Within the object of the invention are also all the possible isomers, stereoisomers and their mixtures of the compounds of formula (I) .
Preferred compounds are those of formula (I) and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof, wherein Y has the following meaning : a)
- straight or branched Ci-Ci0 alkylene; b)
Figure imgf000010_0001
wherein n is 0 or 1, n1 is 1 ; with the proviso that the -ONO2 group is linked to - (CH2) n1 group; g)
Figure imgf000010_0002
wherein X3 is -O- or -S-, n3 is 1 and R2 is H;
The following are preferred compounds according to the present invention:
Figure imgf000010_0003
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0003
Figure imgf000012_0001
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:
Figure imgf000023_0002
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Figure imgf000067_0001
Figure imgf000067_0002
and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof.
Synthesis
1. The compound of general formula (I) as above defined wherein: s is 1; Xo is -Xi-Y- wherein Xi is -CO- and Y is as above defined and A is selected among compounds (Ia-Ii) wherein Ni is -N- , Nia is -NH and N2 is -OH, can be obtained by a process comprising:
Ia. reacting a compound of formula B with a compound of formula (Ilia) :
B + HOOC-Y-ONO2
(Ilia)
wherein Y is as above defined; B is equal to A with A selected among (Ia-Ii) wherein Ni is -NH-, Nia is -NH2 and N2 is -OH, in the presence of a condensing agent like dicyclohexylcarbodiimide (DCC) or N, N' -carbonyldiimidazol (CDI) or other known condensing reagents such as HATU in solvent such as DMF, THF, chloroform at a temperature in the range from -5°C to 500C in the presence or not of a base as for example DMAP.
The nitric acid ester compounds of formula (Ilia) can be obtained from the corresponding alcohols of formula (HIb)
HOOC-Y-OH (HIb) that are commercially available or can be prepared by known compounds by methods known in the art, by reaction with nitric acid and acetic anhydride in a temperature range from -500C to 00C, or reacting the corresponding halogen derivatives of formula (IIIc)
HOOC-Y-HaI (IIIc) wherein Hal is an halogen atom preferable Cl, Br, I, that are commercially available or can be prepared from known compounds by methods known in the art, with AgNθ3 as described in the international application No. PCT/EP2005/050459. Compound of formula B wherein B is equal to A when A is (Ia) wherein Ni is -NH- is a known compound named clonidine and can be prepared as described in US 3,202, 660.
Compound of formula B wherein B is equal to A when A is (Ib) wherein Ni is -NH- is a known compound named moxonidine and can be prepared as described in US 4,323,570.
Compound of formula B wherein B is equal to A when A is
(Ic) wherein Nia is -NH2 is a known compound named guanfacine and can be prepared as described in US 3,632,645.
Compound of formula B wherein B is equal to A when A is (Id) wherein Nia is -NH2 is a known compound named guanabenz and can be prepared as described in GB1019120. Compound of formula B wherein B is equal to A when A is (Ie) wherein Ni is -NH- is a known compound named tiamenidine and can be prepared as described in US 3,758,476.
Compound of formula B wherein B is equal to A when A is (If) wherein Ni is -NH- is a known compound named rilmenidine and can be prepared as described in US 4,102,890.
Compound of formula B wherein B is equal to A when A is
(Ig) wherein Nia is -NH2, and N2 is -OH is a known compound named methyldopa and can be prepared as described in US 2,868,818.
Compound of formula B wherein B is equal to A when A is (Ih) wherein Nia is -NH2 and N2 is -OH is a known compound named methyldopate and can be prepared as described in FR M2153. Compound of formula B wherein B is equal to A when A is
(Ii) wherein Nia is -NH2 and N2 is -OH is a known compound named l-methyl-2- (3, 4-dihydroxyphenyl) -ethylamina and can be prepared as described in "N-Alkyl derivatives of (±) -a- methyldopamine", Cannon et al ., Journal of Medicinal Chemistry (1979), 22(8), 901-7.
Ib. Reacting a compound of formula B as above defined with a compound of formula (HId) :
B ACt-CO-Y-ONO2 (HId)
wherein Y is as above defined; Act is an Halogen atom or a carboxylic acid activating group used in peptide chemistry as :
Figure imgf000070_0001
The reaction can be carried out in the presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C or in a double phase system H20/Et20 at temperatures range between 20°- 40 0C; or in the presence of DMAP and a Lewis acid such as Sc(OTf)3 or Bi(OTf)3 in solvents such as DMF, CH2Cl2.
The compounds of formula (HId) can be obtained as described in the international application No. PCT/EP2005/050459.
Ic. Reacting a compound of formula (Iva)
A-(X0-HaI)3 (IVa) wherein s is 1, A is selected among (Ia-Ii) wherein Ni is - N-, Nia is -NH, N2 is -OH and Xo is as above defined, with AgNU3 as already described. Compounds (IVa) can be obtained by reacting compound B wherein B is equal to A with A selected among (Ia-Ii) wherein Ni is -NH-, Nia is -NH2, N2 is -OH with compounds (IIIc), as above defined, with a condensing reagent such as DCC or CDI as above described.
Id. Reacting a compound of formula (Va) A-(X0-OH)3 (Va) wherein s is 1; A is selected among (Ia-Ii) wherein Ni is - N-, Nia is -NH and N2 is -OH and X0 is as above defined, with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between -60° to 65°C as already described. Compounds (Va) can be obtained by reacting compound B wherein B is equal to A with A selected among (Ia-Ii) wherein N1 is -NH-, Nia is -NH2, N2 is -OH with compounds (HIb), as above defined, with a condensing reagent as above described.
2. The compound of general formula (I) as above defined wherein : s is 1; Xo is -Xi-Y- wherein Xi is -C(O)O- and Y is as above defined and A is selected among compounds (Ia-Ii) wherein
Ni is -N-, Nia is -NH and N2 is -OH, can be obtained by a process comprising:
2a. Reacting a compound of formula B with a compound of formula (Via) :
B + Act—CO O—Y—ONO2
(Via) wherein B is equal to A and A is selected among compounds (Ia-Ii) wherein Ni is -NH- and Nia is -NH2 and N2 is -OH; Act and Y are as above described.
The reaction is generally carried out in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C or in a double phase system H20/Et20 at temperatures range between 20°- 400C; or in the presence of DMAP and a Lewis acid such as Sc(OTf)3 or Bi(OTf)3 in solvents such as DMF, CH2Cl2.
The synthesis of compounds (Via) is described in the international application No. PCT/EP2005/050459.
2b. Reacting a compound of formula A-(Xo-HaI)3 (Vila) wherein s is 1; A is selected among compounds (Ia-Ii) wherein Ni is -N-, Nia is -NH and N2 is -OH, X0 and Hal are as above defined, with AgNO3 as above described. The compounds of formula (Vila) can be obtained by reacting compound B with compounds Act-CO-O-Y-Hal (VIIb) . The reaction is generally carried out in the presence of an inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C as above described.
Compound (VIIb) are commercially available or can be synthesized as described in WO 05/011646.
3. The compound of general formula (I) as above defined or a pharmaceutically acceptable salt thereof, wherein: s is 2; X0 is -Xi-Y- wherein X1 is -CO- or -C(O)O and Y is as above defined and A is selected among (Ig-Ii), wherein Nia is -NH2 and N2 is -O can be obtained by a process comprising: 3a. when Xi is -CO-, reacting a compound of formula C
Figure imgf000073_0001
wherein PG is an amino protective group such as BOC and W is H, COOH, or COOEt with compounds of formula (Ilia) or
(HId) as above defined, or when Xi is -C(O)O- with compounds of formula (Via) with the same procedure already described for compounds of formula B, and eventually acid hydrolysing the NH-BOC protective group with well known methods as described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980; optionally converting the resulting compounds of formula
(I) into a pharmaceutically acceptable salt. Compound C can be obtained from compound B, wherein B is equal to A with A selected among (Ig-Ii) wherein Nia is NH2 and N2 is -OH, by reacting with (BOC)2O and TEA or with other well known methods as described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980.
4. The compound of general formula (I) as above defined wherein : s is 3; X0 is -Xi-Y- wherein Xi is -CO- or -C(O)O- and Y is as above defined and A is selected among compounds (Ig-Ii), wherein Nia is equal to -NH and N2 is equal to -0 can be obtained by a process comprising:
4a. reacting a compound of formula B wherein B is equal to
A with A selected among (Ig-Ii) wherein Nia is -NH2 and N2 is -OH with an excess of a compound of formula (Ilia), or (HId) or (Via) as above described for analogous reactions of compounds B and C.
5. The compound of general formula (I) as above defined wherein: s is 1; XQ is -Xi-Y- wherein Xi is:
Figure imgf000074_0001
and Y is as above defined and A is selected among compounds (Ia-Ii), wherein Ni is -N-, Nia is -NH and N2 is -OH can be obtained by a process comprising:
5a. reacting a compounds of formula B wherein B is equal to A with A selected among (Ia-Ii) wherein Ni is -NH-, Nia is -NH2 and N2 is -OH with stoichiometric amount of compounds of formula (Villa)
HaI-Wi-OC(O)O-Y-ONO2 (Villa)
wherein Hal and Y are as above reported and Wi is -CH2- or -CH(CH3)- in the presence of an inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0° to 65° or in a double phase system H20/Et20 at temperatures range between 20° to 400C. Compounds (Villa) can be prepared from compounds (IXa)
HaI-Wi-OC(O)O-Y-OH (IXa)
wherein Hal, Wx and Y are as above described with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between -60° to 65°C as already described. The compounds of formula (IXa) are obtained by reacting the commercially available haloalkylhalocarbonate of formula (Xa)
HaI-Wi-OC(O)HaI (Xa) wherein Hal and Wi are as above defined, with a commercially available compound of formula (Xb)
HO-Y-OH (Xb) wherein Y is as above defined, in the presence of a inorganic or organic base in an aprotic polar or in an aprotic non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0° to 65°C.
Alternatively the compounds of formula (Villa) can be obtained reacting (Xa) with compounds of formula (Xc)
HO-Y-ONO2 (Xc)
wherein Y is as above defined, in the presence of a inorganic or organic base in an aprotic polar or in an aprotic non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0° to 65 0C. The compound of formula (Xc) can be obtained by reacting a commercially available compound of formula (Xd)
HO-Y-HaI (Xd)
wherein Hal is as above reported with AgNθ3 in a suitable organic solvent such as acetonitrile or THF under nitrogen at temperatures range between 20°-80°C as already reported.
Alternatively the reaction with AgNθ3 can be performed under microwave irradiation in solvents such acetonitrile or THF at temperatures in the range between 100-1800C for short time (1-60 min) .
The compounds and compositions of the present invention can be administered by any available and effective delivery system including but not limited to, orally, bucally, parenterally, by inhalation spray, by topical application, by injection, transdermally such as patch, or rectally (e.g. by the use of suppositories) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion technique.
Solid dosage forms for oral administration can include for example capsule, tablets, pills, powders, granules and gel. In such solid dosage forms, the active compounds can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage form can also comprise, as normal practice, additional substance other than inert diluent, e.g., lubricating agent such as magnesium stearate .
Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents.
The composition of this invention can further include conventional excipients, i.e., pharmaceutical acceptable organic or inorganic substances which do not deleteriously react with the active compounds. The doses of a∑ adrenergic agonist nitrooxyderivatives of the invention can be determinated by standard clinique technique and are in the same ranges or less than as described for commercially available compounds as reported in the: Physician's Desk Reference, Medical Economics Company, Inc., Oradell, N.J., 58th Ed., 2004; The pharmacological basis of therapeutics, Goodman and Gilman, J. G. Hardman, L. e. Limbird, 20th Ed. Another aspect of the present invention provides the use of the compounds of formula (I) in combination with at least a compound used to treat cardiovascular disease selected from the group consisting of: ACE inhibitors, angiotensin II receptor blockers, HMGCoA reductase inhibitors, beta-adrenergic blockers, calcium channel blockers, antithrombotics such as aspirin and clopidogrel, renin inhibitors such as aliskiren, nitrosated ACE inhibitors (WO 98/21193 and WO 2004/110432), nitrosated HMGCoA reductase inhibitors (WO 2005/011646), nitrosated beta-adrenergic blockers (WO 98/21193, WO 2005/053685 and WO 2005/054218) and nitrosated aspirin (WO 97/16405) .
Suitable ACE agonists, HMGCoA reductase inhibitors, beta-adrenergic blockers, calcium channel blockers, antithrombotics are described in the literature such as The Merck Index (13th edition) .
The following examples are to further illustrate the invention without limiting it.
Example 1
4- {2- [ (2 , 6-dichlorophenyl) imino] imidazolidin-1-yl} -4- oxobutyl nitrate (corresponding to compound (2))
To a solution of Clonidine hydrochloride (0.250 g, 0.94 mmol) TEA (0.26 ml, 1.88 mmol) and DMAP (0.115 g, 0.94 mmol) in CH2Cl2 (10 ml) kept at 00C, under stirring and under argon atmosphere, a solution of pentafluorophenyl 4-
(nitrooxy)butanoate (0.28 g, 0.89 mmol) in CH2Cl2 (5 ml) was added. After stirring for 2h at room temperature, the reaction mixture was diluted with CH2Cl2 (100 ml), and successively washed with 5% aqueous NaHCθ3 (100 ml), brine (100 ml) and water (100 ml) . The organic phase was dried over MgSO4 and evaporated under vacuum. Purification by flash chromatography of the residue (CH2Cl2/Me0H 95/5) gave the title compound as a white solid (0.300 g, yield=94%) .
MS (ESI Pos) : 361 (M+l) IR (KBr) : λmax 3317, 1683, 1626, 1478, 1400, 1276, 1137, 1074, 970, 932, 869, 770, 700 cirfl.
1H NMR (400MHz, d6-DMSO) δ 7.39 (2H, d) , 6.99 (IH, t) , 6.93 (IH, s), 4.56 (2H, t) , 3.87 (2H, t) , 3.39-3.26 (2H, m) , 3.17 (2H, t) , 2.03 (2H, dt) .
Example 2
4- (nitrooxy)butyl-2- [ (2 , 6-dichlorophenyl) imino] imidazolidine-1-carboxylate (corresponding to compound (13) To a solution of Clonidine hydrochloride (0.250 g, 0.89 mmol) TEA (0.26 ml, 1.88 mmol) and DMAP (0.115 g, 0.94 mmol) in CH2Cl2 (10 ml) kept at 00C, under stirring and under argon atmosphere, a solution of pentafluorophenyl 4-
(nitrooxy) butyl 4-nitrophenyl carbonate (0.268 g, 0.89 mmol) in CH2Cl2 (5 ml) was added. After stirring for 2h at room temperature, the reaction mixture was diluted with CH2Cl2 (100 ml), and successively washed with 5% aqueous NaHCO3 (100 ml), brine (100 ml) and water (100 ml) . The organic phase was dried over MgSO4 and evaporated under vacuum. Purification by flash chromatography of the residue (CH2Cl2/Me0H 95/5) gave 300 mg of a yellow oil that was purified again by preparative TLC (Cyclohexane/EtOAc 50/50) .
The obtained yellow solid (150 mg) was crystallized from ethyl ether to give 30 mg of the desired compound as a white solid (yield = 10%) .
MS (ESI Pos) : 391 (M+l)
IR (KBr) : λmax 3349, 2967, 1694, 1615, 1412, 1338, 1278, 1159, 1067, 974, 873, 763, 659, 574 crrfl. 1H NMR (400MHz, d6-DMSO) δ 7.34 (2H, d) , 6.92 (IH, t) , 6.66
(IH, s) , 4.56 (2H, t) , 4.16 (2H, t) , 3.87 (2H, t) , 3.34-
3.24 (2H, m) , 1.86-1.75 (2H, m) , 1.74-1.63 (2H, m) .

Claims

1. A compound of general formula (I) :
Figure imgf000080_0001
and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof, wherein : s is an integer equal to 1 or 2 or 3; A is selected from the following groups:
Figure imgf000080_0002
Figure imgf000080_0003
Figure imgf000080_0004
Figure imgf000081_0001
Figure imgf000081_0002
Figure imgf000081_0003
Figure imgf000081_0004
Figure imgf000082_0001
wherein : Ni is -N-, Nia is -NH or -NH2; N2 is -O or -OH; with the proviso that at least one of Nia , and N2, is group -NH, or -0 able to bind to Xo; Xo is equal to -Xi-Y- wherein Xi is: -CO-, -COO-,
Figure imgf000082_0002
Y is a bivalent radical having the following meaning: a) - straight or branched Ci-C2O alkylene, preferably Ci-Cio, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO2 or T0, wherein T0 is
-OC(O) (Ci-Cio alkyl)-ONO2 or -0(Ci-Ci0 alkyl)-ONO2; - cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T, wherein T is straight or branched alkyl with from
1 to 10 carbon atoms, preferably CH3; b)
Figure imgf000083_0001
c)
Figure imgf000083_0002
wherein n is an integer from 0 to 20, and n1 is an integer from 1 to 20; d)
Figure imgf000083_0003
wherein : n is as defined above and n 2 is an integer from 0 to 2 ;
X2 = -OCO- or -COO- and R2 is H or CH3; e)
Figure imgf000083_0004
wherein : n1, n2,R2 and X2 are as defined above; Y1 is -CH2-CH2- or -CH=CH- (CH2) n 2-; f)
Figure imgf000083_0005
wherein : n1 and R2 are as defined above, R3 is H or -COCH3; with the proviso that when Y is selected from the bivalent radicals mentioned under b) -f) , the -ONO2 group is linked to a -(CH2In 1 group;
Figure imgf000084_0001
wherein X3 is -O- or -S-, n3 is an integer from 1 to 6, preferably from 1 to 4, R2 is as defined above; h)
Figure imgf000084_0002
wherein : n4 is an integer from 0 to 10; n5 is an integer from 1 to 10; R4, R5, R6, R7 are the same or different, and are H or straight or branched Ci-C4 alkyl, preferably R4, R5, R6, R7 are H; wherein the -ONO2 group is linked to
Figure imgf000084_0004
wherein n5 is as defined a ove;
Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from
Figure imgf000084_0003
Figure imgf000085_0001
2. A compound of general formula (I) and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof, according to claim 1 wherein Y is a bivalent radical having the following meaning: a)
- straight or branched Ci-Cio alkylene; b)
Figure imgf000085_0002
wherein n is 0 or 1, n1 is 1; with the proviso that the -ONO2 group is linked to -(CH2)I1 1 group; g)
Figure imgf000085_0003
wherein X3 is -O- or -S-, n3 is 1 and R2 is H.
3. A compound according to claims 1-2, selected from the group consisting of:
Figure imgf000086_0001
Figure imgf000086_0003
Figure imgf000086_0002
Figure imgf000086_0004
Figure imgf000087_0001
Figure imgf000087_0002
Figure imgf000087_0003
Figure imgf000088_0001
Figure imgf000088_0002
Figure imgf000088_0003
Figure imgf000088_0004
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000090_0003
Figure imgf000090_0004
Figure imgf000091_0001
Figure imgf000091_0003
Figure imgf000091_0004
Figure imgf000091_0002
Figure imgf000092_0001
Figure imgf000092_0002
Figure imgf000092_0003
Figure imgf000092_0004
Figure imgf000092_0005
Figure imgf000093_0001
Figure imgf000093_0002
Figure imgf000093_0003
Figure imgf000093_0004
Figure imgf000093_0005
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000094_0003
Figure imgf000094_0004
Figure imgf000094_0005
Figure imgf000095_0001
Figure imgf000095_0002
Figure imgf000095_0003
Figure imgf000095_0004
Figure imgf000095_0005
Figure imgf000096_0001
Figure imgf000096_0002
Figure imgf000096_0003
Figure imgf000096_0004
Figure imgf000096_0005
Figure imgf000097_0001
Figure imgf000097_0002
Figure imgf000098_0001
Figure imgf000098_0002
Figure imgf000098_0003
Figure imgf000099_0001
Figure imgf000099_0002
Figure imgf000099_0003
Figure imgf000099_0004
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000100_0003
Figure imgf000100_0004
Figure imgf000101_0001
Figure imgf000101_0002
Figure imgf000101_0003
Figure imgf000102_0001
Figure imgf000102_0002
Figure imgf000102_0003
Figure imgf000102_0004
Figure imgf000103_0001
Figure imgf000103_0002
Figure imgf000103_0003
Figure imgf000104_0001
Figure imgf000104_0002
Figure imgf000104_0003
Figure imgf000105_0001
Figure imgf000105_0002
Figure imgf000105_0003
Figure imgf000106_0001
Figure imgf000106_0002
Figure imgf000106_0003
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000108_0002
Figure imgf000108_0003
Figure imgf000109_0001
Figure imgf000109_0002
Figure imgf000109_0003
Figure imgf000110_0001
Figure imgf000110_0002
Figure imgf000110_0003
Figure imgf000111_0001
Figure imgf000111_0002
Figure imgf000111_0003
Figure imgf000112_0001
Figure imgf000112_0002
Figure imgf000112_0003
Figure imgf000113_0001
Figure imgf000113_0002
Figure imgf000113_0003
Figure imgf000114_0001
Figure imgf000114_0002
Figure imgf000114_0003
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000115_0003
Figure imgf000116_0001
Figure imgf000116_0002
Figure imgf000116_0003
Figure imgf000117_0001
Figure imgf000117_0002
Figure imgf000117_0003
Figure imgf000118_0001
Figure imgf000118_0002
Figure imgf000118_0003
Figure imgf000119_0001
Figure imgf000119_0002
Figure imgf000119_0003
Figure imgf000120_0001
Figure imgf000120_0002
Figure imgf000120_0003
Figure imgf000121_0001
Figure imgf000121_0002
Figure imgf000121_0003
Figure imgf000122_0001
Figure imgf000122_0002
Figure imgf000122_0003
Figure imgf000123_0001
Figure imgf000123_0002
Figure imgf000124_0001
Figure imgf000124_0002
Figure imgf000124_0003
Figure imgf000124_0004
Figure imgf000124_0005
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000127_0003
Figure imgf000127_0004
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000129_0002
Figure imgf000130_0001
Figure imgf000130_0002
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000133_0002
Figure imgf000133_0003
Figure imgf000133_0004
Figure imgf000134_0001
Figure imgf000134_0002
Figure imgf000134_0003
Figure imgf000135_0001
Figure imgf000135_0002
Figure imgf000135_0003
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000137_0002
Figure imgf000137_0003
Figure imgf000138_0001
Figure imgf000138_0002
Figure imgf000138_0003
Figure imgf000139_0001
Figure imgf000139_0002
Figure imgf000139_0003
Figure imgf000139_0004
Figure imgf000139_0005
Figure imgf000140_0001
Figure imgf000140_0002
Figure imgf000140_0003
Figure imgf000140_0004
Figure imgf000141_0001
Figure imgf000141_0002
Figure imgf000142_0001
Figure imgf000142_0002
4. A compound of general formula (I) according to claims 1- 3 for use as a medicament.
5. Use of a compound according to claims 1-3 for the manufacture of a drug for the treatment of cardiovascular diseases, renal and chronic liver diseases, inflammatory processes and metabolic syndromes.
6. Use of a compound according to claims 1-3 for the manufacture of a drug for the treatment of systemic hypertension .
7. Use of a compound according to claims 1-3 for the manufacture of a drug for the treatment of heart failure, myocardial infarction, ischemic stroke, atherosclerosis, hypertension associated with hyperlipidemia, pregnancy induced hypertension, chronic hypertension in pregnant women, pheochromocytoma, diabetic nephropathy, peripheral vascular diseases, left ventricular dysfunction, liver fibrosis, portal hypertension and metabolic syndromes.
8. Use of a compound according to claims 1-3 for the manufacture of a drug having anti-inflammatory, antithrombotic, analgesic and antiplatelet activity.
9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of general formula (I) or a salt or stereoisomer thereof according to claims 1-3.
10. A pharmaceutical composition comprising a compound of general formula (I) and at least a compound used to treat cardiovascular disease and a pharmaceutically acceptable carrier .
11. Pharmaceutical composition according to claim 10 wherein the compound used to treat cardiovascular disease is selected from the group consisting of: ACE inhibitors, angiotensin II receptor blockers, HMGCoA reductase inhibitors, beta-adrenergic blockers, alpha-adrenergic antagonists, calcium channel blockers, antithrombotics, renin inhibitors such as aliskiren, or nitrosated compounds thereof .
PCT/EP2007/050627 2006-02-06 2007-01-23 Nitrooxy derivatives suitable as alpha2 adrenergic receptor agonists WO2007090733A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008014299A2 (en) * 2006-07-27 2008-01-31 Allergan, Inc. Use of an alpha2-agonist composition for the treatment of hyperlipidemia
US20120065152A1 (en) * 2010-09-15 2012-03-15 Shire Llc Prodrugs of guanfacine
EP2398761A4 (en) * 2009-02-18 2015-11-04 Bezwada Biomedical Llc Controlled release of nitric oxide and drugs from functionalized macromers and oligomers
US11845736B2 (en) 2021-10-01 2023-12-19 Empathbio, Inc. Prodrugs of MDMA, MDA, and derivatives thereof
US11912680B2 (en) * 2021-12-28 2024-02-27 Empathbio, Inc. Nitric oxide releasing prodrugs of MDA and MDMA

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4312878A (en) * 1979-04-27 1982-01-26 Boehringer Ingelheim International Gmbh Method of eliminating opiate withdrawal symptoms with clonidine in humans
WO2005054218A1 (en) * 2003-12-02 2005-06-16 Nicox S.A. Nitrooxyderivatives of antihypertensive drugs
WO2005053685A1 (en) * 2003-12-02 2005-06-16 Nicox S.A. Nitrooxyderivatives of carvedilol and other beta blockers as antihypertensive drugs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4312878A (en) * 1979-04-27 1982-01-26 Boehringer Ingelheim International Gmbh Method of eliminating opiate withdrawal symptoms with clonidine in humans
WO2005054218A1 (en) * 2003-12-02 2005-06-16 Nicox S.A. Nitrooxyderivatives of antihypertensive drugs
WO2005053685A1 (en) * 2003-12-02 2005-06-16 Nicox S.A. Nitrooxyderivatives of carvedilol and other beta blockers as antihypertensive drugs

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008014299A2 (en) * 2006-07-27 2008-01-31 Allergan, Inc. Use of an alpha2-agonist composition for the treatment of hyperlipidemia
WO2008014299A3 (en) * 2006-07-27 2008-04-24 Allergan Inc Use of an alpha2-agonist composition for the treatment of hyperlipidemia
EP2398761A4 (en) * 2009-02-18 2015-11-04 Bezwada Biomedical Llc Controlled release of nitric oxide and drugs from functionalized macromers and oligomers
US20120065152A1 (en) * 2010-09-15 2012-03-15 Shire Llc Prodrugs of guanfacine
WO2012035346A1 (en) * 2010-09-15 2012-03-22 Shire, Llc Prodrugs of guanfacine
US11845736B2 (en) 2021-10-01 2023-12-19 Empathbio, Inc. Prodrugs of MDMA, MDA, and derivatives thereof
US11912680B2 (en) * 2021-12-28 2024-02-27 Empathbio, Inc. Nitric oxide releasing prodrugs of MDA and MDMA

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