NITROOXY DERIVATIVES SUITABLE AS ALPHA2 ADRENERGIC RECEPTOR AGONISTS

The present invention relates to α ₂ adrenergic receptor agonist derivatives. More particularly, the present invention relates to nitrooxy derivatives of α ₂ 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 α ₂ adrenergic receptor agonists or simply α ₂ adrenergic agonists, a class of compounds is intended, comprising as main components clonidine, moxonidine, guanabenz, guanfacine, rilmenidine, tiamenidine, methyl- DOPA, methyldopate and alpha-methylnoradrenaline . α ₂ adrenergic receptor agonists are used primarily for the treatment of hypertension, the antihypertensive activity is due mainly to the activation of α ₂ 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 α ₂ 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 α ₂ 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 a ₂ 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 α ₂ 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, α ₂ adrenergic agonist nitrooxy derivatives of general formula (I) :

A-(X ₀ -ONO ₂ )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:

wherein : Ni is -N-;

Ni _a is -NH, or -NH ₂ ;

N ₂ is -0, or -OH; with the proviso that at least one of N _ia and N ₂ , is a group, -NH, or -0 able to bind to Xo; X ₀ is equal to -Xi-Y- wherein Xi has the following meanings:

-C(O)-, -C(O)O-,

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 T ₀ , wherein T ₀ is

-OC(O) (Ci-Cio alkyl)-ONO ₂ or -0(Ci-Ci ₀ alkyl)-ONO ₂ ;

- 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 CH ₃ ; b)

C)

wherein n is an integer from 0 to 20, and n ¹ is an integer from 1 to 20; d)

wherein : n ¹ is as defined above and n ² is an integer from 0 to 2;

X ₂ = -OCO- or -COO- and R ² is H or CH ₃ ; e)

wherein : n ¹ , n ² ,R ² and X ₂ are as defined above; Y ¹ is -CH ₂ -CH ₂ - or -CH=CH- (CH ₂ ) _n ² -; f)

wherein : n ¹ and R ² are as defined above, R ³ is H or -COCH ₃ ; with the proviso that when Y is selected from the bivalent radicals mentioned under b) -f) , the -ONO ₂ group is linked to a -(CH ₂ I _n ¹ group; g)

wherein X ₃ is -0- or -S-, n ³ is an integer from 1 to 6, preferably from 1 to 4, R ² is as defined above; h)

wherein : n ⁴ is an integer from 0 to 10; n ⁵ is an integer from 1 to 10;

R ⁴ , R ⁵ , R ⁶ , R ⁷ which can be the same or different each other, are H or straight or branched Ci-C ₄ alkyl, preferably R ⁴ , R ⁵ , R ⁶ , R ⁷ are H;

wherein the -ONO2 group is linked to

wherein n ⁵ is as defined a ove;

Y ² 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

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-Ci ₀ 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 CH ₃ .

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-Ci ₀ alkylene; b)

wherein n is 0 or 1, n ¹ is 1 ; with the proviso that the -ONO ₂ group is linked to - (CH ₂ ) n ¹ group; g ⁾

wherein X3 is -O- or -S-, n ³ is 1 and R ² is H;

The following are preferred compounds according to the present invention:

:

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- , Ni _a is -NH and N ₂ 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-ONO ₂

(Ilia)

wherein Y is as above defined; B is equal to A with A selected among (Ia-Ii) wherein Ni is -NH-, N _ia is -NH ₂ and N ₂ 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 50 ⁰ C 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 -50 ⁰ C to 0 ⁰ C, 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 N _ia is -NH ₂ 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 N _ia is -NH ₂ 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 Ni _a is -NH ₂ , and N ₂ 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 Ni _a is -NH ₂ and N ₂ 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 Ni _a is -NH ₂ and N ₂ 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-ONO ₂ (HId)

wherein Y is as above defined; Act is an Halogen atom or a carboxylic acid activating group used in peptide chemistry as :

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 CH ₂ Cl ₂ at temperatures range between 0°-65°C or in a double phase system H ₂ 0/Et ₂ 0 at temperatures range between 20°- 40 ⁰ C; or in the presence of DMAP and a Lewis acid such as Sc(OTf) ₃ or Bi(OTf) ₃ in solvents such as DMF, CH ₂ Cl ₂ .

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-(X ₀ -HaI) ₃ (IVa)

wherein s is 1, A is selected among (Ia-Ii) wherein Ni is - N-, Ni _a 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-, N _ia is -NH ₂ , N ₂ 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-(X ₀ -OH) ₃ (Va) wherein s is 1; A is selected among (Ia-Ii) wherein Ni is - N-, Ni _a is -NH and N ₂ is -OH and X ₀ is as above defined, with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH ₂ Cl ₂ 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 N ₁ is -NH-, N _ia is -NH ₂ , N ₂ 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-, Ni _a is -NH and N ₂ 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—ONO ₂

(Via)

wherein B is equal to A and A is selected among compounds (Ia-Ii) wherein Ni is -NH- and N _ia is -NH ₂ and N ₂ 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 CH ₂ Cl ₂ at temperatures range between 0°-65°C or in a double phase system H ₂ 0/Et ₂ 0 at temperatures range between 20°- 40 ⁰ C; or in the presence of DMAP and a Lewis acid such as Sc(OTf) ₃ or Bi(OTf) ₃ in solvents such as DMF, CH ₂ Cl ₂ .

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-, N _ia is -NH and N ₂ is -OH, X ₀ and Hal are as above defined, with AgNO ₃ 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 CH ₂ Cl ₂ 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; X ₀ is -Xi-Y- wherein X ₁ is -CO- or -C(O)O and Y is as above defined and A is selected among (Ig-Ii), wherein Ni _a is -NH ₂ and N ₂ is -O can be obtained by a process comprising: 3a. when Xi is -CO-, reacting a compound of formula C

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 N _ia is NH ₂ and N ₂ is -OH, by reacting with (BOC) ₂ O 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; X ₀ 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 N _ia is equal to -NH and N ₂ 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 N _ia is -NH ₂ and N ₂ 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:

and Y is as above defined and A is selected among compounds (Ia-Ii), wherein Ni is -N-, N _ia is -NH and N ₂ 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-, Ni _a is -NH ₂ and N ₂ is -OH with stoichiometric amount of compounds of formula (Villa)

HaI-Wi-OC(O)O-Y-ONO ₂ (Villa)

wherein Hal and Y are as above reported and Wi is -CH ₂ - or -CH(CH3)- in the presence of an inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH ₂ Cl ₂ at temperatures range between 0° to 65° or in a double phase system H ₂ 0/Et ₂ 0 at temperatures range between 20° to 40 ⁰ C. Compounds (Villa) can be prepared from compounds (IXa)

HaI-Wi-OC(O)O-Y-OH (IXa)

wherein Hal, W _x and Y are as above described with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH ₂ Cl ₂ 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 CH ₂ Cl ₂ 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-ONO ₂ (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 CH ₂ Cl ₂ at temperatures range between 0° to 65 ⁰ C. 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 100-180 ⁰ C 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., 58 ^th Ed., 2004; The pharmacological basis of therapeutics, Goodman and Gilman, J. G. Hardman, L. e. Limbird, 20 ^th 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 (13 ^th 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 CH ₂ Cl ₂ (10 ml) kept at 0 ⁰ C, under stirring and under argon atmosphere, a solution of pentafluorophenyl 4-

(nitrooxy)butanoate (0.28 g, 0.89 mmol) in CH ₂ Cl ₂ (5 ml) was added. After stirring for 2h at room temperature, the reaction mixture was diluted with CH ₂ Cl ₂ (100 ml), and successively washed with 5% aqueous NaHCθ3 (100 ml), brine (100 ml) and water (100 ml) . The organic phase was dried over MgSO ₄ and evaporated under vacuum. Purification by

flash chromatography of the residue (CH ₂ Cl2/Me0H 95/5) gave the title compound as a white solid (0.300 g, yield=94%) .

MS (ESI Pos) : 361 (M+l) IR (KBr) : λ _max 3317, 1683, 1626, 1478, 1400, 1276, 1137, 1074, 970, 932, 869, 770, 700 cirfl.

¹ H NMR (400MHz, d ₆ -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 CH ₂ Cl ₂ (10 ml) kept at 0 ⁰ C, under stirring and under argon atmosphere, a solution of pentafluorophenyl 4-

(nitrooxy) butyl 4-nitrophenyl carbonate (0.268 g, 0.89 mmol) in CH ₂ Cl ₂ (5 ml) was added. After stirring for 2h at room temperature, the reaction mixture was diluted with CH ₂ Cl ₂ (100 ml), and successively washed with 5% aqueous NaHCO ₃ (100 ml), brine (100 ml) and water (100 ml) . The organic phase was dried over MgSO ₄ and evaporated under vacuum. Purification by flash chromatography of the residue (CH ₂ Cl ₂ /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) : λ _max 3349, 2967, 1694, 1615, 1412, 1338, 1278, 1159, 1067, 974, 873, 763, 659, 574 crrfl.

¹ H NMR (400MHz, d ₆ -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) .