WO2011092065A1

WO2011092065A1 - Nitric oxide releasing compounds for the treatment of neurophatic pain

Info

Publication number: WO2011092065A1
Application number: PCT/EP2011/050510
Authority: WO
Inventors: Nicoletta Almirante; Alessia Nicotra; Valentina Borghi; Ennio Ongini
Original assignee: Nicox S.A.
Priority date: 2010-01-29
Filing date: 2011-01-17
Publication date: 2011-08-04
Also published as: AR080047A1

Abstract

The present invention relates to nitric oxide releasing derivatives of serotonin norepinephrine reuptake inhibitors and their use for the treatment of pain, having the following general formula (I) or pharmaceutically acceptable salts thereof: wherein : A is selected from the formulas (1a) and (1b). The present invention also relates to pharmaceutical formulation comprising such derivatives, to a process for their preparation and to intermediates useful for their preparation.

Description

NITRIC OXIDE RELEASING COMPOUNDS FOR THE TREATMENT OF NEUROPHATIC PAIN

The present invention relates to nitric oxide releasing derivatives of serotonin norepinephrine reuptake inhibitors and their use for the treatment of pain. The present invention also relates to pharmaceutical formulation comprising such derivatives, to a process for their preparation and to intermediates useful for their preparation .

Pain is associated with a variety of different underlying illnesses or injuries. Pain may be either acute or chronic.

Chronic pain is persistent pain which has long outlasted the onset of any known or suspected physical cause, usually by duration greater than 6 months. It can occur after a known injury or disease or it can occur without any known physical cause whatsoever. Moreover, it can be accompanied by known tissue pathology, such as chronic inflammation that occurs in some types of arthritis, or it can occur long after the healing of the injured tissue which is suspected or known to be the cause of the chronic pain. Chronic pain is a very general concept and there are several varieties of chronic pain related to the musculoskeletal system, visceral organs, skin, and nervous system.

Neuropathic pain is a common variety of chronic pain.

It can be defined as pain that results from an abnormal functioning of the peripheral and/or central nervous system. Neuropathic pain is thought to be a consequence of damage to peripheral nerves or to regions of the central nervous system. However, abnormal functioning of pain- related regions of the nervous system can also occur with chronic inflammatory conditions such as certain types of arthritis and metabolic disorders such as diabetes. Different disease processes may produce neuropathic pain syndromes. Various metabolic diseases may be the cause of neuropathic changes and may subsequently be implicated in neuropathic pain. An example of such a neuropathy is diabetic neuropathy, which occurs in a large number of patients suffering from diabetes mellitus and may be associated with a large number of clinical symptoms such as a feeling of numbness, tingling sensation, or pain.

Neuropathic pain may be more difficult to treat than other types of pain because standard analgesics often do not provide sufficient relief. Moreover standard analgesics may produce serious side effects and can be addictive.

Agents used in control of neuropathic pain include tricyclic antidepressants (amitriptyline, nortriptyne) , serotonin-norepinephrine reuptake inhibitors (duloxetine, milnacipran) , anticonvulsants (gabapentin, pregabalin) , opiates (morphine, methadone, tramadol, oxycodone) and barbiturate-like drugs. These therapies have significant drawbacks. Opiates and barbiturate-like drugs have limiting side effects and are addictive. Tricyclic antidepressants and anticonvulsants are marginally effective, and also are associated with some limiting side effects.

Serotonin-norepinephrine reuptake inhibitors are a class of antidepressants used for the treatment of depression and other affective disorders, including chronic neuropathic pain. They act upon two neurotransmitters in the brain that are known to be essential to mood, namely serotonin and norepinephrine. This is in contrast to the more widely-implemented selective serotonin reuptake inhibitors (SSRIs) , which affect only serotonin.

Duloxetine is (+) - (S) -N-Methyl-3- (naphthalen-l-yloxy) - 3- (thiophen-2-yl) propan-l-amine . It has been disclosed in U.S. Pat. No. 6, 992, 110 as being useful for the treatment of pain. Milnacipran is (±) - [ 1R (S) , 2S (R) ] -2- (aminomethyl) -N, N- diethyl-l-phenylcyclopropanecarboxamide hydrochloride. It has been disclosed in U.S. Pat. No. 4, 478, 836 as being useful for the treatment of pain.

Adverse effects associated with the treatment of diabetic neuropathic pain with serotonin-norepinephrine reuptake inhibitors (SNRIs) include somnolence, dizziness, fatigue, gastrointestinal disturbances and severe renal impairment. SNRIs are contraindicated in patients with liver disease resulting in hepatic impairment. Mydriasis has been reported in association with duloxetine, therefore, caution should be used when prescribing SNRIs to patients with increased intraocular pressure or those at risk of acute narrow-angle glaucoma. SNRIs have been associated with an increase in blood pressure, and clinically significant hypertension in some patients.

It was thus object of the present invention to provide drugs having an improved pharmacotherapeutic profile and/or lower side effects in the treatment of chronic pain, in particular neuropathic pain, including neuropathic pain associated with diabetes and fibromyalgia.

The present invention relates to nitrooxyderivatives having the following general formula (I) or pharmaceutically acceptable salts thereof:

(I)

wherein :

A is selected from the formulas (la) and (lb)

(la) (lb);

r is the integer 1 or 0 ;

y is the integer 1 or 0 ;

when y is 1 then r is 1 ;

preferably y is 1 and r is 1 ;

B is H, or a straight or branched C₁-C₄ alkyl; preferably B is CH₃;

R is selected from the group consisting of:

1) -(R°) _n-CH (ON0₂

2) -(R°) _n-CH (ON0₂ ) -CH (ON0₂ )R^la

3) -(R°) n- (T)_' m-x- (Q)p- (CH₂) _q-CH(ON0₂)R¹,

la

4) -(R°) n- (T)_' m-x- (Q)p- (CH₂) _q-CH (ON0₂) CH (ON0₂) R

5)

ONO

6)

(R° (T)_m-X- (Q)_n- (CH₂ 2)/

7) -(R XH (ON0 ) - (CH,) ^ -X- (CH 2,)^/„q2XH (ON0 ) R

1

- (R (CR R ) - (CH,) XH (ON0 ) R

9) -CH(CH₂CH₂SCH₃ ⁾NHC(0)R⁸

10⁾ -CH (CH₂SC (O) R⁹⁾ NHC (O) R

wherein n is 0 or 1 ;

m is 0 or 1 ;

p is 0 or 1 ;

nl is 0 or 1;

q is an integer from 0 to 10, preferably q is from 0 to 6; ql is an integer from 1 to 10, preferably q is from 1 to 6; q2 is an integer from 1 to 10, preferably q is from 1 to 6; t is an integer from 1 to 4, preferably t is 2 or 3;

R° is a straight or branched Ci-Cio alkylene; preferably R° is a straight or branched C₁-C6 alkylene, more preferably R° is a straight Ci-C₆ alkylene, -C(CH₃)₂- or -C (CH₃) ₂-CH₂- ;

R¹ is selected from hydrogen, a straight or branched C₁-C4 alkyl, -(CH₂)OCH₃, preferably R¹ is hydrogen, -CH₃,

(CH₂)OCH₃ or -CH(CH₃)₂;

R^la is hydrogen or a straight or branched C₁-C4 alkyl, preferably R^la is hydrogen or -CH₃;

X is selected from an oxygen atom, -NH-, -N(CH₃)- or a covalent bond, preferably X is oxygen or a covalent bond;

2 3 2 3

T and Q are -CR R -, wherein R and R at each occurrence are independently selected from hydrogen, C₁-C₄ linear or branched alkyl, OR⁴, NHR⁵, preferably R² and R³ are hydrogen or R² is hydrogen and R³ is NHR⁵;

R⁴ is hydrogen or C₁-C₄ linear or branched alkyl, preferably R⁴ is hydrogen or -CH₃;

R⁵ is hydrogen, C₁-C₄ linear or branched alkyl, -C(0)CH₃ or -C (0) OC (CH₃) 3 (Boc) , more preferably R⁵ is -C(0)CH₃ or

-C(0)OC(CH₃)₃;

R⁶ is hydrogen or C₁-C₄ linear or branched alkyl, preferably R⁶ is -CH₃;

R⁷ is (CH₂) _qCH (ON0₂) R¹ wherein q and R¹ are as above defined; R⁸ is selected from

1') - (R°)_n-CH(ON0₂)R¹,

2') - (R°) -CH (ONOJ -CH (ONOJ R^la 3') - (R^u)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R ,

4' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

preferably R⁸ is 1') or 3' ) ;

wherein R°, R¹ R^la, T, X, Q, n, m, p and q are as above defined;

R⁹ is selected from:

1') - (R°)_n-CH(ON0₂)R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

preferably R⁹ is 1');

wherein R°, R¹, T, X, Q, n, m, p and q are as above defined .

In another embodiment of the invention, there is provided compound of general formula (I) or a pharmaceutically acceptable salt thereof:

(I)

wherein :

A is selected from the formulas (la) and (lb)

(la) (lb) ;

r is the integer 1 or 0,

y is the integer 1 or 0,

when y is 1 then r is 1,

preferably y is 1 and r is 1 ; B is H, or a straight or branched C₁-C4 alkyl; preferably B is CH₃;

R is selected from the group consisting of:

1) - (R°) _n ^_CH (ON0₂) R¹ r

2) - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

wherein

n is 1 ;

m is 0;

p is 0 or 1 ;

q is from 0 to 6;

R° is a straight Ci-C₆ alkylene, -C(CH₃)₂- or -C (CH₃) ₂-CH₂- ; R¹ is hydrogen, -CH₃, -(CH₂)OCH₃ or -CH(CH₃)₂;

R^la is hydrogen or a straight or branched C₁-C4 alkyl;

X is an oxygen atom;

Q is -CR²R³-, wherein R² and R³ are hydrogen or R² is hydrogen and R³ is NHR⁵;

R⁵ is hydrogen, C₁-C₄ linear or branched alkyl, -C(0)CH₃ or -C (0) OC (CH₃) 3 (Boc) .

In another embodiment of the invention, there is provided compound of general formula (I) or a pharmaceutically acc f:

(I)

wherein :

A is selected from the formulas (la) and (lb)

(la) (lb);

r is the integer 1 or 0 ;

y is the integer 1 or 0 ;

when y is 1 then r is 1 ;

preferably y is 1 and r is 1 ;

B is H, or a straight or branched C1-C4 alkyl; preferably B is CH₃;

R is selected from the group consisting of:

5)

ONO

6)

(R°) - (T) -X- (Q) - (CH_? 2)^/

7) -(R^u) -CH (ON0 ) - (CH,) ^ -X- (CH 2 I q2 CH (ON0 ) R

1

8 -(R°) (CR R ) - (CH,)„CH (ON0 ) R

wherein

n is 0 ;

m is 0 or 1 ;

p is 0 or 1 ;

n1 is 0 ;

q is an integer from 0 to 10, preferably q is from 0 to 6; ql is an integer from 1 to 10, preferably q is from 1 to 6; q2 is an integer from 1 to 10, preferably q is from 1 to 6; t is 2 or 3;

R¹ is hydrogen, -CH₃, -(CH₂)OCH₃ or -CH(CH₃)₂;

X is oxygen or a covalent bond;

2 3 2 3

T and Q are -CR R -, wherein R and R at each occurrence are independently selected from hydrogen, C₁-C₄ linear or branched alkyl, OR⁴, NHR⁵;

R⁵ is hydrogen, C₁-C₄ linear or branched alkyl, -C(0)CH₃ or -C (0) OC (CH₃) 3, more preferably R⁵ is -C(0)CH₃ or

-C(0)OC(CH₃)₃;

R⁷ is (C¾) _qCH (ONO₂) R¹ wherein q and R¹ are as above defined.

(I)

wherein :

A is selected from the formulas (la) and (lb)

(la) (lb) ;

r is the integer 1 or 0 ;

y is the integer 1 or 0 ; when y is 1 then r is 1 ;

preferably y is 1 and r is 1 ;

B is H, or a straight or branched C1-C4 alkyl; preferably is CH₃;

R is selected from the group consisting of:

9) -CH(CH₂CH₂SCH₃)NHC(0)R⁸

10) -CH (CH₂SC (0) R⁹) NHC (0) R⁹

wherein

R⁸ is selected from

1' ) - (R^u)_n-CH(ONO_?)R ,

(T) -X- (Q ^) _Pp-- \(^C^H2_?>) q-CH (ONO_?) R ,

R is selected from:

1') - (R°)_n-CH(ON0₂)R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH^_g-CHiO O^R¹

wherein

n is 1 ;

m is 0 ;

p is 0 or 1 ;

q is from 0 to 6;

R° is a straight Ci-C₆ alkylene, -C(CH₃)₂- or -C (CH₃) ₂-CH₂- ;

R¹ is hydrogen, -CH₃, -(CH₂)OCH₃ or -CH(CH₃)₂;

X is an oxygen atom;

2 3 2 3

Q is -CR R -, wherein R and R are hydrogen.

preferred embodiments for the compounds of formula (I) or pharmaceutically acceptable salts thereof, R is:

OMe

In another embodiment of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof

(I)

wherein :

A is

d a ;

r is the integer 1 or 0,

y is the integer 1 or 0,

when y is 1 then r is 1,

preferably y is 1 and r is 1 ; B is H, or a straight or branched C₁-C4 alkyl, preferably B is CH₃;

R is selected from the group consisting of:

1) - (R°) _n ^_CH (ON0₂) R¹ r

2) - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

5)

- (R°) - (T) -X- (Q) - (CH 2 I

6)

7) - (R°)_n-CH(ON0₂) - (CH₂)_ql-X- (CH₂) _q2CH (ON0₂) R¹

8) - (R°) _n- (CR⁶R⁷) - (CH₂) _qCH (ON0₂) R¹

9) -CH(CH₂CH₂SCH₃)NHC(0)R⁸

10) -CH(CH₂SC(0)R⁹)NHC(0)R⁹

wherein

n is 0 or 1,

m is 0 or 1,

p is 0 or 1,

nl is 0 or 1 ;

q is an integer from 0 to 10, preferably q is from 0 to 6; ql is an integer from 1 to 10, preferably q is from 1 to 6; q2 is an integer from 1 to 10, preferably q is from 1 to 6; t is an is an integer from 1 to 4, preferably t is 2 or 3; R° is a straight or branched C₁-C₁₀ alkylene; preferably R° is a straight or branched C₁-C6 alkylene, more preferably R° is a straight Ci-C₆ alkylene, -C(CH₃)₂- or -C (CH₃) ₂-CH₂- ; R¹ is selected from hydrogen, a straight or branched C₁-C4 alkyl, -(CH₂)OCH₃, preferably R¹ is hydrogen, -CH₃, (CH₂)OCH₃ or -CH(CH₃)₂;

2 3 2 3

-C(0)OC(CH₃)₃;

R⁷ is (CH₂) qCH (ONO2) R¹ wherein q and R¹ are as above defined; R⁸ is selected from

1') - (R°)_n-CH(ON0₂)R¹,

2') - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

preferably R⁸ is l')or 3' ) ;

wherein R°, R¹ R^la, T, X, Q, n, m, p and q are as above defined;

R⁹ is selected from:

1') - (R°)_n-CH(ON0₂)R¹,

3') - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

preferably R⁹ is 1'); wherein R , R , T, X, Q, n, m, p and q are as above defined .

(i)

wherein :

A is la)

(la)

r is the integer 1 or 0 ;

y is the integer 1 or 0 ;

when y is 1 then r is 1 ;

preferably y is 1 and r is 1 ;

B is H, or a straight or branched C₁-C4 alkyl, preferably B is CH₃;

R is selected from the group consisting of:

1) - (R^u) _n-CH (ON0₂) R ,

la

2) - (R°) -CH (ONO,) -CH (ONO,) R

3) - (R^u) - (T) -X- (Q)p- (CHJ -CH(ONOJR ,

la

4) - (R^u)_n- (T)_m-X- (Q)p- (CHJ -CH(ONO,)CH(ONO,)R ,

wherein

n is 1 ;

m is 0 ;

p is 0 or 1 ; q is from 0 to 6;

R^la is hydrogen or a straight or branched C₁-C4 alkyl;

X is an oxygen atom;

R⁵ is hydrogen, C₁-C₄ linear or branched alkyl, -C(0)CH₃ or -C(0)OC(CH₃)₃.

(I) wherein :

A is (la)

(la)

r is the integer 1 or 0 ;

y is the integer 1 or 0 ;

when y is 1 then r is 1 ;

preferably y is 1 and r is 1 ;

B is H, or a straight or branched C₁-C4 alkyl, preferably B is CH₃;

R is selected from the group consisting of:

5)

6)

7) - (R^u)_n-CH(ON0₂) - (CH₂)_ql-X- (CH₂) _q2CH (ON0₂) R

8) - (R°)_n- (CR⁶R⁷) - (CH₂)_qCH(ON0₂)R¹

wherein

n is 0 ;

m is 0 or 1 ;

p is 0 or 1 ;

nl is 0;

R¹ is hydrogen, -CH₃, -(CH₂)OCH₃ or -CH(CH₃)₂;

X is oxygen or a covalent bond;

2 3 2 3

-C(0)OC(CH₃)₃;

R⁷ is (C¾) _qCH (ONO₂) R¹ wherein q and R¹ are as above defined. In another embodiment of the invention,

provided compound of general formula

pharmaceutically acceptable salt thereof:

(I)

wherein :

A is (la)

(la)

r is the integer 1 or 0 ;

y is the integer 1 or 0 ;

when y is 1 then r is 1 ;

preferably y is 1 and r is 1 ;

B is H, or a straight or branched C₁-C4 alkyl, preferably B is CH₃;

R is selected from the group consisting of:

9) -CH(CH₂CH₂SCH₃ ⁾NHC(0)R⁸

10) -CH(CH₂SC(0)R⁹⁾NHC(0)R⁹

wherein

R⁸ is selected from

1' (R -CH(ONO,)R ,

3' - (R^u) - (T) -X- (Q)p- (CHJ -CH(ONOJR ,

R is selected from:

1' (R -CH(ONO,)R ,

3' - (R^u) - (T) -X- (Q)p- (CH_?) -CH(ONO_?)R wherein

n is 1 ;

m is 0 ;

p is 0 or 1 ;

q is from 0 to 6;

X is an oxygen atom;

2 3 2 3

Q is -CR R -, wherein R and R are hydrogen.

In another embodiment of the invention, there is provided a compound of formula (I) or a salt thereof wherein :

A is (la) ,

and

R is:

In another embodiment of the invention, there is provided a compound of formula (I) or a salt thereof wherein:

A is (la) ,

r is 1 /

y is 1;

B is CH₃ and

R is:

In another embodiment of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salts thereof

(I)

wherein :

A is (lb)

(lb) r is the integer 1 or 0 ;

y is the integer 1 or 0 ;

when y is 1 then r is 1 ;

preferably y is 1 and r is 1 ;

B is H, or a straight or branched C₁-C4 alkyl, preferably B is CH₃;

R is selected from the group consisting of:

1) - (R°) -CH (ON0 ) R¹

la

2) - (R ) -CH (ON0 ) -CH (ON0 ) R

3) - (R^u) - (T) -X- (Q)p- (CH,) -CH(ONO,)R

la

4) - (R")_n- (T)_m-X- ( Q ) _p- (CH,)„-CH (ONO,) CH (ONO,) R

5)

- (R°) - (T) -X- (Q) - (CH 2 /

6)

1

7) - (R^u)_n-CH(ON0₂) - (CH₂)_ql-X- (CH₂) _q2CH (ON0₂) R

8) - (R°) _n- (CR⁶R⁷) - (CH₂) _qCH (ON0₂) R¹

9) -CH(CH₂CH₂SCH₃)NHC(0)R⁸

10) -CH(CH₂SC(0)R⁹)NHC(0)R⁹

wherein

n is 0 or 1 ;

m is 0 or 1 ;

p is O or l;

nl is 0 or 1;

q is an integer from 0 to 10, preferably q is from 0 to 6; ql is an integer from 1 to 10, preferably q is from 1 to 6; q2 is an integer from 1 to 10, preferably q is from 1 to 6; t is an is an integer from 1 to 4, preferably t is 2 or 3;

R¹ is selected from hydrogen, a straight or branched C₁-C₄ alkyl, -(CH₂)OCH₃, preferably R¹ is hydrogen, -CH₃,

- (CH₂)OCH₃ or -CH(CH₃)₂;

R^la is hydrogen or a straight or branched C₁-C₄ alkyl, preferably R^la is hydrogen or -CH₃;

2 3 2 3

T and Q are -CR R -, wherein R and R at each occurrence are independently selected from hydrogen, C₁-C₄ linear or branched alkyl, OR⁴, NHR⁵, preferably R² and R³ are hydrogen or R² is hydrogen and R³ is NHR⁵; R⁴ is hydrogen or C₁-C₄ linear or branched alkyl, preferably R⁴ is hydrogen or -CH₃;

-C(0)OC(CH₃)₃;

R⁷ is (C¾) _qCH (ONO₂) R¹ wherein q and R¹ are as above defined;

R⁸ is selected from

1') - (R°)_n-CH(ON0₂)R¹,

2') - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

preferably R⁸ is 1') or 3' ) ;

wherein R°, R¹ R^la, T, X, Q, n, m, p and q are as above defined;

R⁹ is selected from:

1') - (R°)_n-CH(ON0₂)R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

preferably R⁹ is 1');

wherein R°, R¹, T, X, Q, n, m, p and q are as above defined .

(I)

wherein :

A is (lb)

(lb)

r is the integer 1 or 0 ;

y is the integer 1 or 0 ;

when y is 1 then r is 1 ;

preferably y is 1 and r is 1 ;

B is H, or a straight or branched C₁-C4 alkyl, preferably B is CH₃;

R is selected from the group consisting of:

1) - (R°)_n-CH(ON0₂)R¹,

2) - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

wherein

n is i;

m is 0 ;

p is 0 or 1 ;

q is from 0 to 6;

R^la is hydrogen or a straight or branched C₁-C4 alkyl;

X is an oxygen atom;

R⁵ is hydrogen, C₁-C₄ linear or branched alkyl, -C(0)CH₃ or -C(0)OC(CH₃)₃. In another embodiment of the invention

provided compound of general formula

pharmaceutically acceptable salt thereof:

(I)

wherein :

A is (lb)

(lb)

r is the integer 1 or 0 ;

y is the integer 1 or 0 ;

when y is 1 then r is 1 ;

preferably y is 1 and r is 1 ;

B is H, or a straight or branched C1-C4 alkyl, preferably B is CH₃;

R is selected from the group consisting of:

5)

ON0₂

(R°)_n- (T)_m-X- (Q)_n- (CH_? 2)^/

6)

1

7) - (R^u)_n-CH(ON0₂) - (CH₂)_ql-X- (CH₂) _q2CH (ON0₂) R 8) - (R°) _n- (CR⁶R⁷) - (CH₂) _qCH (ON0₂) R¹

wherein

n is 0 ;

m is 0 or 1 ;

p is 0 or 1;

n1 is 0 ;

R¹ is hydrogen, -CH₃, -(CH₂)OCH₃ or -CH(CH₃)₂;

X is oxygen or a covalent bond;

2 3 2 3

-C(0)OC(CH₃)₃;

R⁷ is (C¾) _qCH (ONO₂) R¹ wherein q and R¹ are as above defined.

(I)

wherein:

(lb)

r is the integer 1 or 0 ;

y is the integer 1 or 0 ;

when y is 1 then r is 1 ;

preferably y is 1 and r is 1 ;

B is H, or a straight or branched C₁-C4 alkyl, preferably B is CH₃;

R is selected from the group consisting of:

9) -CH(CH₂CH₂SCH₃)NHC(0)R⁸

10) -CH(CH₂SC(0)R⁹)NHC(0)R⁹

wherein

R⁸ is selected from

1') - (R°)_n-CH(ON0₂)R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p-

R⁹ is selected from:

1') - (R°)_n-CH(ON0₂)R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

wherein

n is 1 ;

m is 0 ;

p is 0 or 1 ;

q is from 0 to 6;

R° is a straight Ci-C₆ alkylene, -C(CH₃)₂- or -C (CH₃) ₂-CH₂- ;

R¹ is hydrogen, -CH₃, -(CH₂)OCH₃ or -CH(CH₃)₂;

X is an oxygen atom; 2 3 2 3

Q is -CR R -, wherein R and R are hydrogen.

In another embodiment of the invention, there is provided a compound of formula (I) or a pharmaceutical acceptable salt thereof

wherein:

A is (lb) ,

R is :

wherein :

A is (lb) ,

r is 1; is 1 ;

is C¾ and

is :

Another embodiment of the invention provides a compound formula (I) selected from the group:

(1)

Ĩ5)

Ĩ10)

Ĩ14)

Ĩ18)

Ĩ22)

Ĩ26) 

(30)

(32)

(33)

(34)

(35)

(36)

In yet another embodiment of the invention, there is provided a process for the preparation of compounds of formula (I)

(I)

wherein :

A is selected from the formulas (la) and (lb)

(la) (lb) ; r is 1 and y is 1 ;

B is H, or a straight or branched C1-C4 alkyl;

R is selected from the group consisting of:

1) - (R°) _n ^_CH (ON0₂) R¹ r

2) - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

4) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la

5)

6)

7) - (R°)_n-CH(ON0₂) - (CH₂)_ql-X- (CH₂) _q2CH (ON0₂) R¹

8) - (R°) _n- (CR⁶R⁷) - (CH₂) _qCH (ON0₂) R¹

9) -CH(CH₂CH₂SCH₃)NHC(0)R⁸

10) -CH(CH₂SC(0)R⁹)NHC(0)R⁹

wherein

n is 0 or 1,

m is 0 or 1,

p is 0 or 1,

nl is 0 or 1 ;

q is an integer from 0 to 10;

ql is an integer from 1 to 10;

q2 is an integer from 1 to 10;

t is an is an integer from 1 to 4;

R° is a straight or branched C1-C10 alkylene;

R¹ is selected from hydrogen, a straight or branched Ci~C< alkyl or - (CH₂) OCH₃;

R^la is hydrogen or a straight or branched C1-C4 alkyl; X is selected from an oxygen atom, -NH-, -N(C¾)- or a covalent bond;

2 3 2 3

R⁴ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁵ is hydrogen, C₁-C₄ linear or branched alkyl, -C(0)CH₃ or

-C(0)OC(CH₃)₃;

R⁶ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁷ is (C¾) _qCH (ONO₂) R¹ wherein q and R¹ are as above defined;

R⁸ is selected from

1') - (R°)_n-CH(ON0₂)R¹,

2') - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4') - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

preferably R⁸ is 1') or 3' ) ;

wherein R°, R¹ R^la, T, X, Q, n, m, p and q are as above defined;

R⁹ is selected from:

1') - (R°) _n-CH (ON0₂) R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

wherein R°, R¹, T, X, Q, n, m, p and q are as above defined;

said process, as depicted in Scheme 1, comprises:

0 B

Xa 0 z

R

( X I ) Scheme 1

( i ) reacting a carboxylic acid of formula (VII la)

R-COOH (Villa)

wherein R is as above defined, with Ag₂<3 or Hg₂0 in a molar ratio (compound of formula (Villa) /Ag₂0 or Hg₂0 from 1 to 0.5, in an organic solvent to obtain a carboxylic acid salt of formula (XIII)

RCO-O-Xi (XIII)

wherein R is as above defined and Xi is Ag⁺ or Hg⁺;

( ii ) reacting the compound of formula (XIII) with a compound of formula (XII)

(XII)

wherein B is as above defined, X_a is an activating group selected from the formulas 2a) - (2h)

(2d) (2e; (2f)

(2g) (2h)

preferably Xa is 2d, 2a or 2g, Z is CI, Br or I, in an organic solvent obtaining a compound of formula (XI) 0 B 0

Xa 0 0 R

(XI)

wherein X_a, B and R are as above defined;

iii) reacting the compound of formula (XI), with a compound

(Ila) or (lib)

(Ha) (lib) in an organic solvent in the presence of an organic or inorganic base, obtaining a compound of formula (I) .

Step (i) : the reaction is carried out in an organic solvent, generally an aprotic solvent, such as toluene, methylene chloride, or chloroform or dipolar solvents such as acetonitrile, water, tetrahydrofurane, dimethylformamide (DMF) , N-methylpyrrolidone, or in a mixture thereof, depending on the solubility of the compounds of the reaction; the preferred solvent are acetonitrile, water a mixture of acetonitrile and water.

The molar ratio of compound of formula (Villa) /Ag20 or Hg20 is from 1 to 0.5.

The reaction is generally carried out in a temperature range from about -20°C to about 80°C, preferably from 10°C to 30°C in the dark.

Step (ii) : the reaction is carried out in an organic solvent, generally an aprotic solvent, such as toluene, methylene chloride, or chloroform or dipolar solvents such as tetrahydrofurane, dimethylformamide (DMF) , N- methylpyrrolidone, acetonitrile or in a mixture thereof, depending on the solubility of the compounds of the reaction; the preferred solvent are toluene, methylene chloride, THF, a mixture of methylene chloride and THF. The molar ratio of compound of formula (XIII)/ (XII) is from 2 to 0.5.

The reaction is carried out in a temperature range from about -20°C to about 120°C, preferably from 10°C to 30°C. Compounds of formula (XII), wherein Xa and Z are as above defined, are prepared by known compounds following procedures well known in the art (Jose Alexander,* Robyn Cargill, Stuart R. Michelson, and Harvey Schwamt, (Acyloxy) alkyl Carbamates as Novel Bioreversible Prodrugs for Amines: Increased Permeation through Biological Membranes, J. Med. Chem. , 1988, 31, 318-322).

The nitrate intermediates of formula (XI) are stable compounds obtainable in high yields and purity, suitable for long term storage. Said compounds react with the compound of formula (Ila) or (lib) under mild reaction conditions, allowing to obtain nitrooxyderivatives of formula (I) in high yield and purity.

Step iii) : the reaction is carried out in the presence of an organic or inorganic base such as pyridine or triethylamine or C S 2CO₃ in an aprotic polar/non polar solvent such as THF, DMF or CH2C I2 , at temperature ranging from -80°C to 100°C, preferably between 10-40°C.

(I)

wherein A is (la)

(la)

r is 1 and y is 1,

B is H, or a straight or branched C₁-C4 alkyl; R is selected from the group consisting of:

1) - (R°) _n-CH (ON0₂) R¹ r

2) (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4) (R°) - (T) -X- (Q)p- (CH₂) -CH(ON0₂)CH(ON0₂)R^la, 5)

ONO

6)

7) - (R^u) -CH(ON0 ) - (CH,) .,-X- (CH ^L2 I q2 CH (ON0 ) R

.1

(CR R , (CH_?) CH (ONO,) R

9) -CH(CH₂CH₂SCH₃)NHC(0)R^fc

10) -CH (CH₂SC (O) R⁹) NHC (O) R

wherein

n is 0 or 1

m is 0 or 1

p is 0 or 1

nl is 0 or 1;

q is an integer from 0 to 10 ql is an integer from 1 to 10;

q2 is an integer from 1 to 10;

t is an is an integer from 1 to 4;

R° is a straight or branched Ci-Cio alkylene;

R¹ is selected from hydrogen, a straight or branched C₁-C4 alkyl, -(CH₂)OCH₃;

R^la is hydrogen or a straight or branched C₁-C4 alkyl;

X is selected from an oxygen atom, -NH-, -N(C¾)- or a covalent bond;

2 3 2 3

R⁴ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁵ is hydrogen, C₁-C₄ linear or branched alkyl, -C(0)CH₃ or -C(0)OC(CH₃)₃;

R⁶ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁷ is (C¾) _qCH (ONO₂) R¹ wherein q and R¹ are as above defined;

R⁸ is selected from

1') - (R°)_n-CH(ON0₂)R¹,

2') - (R°)_n-CH(ON0₂)-CH(ON0₂)R^la

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

wherein R°, R¹ R^la, T, X, Q, n, m, p and q are as above defined;

R⁹ is selected from:

1') - (R°)_n-CH(ON0₂)R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

wherein R°, R¹, T, X, Q, n, m, p and q are as above defined;

said process, as depicted in Scheme 2, comprises

(Ι')

Scheme 2

i ' ) reacting a compound of formula (Ila

(Ha)

a compound of formula (XII)

(XII)

wherein B is as above defined, X_a is an activating group selected from the formulas (2a) - (2h)

2a) (2b) (2c)

(2d) (2e; (2f)

(2g) (2h)

preferably Xa is 2d, 2a or 2g and Z is CI, Br or I, in an organic solvent and in the presence of an organic or inor anic base, obtaining a compound of formula (Ilia)

wherein B and z are as above defined;

ii' ) reacting the compound of formula (Ilia) with a compound of formula RCOOH (Villa), wherein R is as above defined, in an organic solvent and in the presence of an organic or inorganic base obtaining a compound of formula (I' )

(ΐ')

wherein B and R are as above defined. Step i' ) : the reaction is carried out in the presence of an organic or inorganic base such as pyridine or triethylamine, in an aprotic polar/non polar solvent such as acetonitrile, THF, DMF or CH₂CI₂, at temperature ranging from -20°C to 60°C.

Compounds (Ilia) wherein z is Br or I can preferably be obtained from compounds (Ilia) wherein z is CI by halogen atom exchange reactions as well known in the literature. The intermediates of formula (Ilia) are stable compounds obtainable in high yields and purity, suitable for long term storage. Said compounds react with the compound of formula RCOOH (Villa) under mild reaction conditions, allowing to obtain nitrooxyderivatives of formula (I) in high yield an purity.

Step ii' ) : the reaction is carried out in the presence of an organic or inorganic base such as pyridine or triethylamine or C S 2CO₃ , preferably C S 2CO₃ , in an aprotic polar/non polar solvent such as THF, DMF or CH2C I 2 , at temperature ranging from 0°C to 60 °C.

The compounds of the present invention have a better efficacy than the correspondent parent drugs in reducing neuropathic pain and, in particular, in reducing neuropathic pain associated with diabetes.

The compounds of the present invention induce less side effects such as less sedation than the correspondent parent drugs .

In yet another aspect of the invention there is provided a pharmaceutical composition containing at least a compound of formula (I) and/or pharmaceutically acceptable salts thereof together with non-toxic adiuvants and/or carriers usually employed in the pharmaceutical field.

The compounds of the invention may be administered orally or parenterally, in formulations eventually containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.

In still another aspect of the invention, there is provided a pharmaceutical composition wherein the compound of the invention is administered as a solution, suspension or emulsion in an acceptable vehicle.

In one embodiment, the invention relates to the use of the compounds of formula (I) for treating or preventing pain, in particular chronic pain.

In one embodiment, the invention relates to the use of the compounds of formula (I) for treating or preventing a neuropathic pain condition, in particular for treating or preventing a diabetes-associated neuropathic pain.

In one embodiment, the invention relates to a method for treating or preventing a neuropathic condition in a subject, the method consisting essentially of administering to the subject at least one compound of formula (I) .

In one embodiment, the invention relates to compounds of formula (I) in neutral form, the form of acid, in the form of a salt, preferably a physiologically acceptable salt, in the form of a solvate or of a polymorph and/or in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, and/or in any mixing ratio.

Synthesis procedure

1. The compounds of general formula (I) wherein A is chosen between the formulas (la), (lb); r is 1; y is 0 and R is as above defined can be obtained by a process comprising reacting a compound of formula A-H (Ila) or (lib)

( H a )

with a compound of formula (IV)

0

Xa 0

(IV)

wherein R is as above defined and Xa is an activating group selected from com ounds of formulas (2a) - (2h)

(2d) (2e; (2f)

(2g) (2h)

preferably A is 2d or 2a or 2g;

in presence of a base such as pyridine or triethylamine with or without catalytic to equimolar amount of DMAP; in an aprotic polar/non polar solvent such as acetonitrile, THF, DMF or CH₂CI₂, in presence or absence of catalytic amount of Sc(OTf)3, at temperature ranging from -80°C to 60°C.

Compounds (IV) can be prepared from the appropriate compound of formula (V) :

RCH₂OH

(V)

wherein R is as above defined, following procedures well known in the literature.

Compounds (V) are known in the literature or can be obtained by nitration of compounds (VI)

R'CH₂OP (VI)

wherein

P is a suitable hydroxyl protecting group, stable to acidic conditions ;

wherein R' is selected from the group consisting of:

2) - (R°) _n-CH (OH) -CH (OH) R^la

3) - (R°)_n- (T)_m-X- (Q)p-

4) - (R°) - (T) -X- (Q)p- (CHJ -CH(OH)CH(OH)R^la,

5)

OH

6)

7) - (R°)_n-CH(OH) - (CH₂)_ql-X- (CH₂) _q2CH (OH) R¹

8) - (R°) _n- (CR⁶R⁷) - (CH₂) _qCH (OH) R¹

9) -CH(CH₂CH₂SCH₃)NHC(0)R⁸

10) -CH (CH₂SC (0) R⁹) NHC (0) R⁹

wherein n is 0 or 1 ;

m is 0 or 1 ;

p is 0 or 1 ;

nl is 0 or 1;

q is an integer from 0 to 10, preferably q is from 0 to 6; ql is an integer from 1 to 10, preferably q is from 1 to 6; q2 is an integer from 1 to 10, preferably q is from 1 to 6; t is an is an integer from 1 to 4, preferably t is 2 or 3; R° is a straight or branched Ci-Cio alkylene; preferably R° is a straight or branched C₁-C6 alkylene, more preferably R° is a straight Ci-C₆ alkylene, -C(CH₃)₂- or -C (CH₃) ₂-CH₂- ;

(CH₂)OCH₃, -CH(CH₃)₂;

2 3 2 3

-C(0)OC(CH₃)₃;

R⁷ is (CH₂) _QCH (OH) R¹ wherein q and R¹ are as above defined; R⁸ is selected from

2') -(R°) -CH (OH) -CH (OH) R^LA 3') - (R^u)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(OH)R ,

4' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(OH)CH(OH)R^la,

preferably R⁸ is 1');

wherein R°, R¹ R^la, T, X, Q, n, m, p and q are as above defined;

R⁹ is selected from:

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH^_g-CHiOHJR¹

preferably R⁹ is 1');

wherein R°, R¹, T, X, Q, n, m, p and q are as above defined;

by reacting with nitric acid and acetic anhydride in a temperature range from -50°C to 0°C, or by reacting with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non polar solvent such as DMF, THF or CH₂CI₂ at temperature ranging from -80°C to 65°C. Eventually removing in basic or other conditions the protective group P, as known by person skilled in the art. Alternatively compounds (V) can be obtained by nitration of compounds (VII)

R"CH₂OH (VII)

wherein R is selected from the group consisting of:

1) - (R^u)_n-CH(z)R ,

2) - (R°) _n-CH (z) -CH (z) R^la

3) - (R°)_n- (T)_m-X- (Q)p-

4) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(z)CH(z

5)

6)

7) - (R°)_n-CH(z) - (CH₂)_ql-X- (CH^CH JR¹

8) - (R°)_n- (CR⁶R⁷) - (CH^_gCHizJR¹

9) -CH(CH₂CH₂SCH₃)NHC(0)R⁸

10) -CH (CH₂SC (0) R⁹) NHC (0) R⁹

wherein

n is 0 or 1,

m is 0 or 1,

p is 0 or 1,

nl is 0 or 1 ;

R¹ is selected from hydrogen, a straight or branched C₁-C₄ alkyl, -(CH₂)OCH₃, preferably R¹ is hydrogen, -CH₃, (CH₂)OCH₃, -CH(CH₃)₂;

2 3 2 3

R⁴ is hydrogen or C₁-C₄ linear or branched alkyl, preferably R⁴ is hydrogen or -CH₃; R⁵ is hydrogen, C₁-C₄ linear or branched alkyl, -C(0)CH₃ or -C (0) OC (CH₃) 3 (Boc) , more preferably R⁵ is -C(0)CH₃ or

-C(0)OC(CH₃)₃;

R⁷ is (C¾) _qCH (z) R¹ wherein q and R¹ are as above defined; R⁸ is selected from

2') - (R°) _n-CH (z) -CH (z) R^la

3') - (R°)_n- (T)_m-X- (Q)p-

4' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(z)CH(z)R^la,

preferably R⁸ is 1');

wherein R°, R¹ R^la, T, X, Q, n, m, p and q are as above defined;

R⁹ is selected from:

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH^-CH JR¹

preferably R⁹ is 1');

wherein R°, R¹, T, X, Q, n, m, p and q are as above defined.

Wherein Z is CI, Br or I, as already described

with AgN0₃ as described in the international application WO

2006/008196.

Compounds (VI) and (VII) are commercially available or are known in the literature or can be prepared by known compounds by methods well known in the art.

Compound (Ila) is known as duloxetine or as (+)-(S)-N- Methyl-3- (naphthalen-l-yloxy) -3- (thiophen-2-yl) propan-1- amine and it has been disclosed in U.S. Pat. No. 6,992,110. Compound (lib) is known as Milnacipran or as (±) - [1R (S) , 2S (R) ] -2- (aminomethyl) -N, -diethyl-1- phenylcyclopropanecarboxamide hydrochloride and it has been disclosed in U.S. Pat. No. 4,478,836.

2. The compounds of general formula (I) wherein A is chosen between the formulas (la), (lb); r and y are 0; can be obtained by a process comprising reacting a compound of formula A-H (Ila) or (lib) as above defined with a compound of formula (Villa) or (VHIb)

0 0

HO R Xb R

(Villa) (VHIb)

wherein R is as above defined and X is selected from the group consisting of:

1) Xa

2) -CI, -Br, -F;

in the presence of a base such as pyridine or triethylamine in the presence of catalytic to equimolar amount of DMAP, in an aprotic polar/non polar solvent such as THF, DMF or CH₂C1₂ for (VHIb), or in presence of DCC, EDAC, HBTU, HATU or other coupling reagents, in the presence of catalytic amount of DMAP, at temperature ranging from -80 °C to 60 °C for (Villa) .

The compounds of general formula (Vlllb) wherein R and X are as above defined can be prepared by methods well known in the art, from the appropriate compound of general formula (Villa) .

Compounds of general formula (Villa) , wherein R is as above defined are known in the literature or can be obtained: a) by oxidation of the compound of formula (V)

RCH₂OH

(V)

wherein R is as above defined, by oxidation with TCCA or NaOCl or aI0₄ in the presence of a catalyst such as TEMPO or ruthenium (IV) oxide hydrate in an aprotic polar/protic polar/non polar solvent such as acetone, CH₃CN, water, CH₃CI or CH₂CI₂ or mixtures, at temperatures ranging from - 80°C to 65°C. b) from the corresponding compounds of formula (IX)

R' COOH (IX)

wherein R' is as above defined

by reacting with nitric acid and acetic anhydride in a temperature range from -50°C to 0°C, or by reacting with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non polar solvent such as DMF, THF or CH₂CI₂ at temperature ranging from -80°C to 65°C.

Compounds (IX) are commercially available or are known in the literature or can be prepared by known compounds by methods well known in the art. c) by reacting the corresponding compound (X)

R"COOH (X)

wherein R" is above defined, with AgNC>3 as described in the international application WO 2006/008196.

Compounds (X) are commercially available or are known in the literature or can be prepared by known compounds by methods well known in the art. 3. The compounds of general formula (I) wherein

A is chosen between the formulas (la), (lb); r and y are 1 ; B and R are as above defined;

can be obtained by a process comprising reacting a compound of formula A-H (Ila) or (lib) with a compound of formula

(XI)

0 B 0

Xa 0 0 R

(XI)

wherein R, B and Xa are as above defined in the presence of an organic or inorganic base such as pyridine or triethylamine in the presence of catalytic to equimolar amount of DMAP, in an aprotic polar/non polar solvent such as THF, DMF or CH₂CI₂, at temperature ranging from -80°C to 100°C.

The compound of formula (XI), wherein R, B and Xa are as above defined, can be obtained by a process comprising reacting a compound of formula (XII) :

(XII)

wherein X_a and B are as above defined and Z is CI, Br or I, with the appropriate compound of formula (XIII)

RCO-O-Xi (XIII)

wherein R is as above defined and Xi is Ag⁺ or Hg⁺,

in a non polar/aprotic polar solvent such as toluene,

CH₂CI₂, THF, or DMF at temperatures ranging between -80 °C to 60°C.

Compound of formula (XII) are prepared by known compounds following procedures well known in the art (Jose Alexander,* Robyn Cargill, Stuart R. Michelson, and Harvey Schwamt, (Acyloxy) alkyl Carbamates as Novel Bioreversible Prodrugs for Amines: Increased Permeation through Biological Membranes, J. Med. Chem. , 1988, 31, 318-322) Compound of formula (XIII) are prepared by reacting the appropriate compound of formula (Villa)

RCOOH (Villa)

wherein R is as above defined,

with Ag₂0 or Hg₂0 in the dark, in a polar/non polar solvent such as CH₃CN, H₂0, THF, or DMF toluene, CH₂C1₂, at temperature ranging from -80°C to 60°C.

4. Alternatively, compounds of general formula (I) wherein A is (la) ; r and y are 1; B and R are as above defined; can be obtained by a process comprising reacting a compound of formula (Ilia) with a compound of formula RCOOH (VIII)

(Ilia)

wherein R and B are as above defined

in the presence of an organic or inorganic base such as pyridine or triethylamine or C S 2CO₃ , preferably C S 2CO₃ in an aprotic polar/non polar solvent such as THF, DMF or CH2C I 2 , at temperature ranging from -10°C to 60°C.

The compound of formula (Ilia), wherein B is as above defined, can be obtained by a process comprising reacting a compound of formula (Ila) already described with a compound of formula (XII) :

(XII)

wherein X_a and B are as above defined and Z is CI, Br or I, in the presence of an organic or inorganic base such as pyridine or triethylamine in the presence of catalytic to equimolar amount of DMAP, in an aprotic polar/non polar solvent such as THF, DMF or CH2C I2 , at temperature ranging from -10°C to 60°C.

Compounds (Ilia) wherein z is Br or I can preferably be obtained from compounds (Ilia) wherein z is CI by halogen atom exchange reactions as well known in the literature. Example 1: 2- (2- (nitrooxy) ethoxy) acetic acid

STEP A : 2- (2-hydroxyethoxy) ethyl nitrate.

Diethylenglycol monochloride (10 μL, 94.3 mmol) was dissolved in CH₃CN (250 i ) and Nal (141 g, 943 mmol) was added. The reaction was refluxed for 16 hours. The solvent was removed and CH₂CI₂ (100 mL) was added, the mixture was filtered and the organic phase was washed with a solution of Na₂S₂<0₅ (10%), dried and evaporated. The crude material was dissolved in CH₃CN (250 mL) , Ag 0₃ (55 g, 330 mmol) was added and the reaction refluxed for 2 hours. The mixture was concentrated and diluted with EtOAc, then filtered. The organic phase was washed with water and brine, dried over Na₂SC>4 and concentrated affording the title compound as clear oil. (8.5 g, 60%)

1H-NMR (CDCI3) : 4.66 (2H,m); 3.80 (4H,m); 3.63 (2H,m) .

STEP B : 2- (2- (nitrooxy) ethoxy) acetic acid.

2- (2-hydroxyethoxy) ethyl nitrate (17 g, 112 mmol) was dissolved in acetone and cooled to 0°C; aHC0₃ (15%, 150 mL) , NaBr (2 g, 22 mmol) and TEMPO (170 mg, 1.12 mmol) were added. Trichloroisocyanuric acid (50 g, 224 mmol) was added in portions in 15 minutes. The reaction was stirred at room temperature for 3 hours, then cooled to 0°C and 2-propanol (60 mL) was slowly added in 15 minutes. The reaction was stirred at 0°C for 30 minutes then the precipitate was filtered. The solvent was concentrated and NaOH (10 ~6 ) was added to pH=9. The aqueous phase was extracted with EtOAC, then HC1 was added to pH=3 and the aqueous phase was extracted with CH₂CI₂. The organic phase was dried over Na₂SC>4 and concentrated affording the title compound as oil. (8.7 g, 47%)

¹H-NMR (DMSO) : 4.67 (2H,m); 4.06 (2H,s); 3.78 (2H,m) . Example 2: silver (I) 2- (2- (nitrooxy) ethoxy) acetate .

2- (2- (nitrooxy) ethoxy) acetic acid obtained in Example 1 (0.38 g, 2.30 mmol) was dissolved in CH₃CN (10 mL) . To the solution Ag₂0 (0.32 g, 1.38 mmol) and H₂0 (6 mL) were added and the mixture was stirred at room temperature for 5 hours, and then filtered over celite. The filtrate was concentrated affording the title compound as a pale yellow solid (0.625 g, quantitative yield)

¹H-NMR (DMSO) : 4.66 (2H,m); 3.92 (2H,s); 3.77 (2H,m)

Example 3: 1-iodoethyl 4-nitrophenyl carbonate

STEP A: 1-chloroethyl 4-nitrophenyl carbonate.

To a solution of 4-nitrophenol (3.0 g, 21.6 mmol) and pyridine (1.9 mL, 24 mmol) in CH₂C1₂ (48 mL) cooled to 0°C, 1-chloroethyl chloroformate (2.3 mL, 21.6 mmol) was added. The reaction was stirred at room temperature for 5-6 hours, then washed with NaH₂PC>4 (5%) and brine, dried over Na₂SC>4 and concentrated affording the title compound (4.88 g, 92%) as a pale yellow solid.

1H-NMR (CDC1₃) : 8.32 (2H,m); 7.44 (2H,m); 6.52 ( 1H, q, J=5.8 Hz); 1.94 (3H, d, J=5.5Hz) .

STEP B: 1-iodoethyl 4-nitrophenyl carbonate.

1-chloroethyl 4-nitrophenyl carbonate (4.88 g, 20 mmol) and Nal (20.8 g, 139 mmol) were dissolved in CH₃CN (40 mL) and the mixture was refluxed overnight. CH₃CN was removed and the residue was diluted with EtOAc, washed with brine, Na₂S₂0₅ (10%), K2CO3 (10%) and brine, dried over Na₂S0₄ and concentrated affording the title compound as pale oil (3.56 g, 53%)

1H-NMR (CDCI3) : 8.34 (2H,m); 7.47 (2H,m); 6.86 ( 1H, q, J=6.2 Hz); 2.35 (3H,d, J=6.2Hz) . Example 4: 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 2- (2- (nitrooxy) ethoxy) acetate

1-iodoethyl 4-nitrophenyl carbonate (10.55 g, 31.3 mmol) obtained in Example 3 was dissolved in dry toluene (15 mL) under nitrogen atmosphere at r.t. To this solution Silver (I) 2- (2- (nitrooxy) ethoxy) acetate (11 g, 40.7 mmol) obtained in Example 2 was added and the suspension was stirred in the dark at room temperature for 5 hours. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The crude was purified by silica gel chromatography (eluting with EtOAc/Hexane from 5 to 40%) affording the title compound (7.5 g, 68%) as a pale oil.

¹H-NMR (CDC1₃) : 8.30 (2H,m); 7.4 (2H,m); 6.92 (1H, q, J=5.4Hz) ; 4.67 (2H,m); 4.20 (2H,s); 3.90 (2H,m); 1.67 (3H, d, J=5.4Hz) .

Example 5: 1- (methyl ( (S) -3- (naphthalen-l-yloxy) -3- (thiophen -2-yl) propyl) carbamoyloxy) ethyl-2- (2- (nitrooxy) ethoxy) acetate (Compound (1))

Procedure A:

To a solution of duloxetine hydrochloride (0.294 mg, 0.9 mmol) in CH₂CI₂ (10 mL) , cooled to 0°C, triethylamine (0.245 mL, 1.7 mmol) and 1- ( (4-nitrophenoxy) carbonyloxy) ethyl-2- (2-nitrooxy) ethoxy) acetate, obtained as described in Example 4, (0.300 g, 0.80 mmol) were added. The reaction was stirred at room temperature overnight, then washed with Na¾P0₄ (5%) and brine, dried over Na₂SC>4 and concentrated. The crude material was purified by BIOTAGE (eluting with EtOAc/Hexane from 10 to 50%) affording the title compound (0.620 g, 74 %) as a clear oil.

Procedure B:

To a solution of duloxetine hydrochloride (0.294 g, 0.882 mmol) in CH₂CI₂ (10 mL) , triethylamine (0.245 mL, 1.762 mmol) and 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 2- (2- (nitrooxy) ethoxy) acetate obtained as described in Example 4 (0.300 g, 0.801 mmol) were added. The mixture was heated for 30 min at 70°C in a microwave apparatus, then washed with Na¾P0₄ (5%) and brine, dried over Na₂SC>4 and concentrated .

The crude material was purified by BIOTAGE (eluting with EtOAc/Hexane from 10 to 50%) affording the title compound as clear oil.

¹H-NMR (CDCI3) : 8.39-8.32 (1H, m) ; 7.84-7.76 (1H, m) ; 7.55- 7.46 (2H, m) ; 7.45-7.38 (1H, m) ; 7.32-7.19 (2H, m) ; 7.12- 7.06 (1H, m) ; 6.99-6.92 (1H, m) ; 6.90-6.72 (2H, m) ; 5.77- 5.61 (1H, m) ; 4.66-4.55 (2H, m) ; 4.14-3.99 (2H, m) ; 3.91- 3.39 (4H, m) ; 2.94 (3H, m) ; 2.60-2.24 (2H, m) ; 1.57-1.23 (3H, m) .

Example 6: ( S ) -5 , 6-bis (nitrooxy) hexylmethyl (( S ) -3- (naphthalen-l-yloxy) -3- (thiophen-2-yl) propyl) carbamate (Compound (2 ) )

STEP A: ( S ) -5 , 6-bis (nitrooxy) hexyl 4-nitrophenyl carbonate.

To a solution of (2S) -6-hydroxyhexane-l, 2-diyl dinitrate, prepared as described in WO 2005/070868, (0.25 g, 1.12 mmol) in CH₂CI₂ (5 mL) , triethylamine (0.0233 mL, 1.67 mmol) and 4-nitrophenyl chloroformate were added and the mixture was stirred at room temperature overnight. Then the mixture was washed with Na¾P0₄ (5%) and brine, dried over Na₂SC>4 and concentrated. The crude material was purified by BIOTAGE (eluting with EtOAc/Hexane from 0.5 to 50%) affording the title compound (0.350 g, 80%).

¹H-NMR (CDCI3) : 8.34-8.28 (2H, d) ; 7.44-7.38 (2H, m) ; 5.39-

5.28 (1H, m) ; 4.81-4.74 (1H, m) ; 4.57-4.49 (1H, m) ; 4.37-

4.29 (2H, m) , 1.91-1.82 (4H, m) ; 1.72-1.58 (2H, m) .

STEP B : (S) -5, 6-bis (nitrooxy) hexyl methyl (( S ) -3- (naphthalen-l-yloxy) -3- (thiophen-2-yl) propyl) carbamate .

To a solution of duloxetine hydrochloride (0.330 g, 0.989 mmol) in THF (8 mL) , triethylamine (0.138 mL, 0.989 mmol), DMAP, Sc(OTf)₃ and 1- (carboxyoxy) ethyl 2- (2-

(nitrooxy) ethoxy) acetate (0.300 g, 0.801 mmol) were added. The mixture was heated for 25 min at 80°C then the solvent was evaporated, the residue dissolved in CH₂CI₂, washed with Na¾P0₄ (5%) and brine, dried over Na₂SC>4 and concentrated .

The crude material was purified by BIOTAGE (eluting with EtOAc/Hexane from 10 to 50%) affording the title compound (0.620 g, 74%) as clear oil.

¹H-NMR (CDCI3) : 8.41-8.33 (1H, m) ; 7.84-7.76 (1H, m) ; 7.55- 7.46 (2H, m) ; 7.45-7.38 (1H, m) ; 7.32-7.19 (2H, m) ; 7.12- 7.06 (1H, m) ; 6.99-6.92 (1H, m) ; 6.88-6.77 (1H, m) ; 5.80- 5.61 (1H, m) ; 5.33-4.99 (1H, m) ; 4.78-4.25 (2H, m) ; 4.09- 3.62 (3H, m) ; 3.54-3.30 (1H, m) ; 2.95 (3H, m) ; 2.62-2.24 (2H, m) , 1.82-1.10 (6H, m) .

Example 7: 6- (nitrooxy) hexanoic acid

6-Bromohexanoic acid (1.0 g, 5.1 mmol) was dissolved in CH₃CN (20 mL) and AgN0₃ (1.74 g, 19.2 mmol) was added. The reaction was heated by microwave at 90°C for 14 minutes. The precipitate was filtered off and the reaction was concentrated under reduced pressure; EtOAc (20 mL) was added and the organic phase was washed with water and brine, dried over Na₂SC>4 and concentrated affording the title compound as a yellow oil (840 mg, 93%) .

¹H-NMR (CDC1₃) : 4.47 (2H, t, J=6.6Hz) ; 2.40 ( 2H, t , J=7.3Hz ) ; 1.84-1.63 (4H,m); 1.50 (2H,m).

Example 8: (S) -6- (methyl (3- (naphthalen-l-yloxy) -3- (thiophen -2- l) propyl) amino) -6-oxohexyl nitrate (Compound (20))

To a solution of duloxetine hydrochloride (1.15 g, 3.4 mmol) in CH₂CI₂ (15 mL) , cooled to 0 °C, triethylamine (1.53 mL, 12 mmol), DMAP (60 mg, 0.5 mmol), 6- (nitrooxy) hexanoic acid (500 mg, 3.4 mmol) and 1- (carboxyoxy) ethyl 2- (2- (nitrooxy) ethoxy) acetate (990 mg, 5.2 mmol) were added. The mixture was stirred overnight at room temperature, then washed with NaH₂P0₄ (5%) and brine, dried over a₂S0₄ and concentrated. The crude material was purified by BIOTAGE (eluting with EtOAc/Hexane from 20 to 80%) affording the title compound (1.18 g, 76%) as a pale yellow oil.

¹H-NMR (CDC1₃) mixture of two rotamers : 8.35 (lH,m); 7.80 (lH,m); 7.52 (2H,m); 7.42 (lH,m); 7.25 (2H,m); 7.10 (lH,m); 6.96 (lH,m) ; 6.83 (lH,m); 5.70 (lH,m); 4.35 (2H,m); 3.66 (2H,m); 2.99 (3H,s); 2.33 (4H,m); 1.54 (5H,m); 0.97 (lH,m) . Example 9: (5) -2- (nitroox propanoic acid

HNO₃ (3 mL, 76 mmol) was dissolved in AC2O (10 mL) , cooled to 0°C, and (S) - ( + ) -2-Hydroxy-3-methylbutyric acid (1.5 g, 12.7 mmol) was added. The mixture was stirred for 1 hour, then poured into iced aHC0₃ (10%) and diluted with CH2C I 2 . The organic phase was washed with brine, dried over Na2 S C>4 and concentrated affording the title compound as a clear oil (1.75 g, 85%) .

Example 10: (R) -5 , 6-bis (nitrooxy) hexanoic acid

STEP A: tert-butyl ( 5R) -5 , 6-dihydroxyhexanoate .

Tert-butyl hex-5-enoate (5 g, 29.4 mmol) was added to a suspension of AD-mix-/3 (41 g) in H₂0/t-BuOH (125 mL/125 mL) at 0°C and the reaction was stirred overnight at 5°C. EtOAc (100 mL) was added followed by Na2 S 20s (7.0 g) in portions and the reaction was stirred for 30 minutes at 5°C and 1 hour at room temperature. The organic phase was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over a₂S0₄ and concentrated affording the title compound as an oil (5.8 g,

98%) H-NMR (CDCI3) : 3.67 (2H,m); 3.47 (lH,m); 2.27 (2H,m); 1.73 (4H,m) ; 1.46 (9H, s) .

STEP B: tert-butyl ( 5R) -5 , 6-bis (nitrooxy) hexanoate .

HNO₃ (5.23 mL, 126.2 mmol) was dissolved in AC₂O (20 mL) , cooled to 0°C, and tert-butyl ( 5R) -5 , 6-dihydroxyhexanoate (5.15 g, 25.2 mmol) was added. The mixture was stirred for 1 hour, then poured into iced NaOH (10%) and diluted with CH₂CI₂. The organic phase was washed with brine, dried over Na₂SC>4 and concentrated affording the title compound as a brown oil (7.0 g, 95%)

¹H-NMR (CDCI3) : 5.29 (lH,m); 4.77 (lH,m); 4.50 (lH,m); 2.30 (2H,m); 1.77 (4H,m); 1.46 (9H,s).

STEP C: (R) -5 , 6-bis (nitrooxy) hexanoic acid

Tert-butyl ( 5R) -5 , 6-bis (nitrooxy) hexanoate (7.0 g, 29.4 mmol) was dissolved in CH₂CI₂ and cooled to 0°C. BF₃-Et₂<0 (3 mL, 32.3 mmol) was added and the reaction stirred 30 minutes at 0°C and 4 hours at room temperature. The organic phase was washed with brine, dried over a₂S0₄ and concentrated. The crude material was purified by silica gel chromatography (CH₂Cl₂/MeOH 95:5) affording the title compound as a brown oil. (4.0 g, 60%)

¹H-NMR (CDCI3) : 5.30 (lH,m); 4.77 (lH,m); 4.51 (lH,m); 2.46 (2H,m) ; 1.83 (4H,m) .

Example 11: ( S) -5 , 6-bis (nitrooxy) hexanoic acid

Title compound was synthesized following the procedure of Example 10 except that in STEP A AD-mix-a was used instead of AD-mix-/3.

Example 12: 2 , 2-dimethyl-3- (nitrooxy) propanoic acid.

HNO₃ (2.4 mL, 54 mmol) was dissolved in AC₂O (7.5 mL, 80 mmol) , cooled to 0°C, and methyl 3-hydroxy-2 , 2- dimethylpropanoate (4 mL, 31 mmol) was added. The mixture was stirred for 1 hour, then poured into iced aHC03 (5%) and diluted with EtOAc. The organic phase was washed with brine, dried over Na₂SC>4 and concentrated affording methyl 2 , 2-dimethyl-3- (nitrooxy) propanoate as a clear oil

The residue was dissolved in NaOH (2.5 M, 20 mL) and MeOH (20 mL) and the solution was stirred at room temperature for 6 hours, and then acidified with HC1 (5%) to pH 3-4. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na₂SC>4 and concentrated affording the title compound as a pale yellow solid (5.00 g, 98%)

¹H-NMR (CDCI3) : 4.53 (2H,s); 1.34 (6H,s).

Example 13: silver (I) 2 , 2-dimethyl-3- (nitrooxy) propanoate 2 , 2-dimethyl-3- (nitrooxy) propanoic acid obtained in Example 12 (5.12 g, 31 mmol) was dissolved in CH₃CN (134 mL) . To the solution Ag₂<3 (4.86 g, 21 mmol) and ¾0 (67 mL) were added and the mixture was stirred at room temperature for 5 hours, and then filtered over celite. The filtrate was concentrated affording the title compound as a pale yellow solid (6.60 g, 78%)

1H-NMR (CDCI3) : 4.55 (2H,s); 1.30 (6H,s)

Example 14: 1- ( (4-nitrophenoxy) carbonyloxy) ethyl-2, 2- dimethyl-3- (nitrooxy) propanoate

Silver (I) 2 , 2-dimethyl-3- (nitrooxy) propanoate (3.13 g, 12 mmol) and 1-iodoethyl 4-nitrophenyl carbonate obtained in Example 3 (3.56 g, 11 mmol) were dissolved in dry toluene (50 mL) and the suspension was stirred overnight, filtered and purified by BIOTAGE (eluting with EtOAc/Hexane 5 to 20%) affording the title compound (1.5 g, 38%) as a pale oil .

¹H-NMR (CDC1₃) : 8.31 (2H,m); 7.42 (2H,m); 6.87 (lH,q,J=5.4

Hz); 4.54 (2H,m); 1.65 (3H,d); 1.34 (6H,s).

Example 15: silver (I) 6- (nitrooxy) hexanoate

Title compound was synthesized following the procedure of

Example 13 except that 6- (nitrooxy) hexanoic acid was used instead of 2 , 2-dimethyl-3- (nitrooxy) propanoic acid.

¹H-NMR (DMSO) : 4.50 (2H, t, J=6.6Hz) ; 1.65 (2H,m); 1.53 (2H,m) ; 1.35 (2H,m) .

Example 16: 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 6-

(nitrooxy) hexanoate

Title compound was synthesized following the procedure described in Example 14 except that silver (I) 6- (nitrooxy) hexanoate was used instead of silver(I) 2,2- dimethyl-3- (nitrooxy) propanoate .

¹H-NMR (CDCI3) : 8.31 (2H,m); 7.42 (2H,m); 6.87 (lH,q,J=5.4 Hz); 4.47 (2H, t, J=6.5Hz) ; 2.43 (2H,m); 1.88-1.66 (4H,m); 1.64 (3H, d, J=5.5Hz) ; 1.50 (2H,m).

Example 17: Silver (I) (S) -3-methyl-2- (nitrooxy) butanoate Title compound was synthesized following the procedure of Example 13 except that (S) -3-methyl-2- (nitrooxy) butanoic acid was used instead of 2 , 2-dimethyl-3- (nitrooxy) propanoic acid. H-NMR (DMSO) : 5.17 ( 1H, d, J=4.3Hz ) ; 2.26 (lH,m); 0.98 (6H,dd, J=6.9Hz)

Example 18: (2S) -1- ( (4-nitrophenoxy) carbonyloxy) ethyl 3- methyl-2- (nitrooxy) butanoate

Title compound was synthesized following the procedure described in Example 14 except that silver (I) (S) -3-methyl- 2- (nitrooxy) butanoate was used instead of silver (I) 2,2- dimethyl-3- (nitrooxy) propanoate .

¹H-NMR (CDC1₃) : 8.31 (2H,m); 7.41 (2H,m); 6.93 (lH,m); 5.02 (1H, d, J=4.7Hz) ; 2.36(lH,m); 1.69 (3H,m); 1.11 (6H,m).

Example 19: Silver (I) ( S ) -5 , 6-bis (nitrooxy) hexanoate

Title compound was synthesized following the procedure of Example 13 except that ( S ) -5 , 6-bis (nitrooxy) hexanoic acid acid was used instead of 2 , 2-dimethyl-3- (nitrooxy) propanoic acid .

¹H-NMR (DMSO): 5.42 (lH,m); 4.92 (lH,m); 4.68 (lH,m); 2.5 (2H,m); 2.16 (2H,m); 1.81-1.51 (4H,m).

Example 20: Silver (I) (R) -5 , 6-bis (nitrooxy) hexanoate

Title compound was synthesized following the procedure of Example 13 except that (R) -5 , 6-bis (nitrooxy) hexanoic acid acid was used instead of 2 , 2-dimethyl-3- (nitrooxy) propanoic acid .

1H-NMR (DMSO): 5.42 (lH,m); 4.92 (lH,m); 4.68 (lH,m); 2.5 (2H,m); 2.16 (2H,m); 1.81-1.51 (4H,m).

Example 21: (5S) -1- ( (4-nitrophenoxy) carbonyloxy) ethyl 5,6- bis (nitrooxy) hexanoate

Title compound was synthesized following the procedure described in Example 14 except that silver (I) (S)-5,6- bis (nitrooxy) hexanoate was used instead of silver (I) 2,2- dimethyl-3- (nitrooxy) propanoate .

1H-NMR (CDC1₃) : 8.30 (2H,m); 7.42 (2H,m); 6.85 (lH,m); 5.28 (lH,m); 4.74 (lH,m); 4.47 (lH,m); 2.47 (2H,m); 1.83 (4H,m); 1.64 (3H,m) .

Example 22: (5R) -1- ( (4-nitrophenoxy) carbonyloxy) ethyl 5,6- bis (nitrooxy) hexanoate

Title compound was synthesized following the procedure described in Example 14 except that silver (I) (R)-5,6- bis (nitrooxy) hexanoate was used instead of silver (I) 2,2- dimethyl-3- (nitrooxy) propanoate .

¹H-NMR (CDCI3) : 8.30 (2H,m); 7.42 (2H,m); 6.85 (lH,m); 5.28 (lH,m); 4.74 (lH,m); 4.47 (lH,m); 2.47 (2H,m); 1.83 (4H,m); 1.64 (3H,m) .

Example 23: Synthesis of ( S ) -5 , 6-bis (nitrooxy) hexyl methyl ( (S) -3- (naphthalen-l-yloxy) -3- (thiophen-2- yl ) propyl ) carbamate (compound 12)

Title compound was synthesized following the procedure of Example 5 except that (5S) -1- ( (4-nitrophenoxy) carbonyloxy) ethyl 5 , 6-bis (nitrooxy) hexanoate (obtained in Example 21) was used instead of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl-2- (2-nitrooxy) ethoxy) acetate . H-NMR (CDCI3) : 8.35 (lH,m); 7.80 (lH,m); 7.51 (2H,m); 7.42(lH,d); 7.28(2H,m); 7.10(lH,m); 6.96(lH,m); 6.84- 6.5(2H,m); 5.70 ( 1H, m) ; 5.25(lH,m); 4.68 ( 1H, dd) ; 4.43 (lH,m) ; 3.8-3.45 (2H,m) ; 2.93(3H,s); 2.38-2.28 (4H, m) ; 1.73 (4H, m) ; 1.51-1.27 (3H,m) .

Example 24: Synthesis of 1- (methyl ( (S) -3- (naphthalen-1- yloxy) -3- (thiophen-2-yl) propyl) carbamoyloxy) ethyl 6- (nitrooxy) hexanoate (compound 8)

Title compound was synthesized following the procedure of Example 5 except that 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 6- (nitrooxy) hexanoate (obtained in Example 16) was used instead of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl-2- (2- nitrooxy) ethoxy) acetate .

1H-NMR (CDCI3) : 8.36 ( 1H, m) ; 7.80 (lH,m); 7.52 (2H,m); 7.42(lH,d); 7.28(2H,m); 7.10(lH,m); 6.95(lH,m); 6.83(2H,m); 5.31(lH,m); 4.40(2H,m); 3.55(2H,m); 2.92(3H,m); 2.60- 2.25(4H,m); 1.80-1.59 (5H, m) ; 1.51 - 1.27 ( 4H, m) .

Example 25: Synthesis of 1- (methyl ( (S) -3- (naphthalen-1- yloxy) -3- (thiophen-2-yl) propyl) carbamoyloxy) ethyl 2-((S)- 2 , 3-bis (nitroox ) propoxy) acetate (compound 23)

Title compound was synthesized following the procedure of Example 5 except that 1- ( (4-nitrophenoxy) carbonyloxy) ethyl- 2 , 2-dimethyl-3- (nitrooxy) propanoate (obtained in Example 14) was used instead of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl-2- (2-nitrooxy) ethoxy) acetate . ¹H-NMR (CDCI3) : 8.37 (lH,m); 7.80 (lH,m); 7.52 (2H,m); 7.41(lH,d); 7.28(2H,m); 7.1(lH,m); 6.95(lH,m); 6.86- 6.77(2H,m); 5.69(lH,m); 4.48(2H,m); 3.57(2H,m); 2.92(3H,s); 2.60-2.30 (2H,m) ; 1.52-1.23 ( 9H, m) .

Example 26: Synthesis of (R) -2- (3-methoxy-2- (nitrooxy) propoxy) acetic acid

O ON0₂

STEP A: methyl { [ (4S) -2, 2-dimethyl-l, 3-dioxolan-4-yl] methoxy} acetate

(S) - ( + ) -1, 2-isopropylideneglycerol (14 mL, 112.8 mmol) was slowly added to a suspension of NaH (60, 9.0 g , 225 mmol) in dry THF (350 mL) at 0°C under nitrogen atmosphere. 15- crown-5 (3 mL, 0.15 mmol) was then added. The reaction was stirred for 20 minutes at 0°C and methyl bromoacetate (31 mL, 338 mmol) in THF (30 mL) was slowly added. The reaction was stirred at room temperature for 2 hours. The reaction was quenched by adding a satured solution of NH₄C1 (300 mL) and the aqueous phase was extracted with Et₂0. The combined organic phases were dried over a₂S0₄ and concentrated. The crude material was purified by silica gel chromatography (Hex/AcOEt 8:2) affording the title compound as oil. (7.15 g, 31%)

¹H-NMR (CDCI3) : 4.33 (lH,m); 4.17 (2H,s); 4.08 (lH,m); 3.79 (lH,m) ; 3.76 (3H,s); 3.62 (2H,d); 1.43 (3H,s); 1.36 (3H, s) .

STEP B: Methyl { [ (2R) -2 , 3-dihydroxypropyl ] oxy} acetate

Methyl { [ (4S) -2, 2-dimethyl-l, 3-dioxolan-4-yl ] methoxy } acetate (8.2 g; 40 mmol) was dissolved in MeOH (100 mL) and HCl_gas was bubbled in the solution. The reaction was stirred at room temperature for 3 hours. The mixture was concentrated affording the title compound as oil (6.4 g, 98%) ¹H-NMR (CDCI3) : 4.32 (lH,m) 4.14 (2H,s); 3.90 (2H,m); 3.76 (3H, s) ; 3.74-3.58 (2H,m) .

STEP C : methyl { [ (2S) -2-hydroxy-3- ( tert-Butyldiphenyl silyl)propyl] oxyjacetate

To a solution of methyl { [ (2R) -2 , 3-dihydroxypropyl ] oxyjacetate (1.7 g, 10.4 mmol) in dry DMF (18 mL) , tert- butyldiphenyl silylchloride (3 mL, 11.5 mmol) and imidazole (1.42 g , 20.9 mmol) were added. The solution was stirred 6 hours at room temperature. The organic phase was diluted with NaH₂P0₄ (5%, 60 mL) and extracted with EtOAc, dried over Na₂SC>4 and concentrated. The crude material was purified by silica gel chromatography (Hex/AcOEt 8:2) affording the title compound as oil. (1.0 g, 24%)

1H-NMR (CDCI₃) : 7.66 (4H,m); 7.41 (6H,m); 4.13 (3H,m); 3.94 (lH,m); 3.71 (5H,m); 3.61 (lH,m) 1.06 (9H,m) .

STEP D : methyl { [ (2S) -2- (nitrooxy) -3- (tert-butyl diphenyl silyl)propyl] oxyjacetate

HNO₃ (0.247 mL, 5.95 mmol) was dissolved in Ac₂0 (0.655 mL,

6.9 mmol) and CH₂CI₂ (30 mL) , cooled to 0°C, and methyl { [ (2S) -2-hydroxy-3- (tert-Butyldiphenylsilyl)

propyl ] oxyj acetate (2.0 g, 4.96 mmol) was added. The mixture was stirred for 6 hours, then poured into iced NaOH (10%) . The organic phase was washed with brine, dried over Na₂SC>4 and concentrated affording the title compound as an oil (2.0 g, 90%)

¹H-NMR (CDCI3) : 7.65 (4H,m); 7.42 (6H,m); 5.32 (lH,m);

4.10 (2H,m); 3.86 (2H,m); 3.74 (3H,m); 1.05 (9H,m) .

STEP E : methyl { [ (2R) -3-hydroxy-2- (nitrooxy) propyl ] oxyj acetate

To a solution of methyl { [ (2S) -2- (nitrooxy) -3- (tert- butyldiphenylsilyl ) propyl ] oxyj acetate (2.0 g, 4.47 mmol) in dry THF (30 mL) at 0°C, acetic acid (0.9 mL, 15.7 mmol) was added and a tetrabutylammonium fluoride solution (1M in THF, 13.4 mL , 14.4 mmol) was added dropwise. The mixture was stirred 4 hours at room temperature. The reaction was diluted with EtOAc (30 mL) and the organic phase was washed with Na¾P0₄ (5%) , dried over Na₂SC>4 and concentrated. The crude material was purified by silica gel chromatography (Hex/AcOEt 1:1) affording the title compound as an oil. (600 mg, 65%)

¹H-NMR (CDC1₃) : 5.22 (lH,m); 4.15 (2H,m); 3.95 (2H,m); 3.86 (2H,m) ; 3.78 (3H, s) .

STEP F : methyl {[ (2R) -3-methoxy-2- (nitrooxy) propyl ] oxy} acetate

To a solution of methyl { [ (2R) -3-hydroxy-2- (nitrooxy) propyl] oxy } acetate ( 0.60 g, 2.87 mmol) in dry CH₂CI₂ (18 mL) at 0°C, 2 , 6-di-tert-butyl-4 -methylpyridine (2.36 g, 11.5 mmol) and MeOS0₂CF3 (1.3 mL , 11.5 mmol) were added. The solution was stirred 30 minutes at 0°C and then irradiated by microwave for 1 hour at 80°C. The reaction was washed with Na¾P0₄ (5%) , dried over Na₂SC>4 and concentrated. The crude material was purified by silica gel chromatography (Hex/AcOEt 8:2) affording the title compound as a oil . (520 mg, 82%) .

¹H-NMR (CDCI3) : 5.35 (lH,m); 4.15 (2H,s); 3.82 (2H,m); 3.75 (3H,s); 3.66 (2H,m); 3.39 (3H,s).

STEP G : {[ (2R) -3-methoxy-2- (nitrooxy) propyl ] oxy } acetic acid To a solution of methyl { [ (2R) -3-methoxy-2- (nitrooxy) propyl] oxyjacetate (0.45 g, 2.0 mmol) in acetone (13 mL) , phosphate buffer (PH=8, 50 mL) , water (50 mL) and pig liver esterase in ammonium sulfate suspension (0.533 mL) were added. The reaction was stirred overnight at room temperature then acidified with HC1 (IN) to pH=3. It was extracted with EtOAc, dried over Na₂SC>4 and concentrated affording the title compound as an oil. (350 mg, 85%)

1H-NMR (CDCI₃) : 5.33 (lH,m); 4.18 (2H,s); 3.85 (2H,m); 3.68 (2H, d) ; 3.40 (3H, s) . Example 27: Synthesis of silver (I) (R) -2- (3-methoxy-2- (nitrooxy) propoxy) acetate

Title compound was synthesized following the procedure described in Example 13 except that { [ (2R) -3-methoxy-2- (nitrooxy) propyl ] oxy} acetic acid (prepared in Example 23) was used instead of 2 , 2-dimethyl-3- (nitrooxy) propanoic acid .

¹H-NMR (DMSO) : 5.40 (lH,m); 4.92 (2H,s); 3.73 (2H,m); 3.98 (2H,m) ; 3.26 (3H, s) .

Example 28: Synthesis of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 2- ( (R) -2-hydroxy-3-methoxypropoxy) acetate

Starting from silver (I) (R) -2- (3-methoxy-2- (nitrooxy) propoxy) acetate (prepared in Example 27) and 1-iodoethyl 4-nitrophenyl carbonate (obtained in Example 3) , the title compound was synthesized following the procedure of Example 14.

¹H-NMR (CDC1₃) : 8.30 (2H,d); 7.42 (2H,d); 6.90 (lH,m); 5.35 (lH,m); 4.29 (2H,s); 3.85 (2H,m); 3.65 (2H,m); 3.37 (3H,s); 1.65 (3H,d) .

Example 29: Synthesis of 4- (nitrooxy) butanoic acid

O oNo₂

STEP A: methyl 4-bromobutanoate

To a solution of 4-bromobutanoic acid (6.5 g, 38.9 mmol) in MeOH (120 mL) at 0°C under nitrogen atmosphere, thionyl chloride (2.8 mL, 38.9 mmol) was slowly added and the reaction was stirred overnight at room temperature Solvent was evaporated and the crude material was used directly in next step. (6.0 g, 85%) H-NMR (CDCI3) : 3.71 (3H,s); 3.49 (2H,t J=6.44); 2.53 (2H,t J=7.16) ; 2.20 (2H,m) .

STEP B: methyl 4- (nitrooxy) butanoate

Methyl 4-bromobutanoate (6.0 g; 33 mmol) was dissolved in CH₃CN (120 mL) and silver nitrate (14.0 g, 82.6 mmol) was added. The reaction was heated at 80°C in the dark for 4 hours. Solvent was evaporated and the crude was dissolved in EtOAc (80 mL) .Precipitate was filtered off and organic phase was washed with water (2 x 100 mL) and brine (1 x 100 mL) , dried over Na₂SC>4 and concentrated affording the title compound as an oil. (5.0 g, 93%)

¹H-NMR (CDCI3) : 4.54 (2H,t J=6.31); 3.73 (3H,s); 2.48 (2H,t

J=7.15) ; 2.08 (2H,m) .

STEP C: 4- (nitrooxy) butanoic acid

Methyl 4- (nitrooxy) butanoate (10.0 g; 61.0 mmol) was dissolved in MeOH (240 mL) at 5°C and LiOH 2N (60 mL) was added. The reaction was stirred overnight at 5°C. Solution was acidified to pH 3 with HC1 IN and MeOH was evaporated.

Aqueous phase was exctracted with CH₂CI₂, dried over Na₂SC>4 and concentrated affording the title compound as an oil.

(7.2 g, 79%)

¹H-NMR (CDCI3) : 4.55 (2H,t J=6.30); 2.54 (2H,t); 2.10 (2H,m) .

Example 30: Synthesis of silver (I) 4- (nitrooxy) butanoate

Title compound was synthesized following the procedure described in Example 13 except that 4- (nitrooxy) butanoic acid (prepared in Example 29) was used instead of 2,2- dimethyl-3- (nitrooxy) propanoic acid.

H-NMR (DMSO) : 4.56 (2H,t J=6.71); 2.42 (2H,t J=6.54)

(2H,m) Example 31: Synthesis of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 4- (nitrooxy) butanoate

Starting from silver (I) 4- (nitrooxy) butanoate (Example 30) and 1-iodoethyl 4-nitrophenyl carbonate (obtained in Example 3) , the title compound was synthesized following the procedure of Example 14.

¹H-NMR (CDC1₃) : 8.30 (2H, d) ; 7.42 (2H, d) ; 6.91 (1H, m) ; 4.55 (2H, t) ; 2.56 (2H,t); 2.11 (2H, m) ; 1.65 (3H, s).

Example 32: Synthesis of 1- (methyl ( (S) -3- (naphthalen-1- yloxy) -3- (thiophen-2-yl) propyl) carbamoyloxy) ethyl 4- (nitrooxy) butanoate (compound 24)

Title compound was synthesized following the procedure of Example 5 except that 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 4- (nitrooxy) butanoate (obtained in Example 31) was used instead of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl-2- (2- nitrooxy) ethoxy) acetate .

¹H-NMR (CDCI3) : 8.35 (lH,m); 7.80 (lH,m); 7.51 (2H,m); 7.41 (lH,m) ; 7.25(2H,m); 7.09 ( 1H, m) ; 6.95 ( 1H, m) ; 6.83(2H,m); 5.73 (lH,m) ; 4.47(2H,m); 3.63(2H,m); 2.93(3H,s); 2.36(4H,m); 2.02(2H,m); 1.39-1.25 (3Hm) .

Example 33: Synthesis of 3- (2- (nitrooxy) ethoxy) propanoic acid

STEP A : 2- (but-3-en-l-yloxy) ethyl nitrate

To a solution of HNO₃ fuming (3.2 mL, 78.3 mmol) and Acetic anhydride (6.5 mL, 68.5 mmol) in dry CH₂CI₂ (30 mL) cooled at -50 °C, a solution of 2-allyloxyethanol (5.0 g, 48.9 mmol) in CH₂CI₂ (30 mL) was added dropwise. The solution was stirred at -50 °C 1.5 hours then it was allowed to rich r. t. and stirred for 4h. The solution was then poured into ice, the two phases were separated and the organic phase was washed with brine, dried on Na₂S0₄ and concentrated. The residue was purified by flash chromatography with SP1 Biotage instrument (SNAP 100 g column, n-Hex/EtOAc 95:5, 10 CV) affording the desired product as a colourless oil (6.6 g, yield: 92%) .

¹H-NMR (CDCI3) : 6.05 - 5.77 (1 H, m) , 5.39-5.14 (2 H, m) , 4.69 - 4.57 (2 H, m) , 4.08 - 4.00 (2 H, m) , 3.78 - 3.68 (2 H, m) .

STEP B : 2- (3-hydroxypropoxy) ethyl nitrate

To a solution of 2- (but-3-en-l-yloxy) ethyl nitrate (6.6 g, 44.8 mmol) in dry THF (100 mL) cooled at 0 °C, 9-BBN 0.5M in THF (269 mL, 134.5 mmol) was added dropwise. The solution was stirred at r.t. overnight. Then It was cooled at 0 °C and NaOH 2M (112 mL, 224.2 mmol) and H₂0₂ 30% (77 mL) were added dropwise at the same time. The solution was stirred at 0°C for 1 hour. Then It was diluted with ¾0 (200 mL) and extracted with Et₂0 (5x 200 mL) . The combined organic phases were dried on a₂ S0₄ and concentrated affording 20 g of a clear oil. The residue was purified by flash chromatography ( S P 1 Biotage instrument, SNAP 340 g column, n-Hex/EtOAc from 10:90 to 20:80 in 10 CV) affording the desired product as a clear oil (1.8 g, yield: 24%) .

XH NMR (CDCI3) : 4.63 (t, 2H) , 3.86 - 3.71 (m, 4H) , 3.67 (t, 2H) , 1.93 - 1.81 (m, 2H) .

STEP C : 3- (2- (nitrooxy) ethoxy) propanoic acid To a solution of 2- (3-hydroxypropoxy) ethyl nitrate (1.8 g, 10.9 mmol) in acetone (50 mL) cooled at 0°C , aHC03 saturated solution (15 mL) , NaBr (0.23 mg, 2.2 mmol), TEMPO (0.17 mg, 1.1 mmol) and tricholoisocyanuric acid (5.0 g, 21.8 mmol) were added. The mixture was stirred at r.t. for 3 hours. Then the solution was cooled at 0°C and Isopropanol (8 mL) was added dropwise. The solution was stirred at 0°C for 30 minutes. The precipitate was filterd off and the solution concentrated. The residue was diluted with NaOH 2N (100 mL) and washed with EtOAc (2X50 mL) . The aqueous phase was acidified with HC1 cone, until pH=2 and extracted with EtOAc (5X 30 mL) . The combined organic phases were dried on a₂S0₄ and concentrated affording the desired product as a clear oil (1.7 g, yield: 89%) .

XH NMR (CDC1₃) : 4.70 - 4.56 (m, 2H) , 3.86 - 3.73 (m, 4H) , 2.66 (t, 2H) .

Example 34: Synthesis of silver (I) 3- (2- (nitrooxy) ethoxy) propanoate

Title compound was synthesized following the procedure described in Example 13 except that 3- (2- (nitrooxy) ethoxy) propanoic acid (prepared in Example 33) was used instead of 2, 2-dimethyl-3- (nitrooxy) propanoic acid.

^XH NMR ( DMSO) : 4.71 - 4.55 (m, 2H) , 3.76 - 3.53 (m, 4H) , 2.36 (t, 2H) .

Example 35: Synthesis of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 3- (2- (nitrooxy) ethoxy) propanoate

0₂

Starting from silver (I) 3- (2- (nitrooxy) ethoxy) propanoate (Example 34) and 1-iodoethyl 4-nitrophenyl carbonate (obtained in Example 3) , the title compound was synthesized following the procedure of Example 14.

XH NMR (CDC1₃) : 8.40 - 8.22 (m, 2H) , 7.53 - 7.34 (m, 2H) , 6.98 - 6.80 (m, 1H) , 4.60 (t, 2H) , 3.90 - 3.70 (m, 4H) , 2.68 (t, 2H) , 1.74 - 1.59 (m, 3H) .

Example 36: Synthesis of 1- (methyl ( (S) -3- (naphthalen-1- yloxy) -3- (thiophen-2-yl) propyl) carbamoyloxy) ethyl 3- (2- (nitrooxy) ethoxy) propanoate (compound 25)

Title compound was synthesized following the procedure of Example 5 except that 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 3- (2- (nitrooxy) ethoxy) propanoate (obtained in Example 35) was used instead of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl- 2 - (2-nitrooxy) ethoxy) acetate .

^XH NMR (CDCI3) : 8.35 (lH,m) ; 7.79 ( 1H, m) ; 7.51 (2H,m); 7.41 (lH,m) ; 7.28(2H,m); 7.09 ( 1H, m) ; 6.96 ( 1H, m) ; 6.84(2H,m); 5.71 (lH,m) ; 4.55(2H,t); 3.70-3.57 ( 6H, m) ; 2.93(3H,s); 2.58- 2.51 (4H,m) 1.40 (3H,dt) .

Example 37: Synthesis of (S) -2- (2 , 3-bis (nitrooxy) propoxy) acetic acid

STEP A: (S) -methyl 2- ( (2, 2-dimethyl-l, 3-dioxolan-4-yl) methoxy) acetate . A solution of (S) - (2, 2-dimethyl-l, 3-dioxolan-4-yl) methanol (4,7 mL, 37.8 mmol) in dry THF (10 mL) was slowly dropped into a stirred suspension of NaH (60% in oil, 3 g, 75 mmol) and 15-crown-5 (1 mL, 5.67 mmol) in dry THF (100 mL) , under nitrogen, cooled to 0°C.

After 10 min, a solution of methyl 2-bromoacetate (10 mL, 113,4 mmol) in dry THF (10 mL) , was slowly added.

The mixture was allowed to warm to room temperature and stirred for 4 hrs . Then a saturated solution of NH₄C1 and Diethyl ether were added. The organic layer was extracted dried and evaporated.

The residue was purified by flash chromatography (SP1 Biotage instrument, SNAP 100 g column, n-Pen/Diethyl ether 70:30) affording the desired product as a clear oil (7.0 g, 90%) .

STEP B : (R) -methyl 2- (2 , 3-dihydroxypropoxy) acetate

Compound obtained in STEP A (7 g) was dissolved in MeOH (100 mL) and cooled to 0°C. Then dry HC1 was bubbled into the solution. After 4 hours the solvent was evaporated yielding the title compound (5 g, 90%) that was used for the next step without further purification.

STEP C: (S) -methyl 2- (2 , 3-bis (nitrooxy) propoxy) acetate The title compound was obtained with classic nitration reaction as decribed in WO 2005/070868 (6g, 78%) .

STEP D: ( S ) -2 -( 2 , 3-bis (nitrooxy) propoxy) acetic acid

To a solution of (S) -methyl 2- (2 , 3-bis (nitrooxy) propoxy) acetate (6 g, 23.6 mmol) in MeOH (60 mL) cooled to 5°C, LiOH 2N (20 mL) was added and the reaction was stirred overnight at 5°C.

Then the solution was acidified to pH 3 and extracted with CH₂CI₂. The crude was purified by flash chromatography (SP1 Biotage instrument) yielding the title compound (2.2 g, 40%) as a yellow oil. ^LR NMR (300 MHz, CDC1₃) δ 5.50-5.39 (m, 1H) , 4.96- 4.82 (m, 1H) , 4.79-4.64(m, 1H) , 4.33 - 4.13 (m, 2H) , 3.91 (d, 2H) . Example 38: Synthesis of 1-chloroethyl methyl (( S ) -3- (naphthalen-l-yloxy) -3- (thiophen-2-yl) propyl) carbamate

To a cooled to 0°C stirred and under nitrogen solution of duloxetine (2 g, 6 mmol) and Pyridine (1.5 mL, 19.2 mmol) in CH₂CI₂, 1-chloroethyl chloroformate (0.775 mL, 7.2 mmol) was added. The reaction was stirred at 5°C for 3 hours, then the it was evaporated under reduced pressure.

The mixture was then partitioned between EtOAc and water, the organic phase was then washed with HC1 IN, then with brine, dried over Na₂SC>₄ and concentrated affording the title compound (2.4 g, 99%) as dark oil that was used in the following steps without further purification.

^XH NMR (300 MHz, CDC1₃) δ 8.37 (s, 1H) , 7.80 (s, 1H) , 7.61 - 6.72 (m, 8H) , 6.69 - 6.35 (m, 1H) , 5.75-5.55 (m, 1H) , 3.87 - 3.39 (m, 2H) , 2.95 (d, 3H) , 2.65-2.25 (m, 2H) , 1.90- 1.40 (m, 4H) .

Example 39: Synthesis of 1- (methyl ( (S) -3- (naphthalen-1- yloxy) -3- (thiophen-2-yl) propyl) carbamoyloxy) ethyl 2 - ( (S) - 2 , 3-bis (nitrooxy) propoxy) acetate (compound 26)

To a solution of 1-chloroethyl methyl ( (S) -3- (naphthalen-1- yloxy) -3- (thiophen-2-yl) propyl) carbamate (1.6 g, 3.96 mmol) (obtained in Example 38) and (S)-2-(2,3- bis (nitrooxy) propoxy) acetic acid (1.2 g, 6 mmol) (obtained in Example 37) in dry DMF (50 mL) , (Cs₂C0₃ (2.0 g, 6.53 mmol) was added and the reaction was stirred for 2 hours at room temperature.

Then the mixture was diluted with water and extracted with EtOAc. The organic phase was dried and evaporated. The crude was purified by flash chromatography (SP1 Biotage instrument, SNAP 100, N-Hexane/ EtOAc 75:25) yielding the title compound (750 mg g, 31%) as a brown oil.

XH NMR (300 MHz, CDC1₃) δ 8.35 (s, 1H) , 7.80 (s, 1H) , 7.62 - 7.35 (m, 3H) , 7.35-7.16 (m, 2H) , 7.16-7.03 (m, 1H) , 7.03- 6.64 (m, 3H) , 5.81-5.56 (m, 1H) , 5.49-5.30 (m, 1H) , 4.96- 4.76 (m, 1H) , 4.67-4.54 (s, 1H) , 4.19-3.91 (m, 2H) , 3.92 - 3.35 (m, 4H) , 2.95 (s, 3H) , 2.63-2.22 (m, 2H) , 1.69 - 1.15 (m, 4H) .

Example 40: Synthesis of 2- (2 , 2-dimethyl-3- (nitrooxy) propanamido) -4- (methylthio) butanoic acid

STEP A: 3-chloro-2 , 2-dimethyl-3-oxopropyl nitrate

To a solution of 2 , 2-dimethyl-3- (nitrooxy) propanoic acid, obtained in Example 12, (0.890 mg, 5 mmol) in CH₂CI₂ (20 mL) cooled to 0°c , under nitrogen, oxalyl chloride (0.85 mL, 10 mmol) was added, followed by two drops of dry DMF. The solution was stirred for 1.5 hours at room temperature the evaporated. DCM was added and the solution was evaporated again. Then DCM (5 mL) was added and this solution was used for the next step.

STEP B: 2- (2 , 2-dimethyl-3- (nitrooxy) propanamido) -4-

(methylthio) butanoic acid

To a suspension of L-methionine (0.75g, 5.0 mmol) in CH₂CI₂ (40 mL) , cooled to 0°C under nitrogen, TEA (2.75 mL, 20 mmol) was added, followed by trimethylchlorosilane ( 1.35 mL, 10 mmol) and the mixture was stirred for 2 hours.

Then the solution of Step A was dropped into and the resulting mixture was stirred for 4.5 hours at room temperature .

Then a saturated solution of citric acid was added, pH was adjusted to 3 and the organic phase was separated, dried and evaporated. The crude was purified by flash chromatography (SP1 Biotage instrument, SNAP 50, CH₂CI₂/ MeOH 90:10) yielding the title compound (1.0 g, 68 % ) as a orange solid.

^XH NMR (300 MHz, CDC1₃) δ 6.78 (d, 1H) , 4.83-4.63 (m, 1H) , 4.63-4.39 (m, 2H) , 2.61 (t, 2H) , 2.35 - 2.05 (m, 5H) , 1.34 (d, 6H) .

Example 41: Synthesis of silver (I) 2- (2 , 2-dimethyl-3- (nitrooxy) propanamido) -4- (methylthio) butanoate

Title compound was synthesized following the procedure described in Example 13 except that 2- (2, 2-dimethyl-3- (nitrooxy) propanamido) -4- (methylthio) butanoic acid (prepared in Example 40) was used instead of 2 , 2-dimethyl- 3- (nitrooxy) propanoic acid. Example 42: Synthesis of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 2- (2 , 2-dimethyl-3- (nitrooxy) propanamido) -4- (methyl hio) butanoate

Starting from silver (I) 2- (2 , 2-dimethyl-3- (nitrooxy) propanamido) -4- (methylthio) butanoate (Example 41) and 1- iodoethyl 4-nitrophenyl carbonate (obtained in Example 3) , the title compound was synthesized following the procedure of Example 14.

^XH NMR (300 MHz, CDC1₃) δ 8.31 (d, 2H) , 7.44 (d, 2H) , 7.02

- 6.85 (m, 1H) , 6.74-6.55 (m, 1H) , 4.83-4.64 (m, 1H) , 4.62

- 4.39 (m, 2H) , 2.58 (t, 2H) , 2.34 - 2.02 (m, 5H) , 1.76- 1.62 (m, 3H) , 1.44 - 1.19 (m, 6H) .

Example 43: Synthesis of 1- (methyl ( (S) -3- (naphthalen-1- yloxy) -3- (thiophen-2-yl) propyl) carbamoyloxy) ethyl 2- (2,2- dimethyl-3- (nitrooxy) propanamido) -4- (methylthio) butanoate (compound 27)

Title compound was synthesized following the procedure of Example 5 except that 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 2- (2 , 2-dimethyl-3- (nitrooxy) propanamido) -4-

(methylthio) butanoate (obtained in Example 42) was used instead of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl-2- (2- nitrooxy) ethoxy) acetate .

^XH NMR (CDC1₃) : 8.35 (lH,m) ; 7.79(lH,m); 7.51 (2H,m); 7.41(lH,m); 7.24(2H,m); 7.10 ( 1H, m) ; 6.94(lH,m); 6.84(2H,m); 6.59(lH,m); 5.68(lH,m); 4.68(lH,m); 4.51(2H,m); 3.51 (2H, m) ; 2.93(3H,s); 2.30-2.51 (4H,m) ; 2.2-1.9 (5H, m) ; 1.55(1H); 1.29 (9H,m) .

Example 44: Synthesis of 1- (methyl ( (S) -3- (naphthalen-1- yloxy) -3- (thiophen-2-yl) propyl) carbamoyloxy) ethyl 4- (methyl thio) -2- ( 6- (nitrooxy) hexanamido) butanoate (compound 28)

0

Title compound was prepared as described for 1- (methyl ( (S) - 3- (naphthalen-l-yloxy) -3- (thiophen-2- yl) propyl) carbamoyloxy) ethyl 2- (2, 2-dimethyl-3- (nitrooxy) propanamido) -4- (methylthio) butanoate (Example 43) starting from 6- (nitrooxy) hexanoic acid (Example 7) and following the procedure reported in Examples 40-43.

¹HNMR (CDCI3) : 8.35 (lH,m); 7.80 (lH,m); 7.52-7.40 (3H, m) ; 7.25(2H,m); 7.10 ( 1H, s) -6.97 ( 1H, m) ; 6.83(3H,m); 6.15(lH,dd), 5.69(lH,m); 4.70(lH,m); 4.45(2H,m); 3.5(2H,m); 2.93(3H,s); 2.51-1.9 (llH,m) ; 1.68(5H,m); 1.40(5H,m).

Example 45: Synthesis of 2- (2 , 2-dimethyl-3- (nitrooxy) propanamido) -3- (2 , 2-dimethyl-3- (nitrooxy) propanoylthio) propanoic acid

Title compound was synthesized following the procedure described in Example 40 except that L-cysteine was used instead of L-methionine .

XH NMR (300 MHz, CDC1₃) δ 6.75 (d, 1H) , 4.80-4.64 (m, 1H) , 4.60 - 4.41 (m, 4H) , 3.57 - 3.35 (m, 2H) , 1.45 - 1.14 (m, 12H) .

Example 46: Synthesis of silver (I) 2- (2 , 2-dimethyl-3- (nitrooxy) propanamido) -3- (2 , 2-dimethyl-3- (nitrooxy)

propanoylthio) propanoate

Title compound was synthesized following the procedure described in Example 13 except that 2- (2, 2-dimethyl-3- (nitrooxy) propanamido) -3- (2 , 2-dimethyl-3- (nitrooxy) propanoylthio) propanoic acid (prepared in Example 45) was used instead of 2 , 2-dimethyl-3- (nitrooxy) propanoic acid .

^XH NMR (300 MHz, DMSO) δ 4.68 - 4.47 (m, 4H) , 4.42-4.27 (m, 1H) , 3.55 - 3.00 (m, 2H) , 1.41 - 1.07 (m, 12H) .

Example 47: Synthesis of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl-2- (2 , 2-dimethyl-3- (nitrooxy) propanamido) - 3- (2 , 2-dimethyl-3- (nitrooxy) propanoylthio) propanoate

Starting from silver (I) 2- (2, 2-dimethyl-3-

(nitrooxy) propanamido) -3- (2 , 2-dimethyl-3- (nitrooxy)

propanoylthio) propanoate (Example 46) and 1-iodoethyl 4- nitrophenyl carbonate (obtained in Example 3) , the title compound was synthesized following the procedure of Example 14.

^XH NMR (300 MHz, CDC1₃) δ 8.37 - 8.23 (m, 2H) , 7.51 - 7.35 (m, 2H) , 7.28 (s, 1H) , 6.88 (dq, J = 8.8, 5.5, 1H) , 6.60 (t, J = 6.8, 1H) , 5.32 (s, 1H) , 4.87 - 4.68 (m, 1H) , 4.60 - 4.41 (m, 4H) , 3.53 - 3.29 (m, 2H) , 2.04 (d, J = 11.7, OH), 1.68 (dd, J = 5.4, 3.7, 3H) , 1.65 - 1.33 (m, 8H) , 1.25 (dd, J = 37.6, 29.6, 7H) .

Example 48: Synthesis of 1- (methyl ( (S) -3- (naphthalen-1- yloxy) -3- (thiophen-2-yl) propyl) carbamoyloxy) ethyl 2- (2,2- dimethyl-3- (nitrooxy) propanamido) -3- (2 , 2-dimethyl-3- (nitrooxy) propanoylthio) propanoate (compound 29)

Title compound was synthesized following the procedure of Example 5 except that 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 2- (2 , 2-dimethyl-3- (nitrooxy) propanamido) -3- (2 , 2-dimethyl-3- (nitrooxy) propanoylthio) propanoate (obtained in Example 47) was used instead of 1- ( (4-nitrophenoxy) carbonyloxy) ethyl- 2 - (2-nitrooxy) ethoxy) acetate .

Example 49: Synthesis of 1- (( (IS, 2R) -2- (diethylcarbamoyl) - 2-phenylcyclopropyl) methylcarbamoyloxy) ethyl 6- (nitrooxy) hexanoate (compound 14)

Title compound was synthesized following the procedure of Example 5 starting from 1- ( (4-nitrophenoxy) carbonyloxy) ethyl 6- (nitrooxy) hexanoate (obtained in Example 16) and milnacipran.

Example 50: Synthesis of 6- (( (IS, 2R) -2- (diethylcarbamoyl) - 2-phenylcyclopropyl) methylamino) -6-oxohexyl nitrate (compound 21)

Title compound was synthesized following the procedure described in Example 8 except that milnacipran was used instead of duloxetine.

¹HNMR (CDC1₃) : 7.29(2H,m); 7.18 (3H,m); 4.37 (2H,t); 4.23 (lH,m) ; 3.5-3.3 (4H, m) ; 2.50 ( 1H, m) ; 2.22(2H,t); 1.73- 1.60 (6H,m) ; 1.43 (3H, m) ; 1.13(4H,m); 0.80(3H,t).

Example 51

Evaluation of the efficacy of the compounds in a Rat Spinal Nerve Ligation Model (SNL model)

Test compounds:

Compound 8 (prepared according to example 24) : 18.3 mg Kg ¹ = 0.0336 mmoli Kg ^_1 Duloxetine (reference compound) : 10 mg Kg ^_1 = 0.0336 mmoli Kg ^_1

General Procedure and surgery

34 Male Sprague-Dawley rats weighting 150-200g caged with free access to food and water under 12h light/dark cycles were used. Experiments were carried out according to the Declaration of Helsinki and internally approved animal care protocols. Efforts were made to minimize animal suffering. The method described by Kim and Chung (1992, Pain. 50(3): 355-363) was generally followed. Rats were anesthetized by chloral hydrate at the dose of 400 mg kg^-1. Briefly, neuropathic injury was produced by tightly ligating the right L5 and L6 spinal nerves.

The experiment was than carried out 14 days after surgery. Reference duloxetine (DOCHEM CO., LTD. (HONGKONG) ) and compound 8 were administered to 7-8 rats at the indicated doses dissolved in a vehicle containing PEG400: water (80:30) by oral gavage, and a group of 8 rats was administered with the vehicle (PEG400: water (80:30), 5 ml/kg) . 3 hour after the treatment the mechanical sensitivity was measured to the three groups of rats.

Mechanical allodynia Assessment.

A standardized testing procedure was performed to address tactile allodynia (Chaplan et al . , J Neurosci Methods. 53: 55-63, 1994) . Briefly, rats were transferred to the testing cage with a wire mesh bottom and allowed to acclimatize for 60 min. Von Frey monofilaments (Stoelting, Wood Dale IL, bending force from 0.15 to 15 g applied using a single, steady > Is application) were used to determine the 50% mechanical threshold for foot withdrawal using the up and down method previously described by Chaplan et al . , 1994. All behavioral testing were performed by investigators blind to the treatments. The results reported in Table I as 50% mechanical threshold (g) taken 3h post-treatment showed that compound 8 is more efficacious than duloxetine in reversing established pain behavior .

Example 52

Evaluation of the efficacy of the compounds on allodynic response in streptozotocin (STZ) -treated diabetic mice. Test compounds:

Compound (8) (prepared according to example 24) : 18.3 mg Kg ^_1 = 0.0336 mmoli Kg ^_1 (single dose)

Duloxetine (reference compound) : 10 mg Kg ^_1 = 0.0336 mmoli Kg ^_1 (single dose)

General procedure

Male CD1 mice, weighting 25-35 g were used. Animals were kept under standard conditions of temperature (21-22°C) and illumination (12:12-h light/darkness ) and allowed to adjust to this environment in cages with mesh bottoms with free access to tap water and food for at least 7 days before the experiment began. All experiments were performed to minimize animal suffering and in accordance with approved protocols .

Diabetes was induced by injecting 200 mg/kg i.p. of streptozotocin (STZ) . Blood glucose levels were assessed from the 2^nd day until the end of the experiment using an Accu-Chek blood glucose monitoring system. Only animals reaching glucose plasma levels above 200mg/dl within 24-48 h post-STZ-inj ection were included in the following behavioral experiments which started 14 days after the STZ treatment.

Paw withdrawal threshold (PWT) was determined using the Dynamic Plantar Aesthesiometer (Ugo Basile, Italy) , an apparatus that generates a mechanical force linearly increasing with time. More specifically, mice were placed individually in plastic cages with a wire mesh bottom and allowed to acclimatize for at least 2 h. Increasing mechanical stimulation (0.25 g/s, cut-off force: 10 g) was applied to the plantar surface of a hind paw so to address the respective nociceptive threshold which is defined as the force, in grams, at which the mouse withdraw its paw. When a withdrawal response occurred, the stimulus was terminated and the response threshold electronically determined .

The effects of test compounds were assayed following an acute challenge at the indicated dose by addressing the allodynic threshold at 15, 30, 45, 60, 90, 120, 180 min time points after the oral treatment.

Compound 8 showed a better efficacy than reference compound duloxetine as indicated by the greater mechanical threshold reached by the compound 8. (Table II)

Table II: Acute anti-allodynic effect in mice with STZ- induced diabetes

Paw withdrawal threshold

Time point

(g)

(min)

vehicle Duloxetine Compound 8 pre 1.1 ± 0.1 1.2 ± 0.1 1.2 ± 0.1

15 1.3 ± 0.2 1.5 ± 0.1 3.0 ± 0.3

30 1.5 ± 0.3 2.2 ± 0.1 3.5 ± 0.2

45 1.5 ± 0.1 2.7 ± 0.2 3.8 ± 0.2

60 2.0 ± 0.3 3.0 ± 0.2 3.7 ± 0.2

90 1.5 ± 0.1 2.5 ± 0.1 3.5 ± 0.3

120 2.5 ± 0.2 2.5 ± 0.1 2.4 ± 0.2

180 2.6 ± 0.3 2.5 ± 0.2 2.4 ± 0.2

Example 53

Compounds behaviuor in rat and human Liver S9 fraction

The tested compounds are:

- compound 1 and 8, as test compounds

- duloxetine, as reference

A calibration curve (CC) for compound 1, 8 and for duloxetine in both human and rat liver S9 was prepared in the range 1 - 100 μΜ. To do this, working solutions (WS) of test compounds in DMSO and of duloxetine in water were prepared by serial dilution of 10 mM stock solutions to the following final concentrations:

WS (μΜ) 500 / 250 / 100 / 50 / 25 / 10 / 5

1 mL of human or rat liver S9, 0.5 mg protein/ml at pH 7.4 were protein precipitated using 3 mL of acetonitrile ; 200 yL of each deproteinized matrix were spiked with 10 yL of each working solution to create a calibration curve for each analyte in each matrix to the following final nominal concentrations :

CC (μΜ) 100 / 50 / 20 / 10 / 5 / 2 / 1

980yL of liver S9 at 37°C in absence or in presence of 50mM NADPH were spiked with 10yL of a 1 mM solution of test compound in DMSO. At each timepoint (5, 10, 15, 30 and 60min) , 50yL of the test solution were protein precipitated in duplicate using 150yL of acetonitrile, vortex mixed and centrifuged 10 minutes at 4°C at 4000 rpm. The supernatant was transferred to a clean plate together with all the calibration curves and injected onto a UPLC-UV system.

Analytical conditions were as follows:

Column ACQUITY BEH Phenyl 50 x 2.1 mm (1.7ym)

@ 40°C

Mobile Phase A. water + 0.1% formic acid

B. methanol + 0.1% formic acid

Flow Rate 0.5mL/min

Gradient profile:

Time (min) : 0.0 1.0 1.5 1.6

A%: 90 0.0 0.0 90

B%: 10 100 100 10

Injection Volume 2yL

Detector Wavelength 210nm

The raw data (average peak area at each timepoint) were interpolated using Quanlynx v 4.1 software to obtain the concentration of uncleaved compounds 1, 8 and of duloxetine at each time point. The extrapolated concentrations were used to calculate the half-life (ti_/2) of compound in each matrix .

The half-life (ti_/2) for compounds 1 and 8 is less than 5 minutes in both matrix (rat and human plasma) . The results show that the test compounds 1 and 8 are readily metabolized in rat and human plasma.

Claims

1. A compound of formula (I) or pharmaceutically acceptable salts thereof:

(I)

wherein :

A is selected from the formulas (la) and (lb)

(la) (lb);

r is the integer 1 or 0,

y is the integer 1 or 0,

when y is 1 then r is 1,

B is H, or a straight or branched C1-C4 alkyl;

R is selected from the group consisting of:

1) - (R^u) -CH (ON0 ) R ,

la

2) - (R ) -CH (ON0 ) -CH (ON0 ) R

3) (R^u) - (T) -X- (Q)p- (CHJ -CH(ONOJR ,

la

4) (R^u) - (T) -X- (Q)p- (CHJ -CH(ONOJCH(ONOJR ,

5)

- (R^c - (T)_m-X- (Q) - (CH 2 I

6)

1

7) - (R^u)_n-CH(ON0₂) - (CH₂) _ql-X- (CH₂) _q2CH (ON0₂) R

8) - (R°) _n- (CR⁶R⁷) - (CH₂) _qCH (ON0₂) R¹

9) -CH(CH₂CH₂SCH₃)NHC(0)R⁸

10) -CH (CH₂SC (0) R⁹) NHC (0) R⁹

wherein

n is 0 or 1 ;

m is 0 or 1 ;

p is 0 or 1 ;

nl is 0 or 1 ;

q is an integer from 0 to 10;

ql is an integer from 1 to 10;

q2 is an integer from 1 to 10;

t is an integer from 1 to 4;

R° is a straight or branched Ci-Cio alkylene;

R¹ is selected from hydrogen, a straight or branched C1-C₄ alkyl or - (CH₂) OCH₃;

R^la is hydrogen or a straight or branched C1-C₄ alkyl;

X is selected from an oxygen atom, -NH-, -N(C¾)- or a covalent bond;

2 3 2 3

R⁴ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁶ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁷ is (CH₂) _qCH (ON0₂) R¹ wherein q and R¹ are as above defined;

R⁸ is selected from

1') - (R°) -CH fONOJ R¹/ 2') - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3' ) - (R°)_n- (T)_m-X- (Q)p-

4' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

wherein R°, R¹ R^la, T, X, Q, n, m, p and q are as above defined;

R⁹ is selected from:

1') - (R°)_n-CH(ON0₂)R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

wherein R°, R¹, T, X, Q, n, m, p and q are as above defined.

2. The compound according to claim 1 wherein R is selected from the group consisting of:

1) - (R°) _n-CH (ON0₂) R¹,

2) - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

wherein

n is 1 ;

m is 0 ;

p is 0 or 1 ;

q is from 0 to 6;

R° is a straight Ci-C₆ alkylene, -C(CH₃)₂- or -C (CH₃) ₂-CH₂- ; R¹ is hydrogen, -CH₃, -CH(CH₃)₂ or -(CH₂)OCH₃;

R^la is hydrogen or a straight or branched C1-C4 alkyl;

X is an oxygen atom;

R⁵ is hydrogen, C₁-C₄ linear or branched alkyl, -C(0)CH₃ or -C (0) OC (CH₃) ₃.

3. The compound according to claim 1 wherein R is selected from the group consisting of:

5)

- (R°) - (T) -X- (Q) - (CH 2 I

6)

7) - (R°)_n-CH(ON0₂) - (CH₂)_ql-X- (CH₂) _q2CH (ON0₂) R¹

8) - (R°) _n- (CR⁶R⁷) - (CH₂) _qCH (ON0₂) R¹

wherein

n is 0;

m is 0 or 1 ;

p is 0 or 1 ;

n1 is 0 ;

q is an integer from 0 to 10;

ql is an integer from 1 to 10;

q2 is an integer from 1 to 10;

t is 2 or 3;

R¹ is hydrogen, -CH₃, -CH(CH₃)₂ or -(CH₂)OCH₃;

X is oxygen or a covalent bond;

2 3 2 3

R⁴ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁵ is hydrogen, C₁-C₄ linear or branched alkyl, -C(0)CH₃ or -C (0) OC (CH₃) 3 (Boc) ;

R⁶ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁷ is (C¾) qCH (ONO₂) R¹ wherein q and R¹ are as above defined.

4 . The compound according to claim 1 wherein R is selected from the group consisting of:

9) -CH(CH₂CH₂SCH₃)NHC(0)R⁸

10) -CH(CH₂SC(0)R⁹)NHC(0)R⁹

wherein

R⁸ is selected from

1') - (R°)_n-CH(ON0₂)R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p-

R⁹ is selected from:

1') - (R°)_n-CH(ON0₂)R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

wherein

n is 1 ;

m is 0 ;

p is 0 or 1;

q is from 0 to 6;

R° is a straight Ci-C₆ alkylene, -C(CH₃)₂- or -C (CH₃) ₂-CH₂- ; R¹ is hydrogen, -CH₃, -(CH₂)OCH₃, -CH(CH₃)₂;

X is an oxygen atom;

2 3 2 3

Q is -CR R -, wherein R and R are hydrogen.

5 . The compound according to claim 1 wherein R is:

6. The compound according to claims 1 to 5 wherein y is 1, r is 1 and B is C¾ .

7. The compound according to any of claims 1 to 6 wherein A is (la)

(la)

8. The compound according to any of claims 1 to 6 wherein A is (lb)

(lb)

9. The compound according to claim 1 selected from the group :

Ĩ4) 103

Ĩ13)

Ĩ17)

Ĩ21)

Ĩ25)

Ĩ28)

Ĩ32)

Ĩ36)

10. A compound according to any of claims 1 to 9 for use as medicament .

11. A compound according to any of claims 1 to 9 for use for treating or preventing neuropathic pain.

12. A compound according to any of claims 1 to 9 for use for treating or preventing diabetes-associated neuropathic pain .

13. A compound according to any of claims 1 to 9 for use for treating fibromyalgia.

14. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula

(I) according to any of claims 1 to 9 and at least a pharmaceutically acceptable excipient.

15. A process for the preparation of compounds of formula (I)

(I)

wherein :

A is selected from the formulas (la) and (lb)

(la) (lb) ; r is 1 and y is 1 ;

B is H, or a straight or branched C1-C4 alkyl;

R is selected from the group consisting of:

1) - (R°) _n ^_CH (ON0₂) R¹ r

2) - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

4) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la

5)

6)

7) - (R°)_n-CH(ON0₂) - (CH₂)_ql-X- (CH₂) _q2CH (ON0₂) R¹

8) - (R°) _n- (CR⁶R⁷) - (CH₂) _qCH (ON0₂) R¹

9) -CH(CH₂CH₂SCH₃)NHC(0)R⁸

10) -CH(CH₂SC(0)R⁹)NHC(0)R⁹

wherein

n is 0 or 1,

m is 0 or 1,

p is 0 or 1,

nl is 0 or 1 ;

q is an integer from 0 to 10;

ql is an integer from 1 to 10;

q2 is an integer from 1 to 10;

t is an is an integer from 1 to 4;

R° is a straight or branched C1-C10 alkylene;

2 3 2 3

R⁴ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁵ is hydrogen, C₁-C₄ linear or branched alkyl, -C(0)CH₃ or

-C(0)OC(CH₃)₃;

R⁶ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁷ is (C¾) _qCH (ONO₂) R¹ wherein q and R¹ are as above defined;

R⁸ is selected from

1') - (R°)_n-CH(ON0₂)R¹,

2') - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4') - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

wherein R°, R¹ R^la, T, X, Q, n, m, p and q are as above defined;

R⁹ is selected from:

1') - (R°)_n-CH(ON0₂)R¹,

3') - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

wherein R°, R¹, T, X, Q, n, m, p and q are as above defined;

said process, comprises:

(i) reacting a carboxylic acid of formula (VII la)

R-COOH (Villa)

wherein R is as above defined, with Ag₂0 or Hg₂0, in an organic solvent to obtain a carboxylic acid salt of formula (XIII)

RCO-O-Xi (XIII)

wherein R is as above defined and Xi is Ag⁺ or Hg⁺;

(ii) reacting the compound of formula (XIII) with a compound of formula (XII)

(XII)

(2a; (2b) (2c)

(2d) (2e; (2f)

(2g) (2h)

Z is CI, Br or I, in an organic solvent obtaining a compound of formula (XI)

(XI)

wherein X_a, B and R are as above defined;

iii ) reacting the compound of formula (XI), with a compound (Ila) or (lib)

(Ila) (lib)

in an organic solvent and in the presence of an organic or inorganic base, to obtain a compound of formula (I) .

16. Compounds of formula (XI)

(XI)

wherein X_a is an activating group selected from the formulas (2a) - (2h)

R is selected from the group consisting of:

1) - (R°) _n ^_CH (ON0₂) R¹ r

2) - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

4) - (R°) - (T) -X- (Q)_p- (CH,) -CH(ONO_?)CH(ONO_?)R

5)

6)

7) - (R°) _n-CH (ON0₂) - (CH₂) _ql-X- (CH₂) _q2CH (ON0₂) R¹

8) - (R°) _n- (CR⁶R⁷) - (CH₂) _qCH (ON0₂) R¹

9) -CH(CH₂CH₂SCH₃)NHC(0)R⁸

10) -CH(CH₂SC(0)R⁹)NHC(0)R⁹

wherein

n is O or l;

m is 0 or 1 ;

p is 0 or 1 ;

nl is 0 or 1;

q is an integer from 0 to 10;

ql is an integer from 1 to 10;

q2 is an integer from 1 to 10;

t is an is an integer from 1 to 4;

R° is a straight or branched Ci-Cio alkylene;

R¹ is selected from hydrogen, a straight or branched C₁-C₄ alkyl or -(CH₂)OCH₃;

R^la is hydrogen or a straight or branched C₁-C₄ alkyl;

X is selected from an oxygen atom, -NH-, -N(C¾)- or a covalent bond; 2 3 2 3

R⁴ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁶ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁷ is (C¾) _qCH (ONO₂) R¹ wherein q and R¹ are as above defined; R⁸ is selected from

1') - (R°)_n-CH(ON0₂)R¹,

2') - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

wherein R°, R¹ R^la, T, X, Q, n, m, p and q are as above defined;

R⁹ is selected from:

1') - (R°)_n-CH(ON0₂)R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

wherein R°, R¹, T, X, Q, n, m, p and q are as above defined;

17. A process for the preparation of compounds of formula (I)

(I)

wherein A is (la)

(la)

r is 1 and y is 1,

1) - (R^u) _n-CH (ON0₂) R ,

2) - (R°) _n-CH (ON0₂) -CH (ON0₂) R^la

3) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4) - (R°) - (T) -X- (Q)p- (CH₂) -CH(ON0₂)CH(ON0₂)R^la,

5)

6)

7) - (R°)_n-CH(ON0₂) - (CH₂)_ql-X- (CH₂) _q2CH (ON0₂) R¹

8⁾ - (R°) _n- (CR⁶R⁷) - (CH₂) _qCH (ON0₂) R¹

9) -CH(CH₂CH₂SCH₃ ⁾NHC(0)R⁸

10⁾ -CH (CH₂SC (0) R⁹⁾ NHC (0) R⁹

wherein

n is 0 or 1 ;

m is 0 or 1 ;

p is 0 or 1 ;

nl is 0 or 1;

q is an integer from 0 to 10; ql is an integer from 1 to 10;

q2 is an integer from 1 to 10;

t is an is an integer from 1 to 4;

R° is a straight or branched Ci-Cio alkylene;

R^la is hydrogen or a straight or branched C₁-C4 alkyl;

X is selected from an oxygen atom, -NH-, -N(C¾)- or a covalent bond;

2 3 2 3

R⁴ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁶ is hydrogen or C₁-C₄ linear or branched alkyl;

R⁷ is (C¾) _qCH (ONO₂) R¹ wherein q and R¹ are as above defined;

R⁸ is selected from

1') - (R°)_n-CH(ON0₂)R¹,

2') - (R°)_n-CH(ON0₂)-CH(ON0₂)R^la

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹,

4' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)CH(ON0₂)R^la,

wherein R°, R¹ R^la, T, X, Q, n, m, p and q are as above defined;

R⁹ is selected from:

1') - (R°)_n-CH(ON0₂)R¹,

3' ) - (R°)_n- (T)_m-X- (Q)p- (CH₂)_q-CH(ON0₂)R¹

wherein R°, R¹, T, X, Q, n, m, p and q are as above defined;

said process comprises:

i' ) reacting a compound of formula (Ila)

(Ha)

with a compound of formula (XII)

(2d) (2e) (2f)

(2g) (2h)

Z is CI, Br or I, in an organic solvent and in the presence of an organic or inorganic base, obtaining a compound of formula (Ilia)

(Ilia)

wherein B and z are as above defined;

ii' ) reacting the compound of formula (Ilia) with a compound of formula

RCOOH (Villa)

wherein R is as above defined, in an organic solvent and in the presence of an organic or inorganic base obtaining a com ound of formula (Ι')

wherein B and R are as above defined.

18. A compound of formula (Ilia)

(Ilia)

wherein

B is H, or a straight or branched C₁-C4 alkyl;

Z is CI, Br or I.