CA2338912A1 - Medicine nitrate salts - Google Patents

Medicine nitrate salts Download PDF

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Publication number
CA2338912A1
CA2338912A1 CA002338912A CA2338912A CA2338912A1 CA 2338912 A1 CA2338912 A1 CA 2338912A1 CA 002338912 A CA002338912 A CA 002338912A CA 2338912 A CA2338912 A CA 2338912A CA 2338912 A1 CA2338912 A1 CA 2338912A1
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Canada
Prior art keywords
class
salt
nitrate
acid
nitrate salts
Prior art date
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Abandoned
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CA002338912A
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French (fr)
Inventor
Piero Del Soldato
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Nicox SA
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
    • C07C229/58—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids
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    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/5765—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

Abstract

Nitric acid salts with medicines active in bony disorders.

Description

I

a w MEDICINE NITRATE SF.hTS
The present invention relates to compositions to be used in the therapy and prevention of bony disorders, such as those of the bony tissue and articulations. More specifically it relates to compositions having an irr~roved therapeutic activity and improved gastrointestinal tolerability_ It is known in the art that the pharmacologic treatment of bony disorders itrmlies therapies directed to control pa-thophysiologic processes such-as those concerning the bony tissue and articulations.

AMENDED SHEET

i _ -______-.__~ _.._~.. _.. . _ - - .. _._ . _.~. y 02338912 2001-O1-29 -- .._ . . .. _. . ... _ __. . . _ . .._ . . . ._ EP 186.405 discloses pharmaceutical compositions useful for treating abnormal calcium and phosphate metabolism, containing geminal-diphosphonic acid compounds EP 210.728 discloses a method for treating or preventing osteoporosis utilizing acyclic regimen comprising alternating for two or more cycles the administration of a bone resorption inhibiting polyphosphonate and a no treatment period.
w0 95/30641 discloses compounds of formula A-X1-N02, wherein the group -NO2 is covalently linked to the bivalent linking bridge X1. The compounds of WO 95/30641 are endowed of antiinflammatory, analgesic and antithrombotic activity.
- 1~-AMENDED SHEET

i HF .9915/PCT/061 Among the compounds known in the art for the pharmacolo-gic treatment of the muscle skeletal and articular system disorders the following ones can be mentioned (see "NeTa Guide to Medicine & Drugs", Brit. Med. Associati~an 1997, pag. 115;
"Martindale, The Extra Pharmacopeia" vol. 31, 1990 pages L1~-13) - diphosphonates (Alendronate, PamidT-ovate, Risedronate, etc . ) ;
- "oxica~ns" ,. i . a o Piroxicam, Tenoxicam; Ama.nopyrine; Tomo-X7~p~o.~,; P~I~1~:L.~~i3:d~7.5'lE'..; Met~7.O~rf'f~ate; (_'F:C .~
'Wey are medicines having a limited efficacy and having the inconvenience of causing lesions of the gastrointestinal duct, in particular of the stornach._ Diphosphonates cause also AMENDED SHEET

I

lesions in the esophagus.

Other compounds used in the bony disorder therapy are anti-leukotriene medicines, for intance Ibudilast, Pranlukast, etc.; aminosalicylates. The efficacy and the gastrointestinal tolerability of these medicines is not optimal.
Compounds suitable to overcome the drawbacks shown by the medicines used in the bony disorder treatment have not yet been available in the art.
The need was felt to have available compounds for use in the bony disorder treatment with improved therapeutic features and tolerability and/or having an higher efficay.
The Applicant has unexpectedly and surprisingly found compounds and their compositions having improved pharmacothe-rapeutic properties.
It is an object of the present invention nitrate salts of compounds having a therapeutic activity in bony disorders, or their pharmaceutical compositions, said compounds being characterized in that they contain_at least a reactive group capable to be salified with nitric acid, said compounds being selected from the following classes:
Class. F1) a yoH
P
H2N ~O-ya OH
yP _ ( .-~-! a ) O ~ I ~ O N~' OH
lmown as disodic -Alenc~ronate ( I~OH
N F
H3C \O'i,l~f H20 ~OH
( FIb) ;
O~(~OH
OH
lmowii as sodic Ibandronate O O

H2N P' P, O' Na+ / ~ OH
/ P'OH ~ (FIC) w ~ ~P~ ~H + (F1d) O ~ t O Na N O ~ O Na OH OH
(F1C) is lmown as diaodic Pamidronate';. (FId) ~is lmown as sodic Risedronate;
O
H t ~,OH
N P
OOH (FIe) ;
P
O~t OOH
OH

O N N P~
\OH (FIf) ;
P
O~I OOH
OH
SUBSTITUTE SHEET (RULE 26) CH3 ~
t I I OH
N P~
h-t3C OOH (Flcj ;
O
O~p~OH
OH
O
! I~OJ
P
OOH (=, ~) ;
[H
P
O'' l OOH
O;-!
Nn O
(OOH
H2N N P ~ OH
(Fli) ;
H
P
O~ ~ OOH
OH
O' 10~ OH ~H" OH
P
HO~
P N
H0~11 (Fll;
O ~N
O
O
~N POOH
OOH (FIm) ;
P
O ' I ~ OH
OH
Ct IRCTITi ~TF SHErT (P,'J! E 26) O O
HO\11 I I~OH
P P _ Na~'O~' ~O Na1 HO ./ N tF?~,) ;
Ol-~

O
H t 1 O- N~f Na+ O' N P ~ O-NG
~P
Na+ O ~ 101 OiP~O'NaT (Flo) O'N21 n nN
O
i I~OH
P

OH (FIp) v Classe F2A:
O O
S ~N/CH3 ~ ( F2AI ) v / /
s ~ ~corrH ,;
oh lmown as Tenoxi.cam;

SUBSTITUTE SHEET (RULE 26) I

s /0\ /C:_3 (F2AII) known as Ampiro:ticam;
/~
-'~ H o Ii (F2AIII) known as Lornoxicam;
OI-i CONH
. - I N
N (F2AIV) ~ CF-I3 O O
known as Piroxicam;
~3~
C
C~s3 (F2AV) ;
r~ m~-rmn iT~ cuCCT !QI II G 7Rl OH O

W ' ~ ~~"'_ C H3 ( F2 A'7I ) C
known as ivIeloxicam;
COOH
H
N ~ CF3 (F2AVT_I) /
.known ~ as Fluf enamic acid ;
COOH C!
H

(F2AVIII) C!
known as Meclofenamic~.,acid;

H
/ N ~ CH3 (F2AIX) knourn as Mef enamic~ acid;
H
N\ N ~ CF3 (FaAx) / /
COOH
known as Niflumic acid;
ci ncTiT~ ~TF SNEET (RULE 261 _ O~COON
. s NH ( F2P..:iI ) CI ~CI
knOWri aS AC~C~O_enaC~
COO Na CI
H (F2PXII) N
CI
known as Diclofenac (sodic salt);

:H3 (F2AXIII) known as: Etodolac;
COOH
OH
(F2AXIV) known as Mesalamine N\ N ~ NHZ

N ~ N/ / N
HOOC N ~ / ~ HZ
' (F2ilXV) COON O
known as Methotrexate.;
SUBSTITUTE SHEET (RULE 26~

SN
H3C ~ C~O~i ( r 2~ ~m 1 H3C , L
N, ,Z
known: as ?~niC? 1? ~:~ti n e;
CH2N(CH3)2 H. _.
(F2AXVII) HO

Known as Tramadol;
Class F?~
-- o ) (F29I
J
H C~3 known as ~ Tocttoxipro ~ . ;
O
O "
I
(F2BII) N
~ CH3 O O
known as DroxiCam;
CI IRCTITi ITF CN~FT lift II G ~t;1 S~ O s F
F
~N~ ~ (F2HIII) '~F
H

Celecolcib;

(F2BIV) r \
~ ~ / S~ZCN3 ~3~r N (F2BV) ~ ~ (F2BVI) N N

io SUBSTITUTE SHEET (RULE 26) i _ WO 00/06585 PCT/EP99/05I70 Class . F3:
(F3a) ~'N

known as Pranlukast;
(F3b) CH

known as . Ibudilast;

o Na _ t (F3c) ci cA

known as sodic salt Montelukast.

SUBSTITUTE SHEET (RULE 26~

i The nitrate salts of the present invention can be o~btai-ned also by using the above mentioned compounds of the de-scribed classes, which optionally contain one or more -ON02 groups covalently bound to the molecule by one of the follo-wing bivalent linking bridges - YO wherein Y is a C1-C2o alkylene linear or branched when possible, preferably from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene from 5 to 7 carbon atoms;
- Y1 selected from:
CH 2-~
I ~ ~ r_3 _(CH
2' n3 wherein n3 is an integer from 0 to 3;
CH 0=
\2 COON ~H -SUBSTITUTE SHEET (RULE 26) - (CH2-CH-CH2-O)nf,-- - (CHZ-CH-CH2-O) nf' -wherein of ~ is an integer f rom 1 to 6 preferably from 2 to 4;
- - (CH-CH2-O) nf-Rif wherein Rlf = H, CH3 and of is an integer from 1 to 6 ; pref erably f rom 2 to 4 .
Said compounds containing a -ON02 group covalently bound to the molecule through one or more of said bivalent linking bridges, or spacers, are prepared as described in the European patent application 759,899 in the name of the Applicant, herein incorporated by reference.
Preferably these compounds containaing -ON02 groups cova-lently bound to the molecule by said spacers are selected from the compounds of class F2A (in the Ampiroxicam (F2AII) case by previously hydrolising the ethyl ester) and Montelukast of class F3.
It has been found by the Applicant that the nitrate salts of compounds containing at least a nitrate group covalently bound to the molecule by one or more of the above spacers, show an higher pharmacological activity. For instance the i nitrate salt of the 5-aminosalicylic acid derivative (mesalamine) containing a nitrate group covalently bound to the molecule by a butyl spacer, has resulted more active than the unsalified compound in the pharmacological model indicated in the examples.
The precursors to obtain the salts of the present inven-tion are preferably selected from the following:
- class F1: Alendronate;
- class F2A: Piroxicam, Diclofenac, Etodolac, Flufenamic acid;
- class F2B: Tomoxiprole;
class F3: Pranlukast.
In the compositions according to the present invention also the isomers, when they are available, of the compounds belonging to the above described classes, can be used.
Examples of isomers are cis-, trans-, optical isomers D and L
or the racemic, enantiomer. In general one isomeric form has higher activity with respect to the other, e.g. D form with respect to L form or viceversa.
The compound salts belonging to above classes contain at least one nitrate ion mole/compound mole. Preferably the ratio between the nitrate ion moles and the precursor moles is uni-tary. Salts with higher molar ratio are obtained when in the molecule other aminic groups basic enough to be salified, are present.

The salts of t.ze present invention are formulated in the corresponding pharmaceutical compositions according to well known techniques in the field, together with the usual exci-pients; see for instance the "Remington~s Pharmaceutical Sci-ences 15a Ed." volume.
The invention salt dosages in their pharmaceutical com-positions are the same, and generally lower than those of their precursors of the mentioned classes. However since they are generally more tolerated, it is possible to use them also in dose higher than those of the precursors without having the side effects appearing with the precursors at high doses.
The precursors of the salts belonging to the above me-ntioned classes are prepared according to the methods descri-bed in the following references:
class F1:
disodic Alendronate, disodic Pamidronate, sodic Risedro-nate: see the "Index Merck 14a Ed.!' volume, herein incorpora-ted by reference; disodic Ibandronate EP 252,502, formula (Fle) compound EP 325,482, formula (Flf) compound: EP
531,253, formula (Flg) compound: EP 592,488, formula (Flh) compound: EP 522,576, formula (Fli) compound: EP 546,548, formula (F11) compound: EP 561,296, formula (Flm) compound:
JP 93032684 (C. A. ref. Vo1.119 226194d), formula (F1n) compound: JP 93222073 (C. A. ref. Vo1.120 134926m), formula (Flo) compound: JP 92356496 (C. A. ref. Vo1.119 095828p), formula (Flp) compound: WO 93/12122;
class F2A:
Tenoxicam, Ampiroxicam, Lornoxicam, Piroxicam, Meloxicam, Flufenamic acid, Meclofenamic acid, Mefenamic acid, Niflumic acid, Aceclofenac, Diclofenac, Etodolac, Mesalamine, Methotre-xate, Penicillamine, Tramadol: see "Index Merck volume, 14a Ed." , herein incorporated by reference;
Class F2B:
Tomoxiprole: EP 12,866; Droxicam: "Index Merck 14a Ed.";
Celecoxib: WO 94/2,798, formula (F2BIV) compound WO 95/15,315; the compounds of formula F2BV (7-vitro indazol) and F2BVI (1,2-(trifluoromethylphenyl)imydazol) are commer-cialized by Lancaster Synthesis, Morecam - England.
Class F3:
sodic salt Pranlukast, Ibudilast, Montelukast: see the rflndex Merck volume, 14a Ed.".
The salts of the present invention are obtainable accor-ding to one of the following methods.
If the substance to be salified is available as free base or as a corresponding salt soluble in an organic solvent, which preferably does not contain hydroxyl groups, for example acetonitrile, ethyl acetate, tetrahydrofuran, etc., the salt is prepared by dissolving the substance in the solvent at a concentration preferably equal or higher than 10~ w/v, adding the amount of concentrated nitric acid corresponding to the moles of salifiable aminic groups present in the compound. The nitric acid is preferably diluted in the same solvent.
Preferably during and after the addition the mixture is cooled at temperatures between 20 ° C and 0 ° C . The product is generally recovered by filtration and washed with the solvent.
When on the contrary the substance is not very soluble, or it is available as a not very soluble salt in the above mentioned solvents, the corresponding mixtures with hydroxylated solvents can be used. Examples of such solvents are methyl alcohol, ethyl alcohol and water. Precipitation can be quickened by diluting the so obtained mixture, after the addition of nitric acid, with an apolar solvent.
When the starting product is salified with hydrochloric acid, it is possible to prepare the salt with nitric acid directly adding silver nitrate to the compound solution. After filtering silver chloride, the solution is concentrated and cooled to recover the nitrate salt.
When the starting product is a salt, it is also possible to free the corresponding base by a treatment with a sodium or potassium bicarbonate or carbonate saturated solution, or with a sodium or potassiumn hydroxide diluted solution. The base is then extracted by a suitable organic solvent (for example halogenated solvents, esters, ethers), which is then dried.
The organic solution is evaporated and then one proceeds i according to the preceding preparation methods, by dissolving the base in acetonitrile or in the other above mentioned solvents.
The following examples are given with the purpose to illustrate the invention and they are not limitative of the same.
EXAMPLE I
Piroxicam nitrate salt preparation A Piroxicam solution (3 g, 9.05 mmoles) in acetonitrile (30 ml) and tetrahydrofuran (50 ml) is treated at + 4°C with nitric acid at 65% (0.63 ml) dissolved in acetonitrile (5 ml). The mixture is stirred and then let stay. After 30 minutes at +4°C, it is filtered and a precipitate is collected, which is washed with ethyl ether and dried under vacuum.
A white solid (3.23 g) having melting point 120°-123°C
is obtained.
Elemental analysis:
calc (%) C 45.68 H 3.58 N 14.12 S
8.13 exper. (%) C 45.76 H 3.54 N 14.11 S
8.16 Alendronate nitrate salt preparation An Alendronate solution (0.92 g, 3.7 mmoles) in 50% ni-tric acid (2 ml) is dropped at the temperature of +4°C in ethyl ether (30 ml). The mixture is stirred and then let stay.
After 40 minutes at +4°C, the precipitate is filtered, washed with ethyl ether and dried under vacuum. A white amorphous solid is obtained.
Elemental analysis:
calc (%) C 15.39 H 4.52 N 9.01 exper. (%) C 15.41 H 4.50 N 8.99 Penicillamine nitrate salt preparation A (L)-Penicillamine (5 g, 33.5 mmoles) in methanol (50 ml) is treated at +4°C with nitric acid 65% (2.5 ml) dissolved in acetonitrile (7 ml). The mixture is stirred and let stay.
After 15 minutes at +4°C ethyl ether is added, the precipitate is filtered and dried under vacuum. An amorphous solid is obtained (3.2 g) .
Elemental analysis:
calc (%) C 28.30 H 5.65 N 13.19 S 15.11 exper. (%) C 28.29 H 5.66 N 13.22 S 15.08 Methotrexate nitrate salt preparation A Methotrexate solution (5 g, 11.00 mmoles) in methanol (60 ml) is treated at +4°C, under stirring, with nitric acid 65% (0.82 ml) dissolved in acetonitrile (5 ml).
After 30 minutes at +4°C the solution is treated with i ethyl ether. The precipitate is filtered and washed with ethyl ether. It is dried under vacuum. An amorphous solid (2.2 g) is obtained.
Elemental analysis:
talc (%) C 46.42 H 4.44 N 24.35 exper. (%) C 46.44 H 4.40 N 24.39 Tomoxibrole nitrate salt preparation A Tomoxiprole solution (2 g, 6.32 mmoles) in acetonitrile (50 ml) and methanol (18 ml) is treated at +4°C with nitric acid at 65% (0.432 ml) dissolved in acetonitrile (10 ml).
The mixture is stirred and then let stay at +4°C. After 30 minutes the solution is treated with ethyl ether.
The formed precipitate is filtered, washed with ethyl ether and dried under vacuum. A white solid m.p. 197°-199°C is obtained.
Elemental analysis:
talc (%) C 65.81 H 5.52 N 11.01 exper. (%) C 65.78 H 5.59 N 11.02 Preparation of the 5-amino-2-hydroxybenzoic acid (4 nitroxv) butyl ester (5-ASA-N02~
EXAMPLE 6a Preparation of they-tert-butoxycarbonylamino-2-hydroxybenzaic acid To a suspension of 5-amino-2-hydroxybenzoic acid (15 g, 98 mmoles) in dioxane (105 ml) and water (150 ml) trie-thylamine (24.6 ml, 176 mmoles) is added. To the obtained solution di-tert-butyl-dicarbonate (25.65 g, 118 mmoles) is added. The reaction mixture is left under stirring at room temperature for 4 days. Finally the solution is concentrated under vacuum up to a volume of a about 150 ml, cooled by ice and acidified with hydrochloric acid at 5%, extracting then with ethyl acetate. The organic phase is recovered and washed with water. The organic phase is anhydrified by sodium sulphate. By evaporating the solvent under vacuum the product is recovered as amorphous solid (20.8 g).
EXAMPLE 6b Preparation of the 5-tert-butyloxy-carbonylamino-2-hydroxy-benzoic-(4-bromo-butyl) ester acid To a solution of 5-tertbutyloxy-carbonylamino-2-hydroxy-benzoic acid (20 g, 85.7 mmoles) in tetrahydrofuran (200 ml) triphenylphosphine (44.9 g, 171 mmoles) and lastly carbon tetrabromide (56.7 g, 171 mmoles) are added. The reaction mixture is left under stirring at room temperature for 24 hours and then evaporated under vacuum. The obtained residue is purified by silica gel column chromatography (eluent: n.-hexane/ethyl acetate 8/2 vol . /vol . ) , monitoring the content of the collected fractions by chromatography on thin layer. The product is obtained by collecting the head fractions, after elution from the column of the CBr4 reactive used in the synthesis. The fractions are collected and dried. A white solid (21.16 mg) having m.p. 108°-111°C is recovered.
EXAMPLE 6c Preparation of the 5-tertbutyloxy-carbonylamino-2-hydroxy-benzoic-(4-nitroxy-butyl) ester acid A solution of 5-tertbutyloxy-carbonylamino-2-hydroxy-benzoic acid-(4-bromo-butyl) ester (21.16 g, 57.6 mmoles) in acetonitrile (150 ml) is heated at 80°C, in the dark, for 5 hours. After cooling at room temperature the solid is filtered and the solvent is recovered, which is evaporated to dryness obtaining a residue which is purified by silica gel column chromatography by using as eluent n.hexane/ethyl acetate 7/3 vol./vol.), monitoring the content of .the collected fractions by chromatography on thin layer. The head fractions containing the compound are evaporated to dryness obtaining 12.6 g of a white solid having m.p. 107°-109°C.
EXAMPLE 7 (comparative) Preparation of the h~rdrochloride salt of the 5-aminosalicylic acid (4-nitroxy)-butyl ester (5-ASA-N02.HC1 A solution of the 5-tert-butyloxy-carbonylamino-2-hydro-xy-benzoic acid -(4-nitroxy-butyl) ester (10 g, 28.6 mmoles) is dissolved in ethyl acetate (8 ml) and cooled at 0°C. Ethyl acetate/HC1 3 M (30 ml), prepared by bubbling gaseous HC1 in ethyl acetate is added under stirring until the required HC1 i molar concentration is obtained. The mixture is allowed to reach the room temperature and is left under stirring for 2 hours. A solid is formed, which is filtered, washed with ethyl ether and dried under vacuum. The product (7.1 g) is obtained as a white solid having m.p. 136°-140°C.
Elemental analysis:
calc (%) C 43.09 H 4.89 N 9.13 C1 11.56 exper. (%) C 43.05 H 4.88 N 9.10 C1 11.54 Preparation of the nitrate salt of the 5-amino-2-hYdroxyben-zoic acid (4-nitroxy)butyl ester (5-ASA-N02:HN03Z
To a solution of the hydrocloride salt of the 5-amino-salicylic acid 4-nitroxybutyl ester (2g, 7 mmoles) in a mixture of acetonitrile (50 ml) and tetrahydrofuran (15 ml) nitrate silver (1.19 g, 7 mmoles) is added. After 10 minutes the formed salt (AgCl) is filtered. The solution is let stay at room temperature for 30 minutes, then the precipitate is filtered, washed with ethyl ether and dried under vacuum. The salt (1.27 g) is obtained as a whitish solid having m.p. 123°-128°C.
Elemental analysis:
calc. (%) C 39.66 H 4.50 N 12.61 exper. (%) C 39.70 H 4.53 N 12.67 PHARMACOLOGICAL TESTS

Acute toxicity To a group of 10 rats weighing 20 g a single dose equal to 100 mg/kg of Piroxicam nitrate salt (Example 1), has been administered by cannula orally in a carboxymethylcellulose aqueous suspension 2% w/v.
The animals are kept under obsevation for 14 days. In no one of the animals of the group the toxic symptom presence was noticed.

Gastric toxicity of Piroxicam nitrate salt (Ex. 1) compered with Piroxicam To 3 groups of 10 rats each, kept on empty stomach since 24 hours, orally are administered:
- 5 ml/Kg of carboxymethylcellulose aqueous suspension 2%.
- an amount of nitrate Piroxicam corresponding to 100 mg/kg of Piroxicam in 5 ml/kg of carboxymethylcellulose aqueous suspension 2%.
- an amount of hydrocloride Piroxicam corresponding to 100 mg/kg of Piroxicam in 5 ml/kg of carboxymethylcellulose aqueous suspension 2%.
Six hours later the animals are sacrificed and the gastric lesion incidence is evaluated. The results are repor-ted in Table 1 and they show that the rats treated with Piro-i _ WO 00/06585 PCT/EP99/05170 xicam nitrate show an improved gastric tolerability compared with Piroxicam hydrochloride.

Myeloperoxydase activity of the 5-aminosalicylic acid (4-ni-troxy)butyl ester compared with that of the correspondincr hydrochloride and nitrate salts, in an acute colitis model.
4 groups of 6 animals each have been formed. The groups were treated, respectively, with the carrier (carbox-ymethylcellulose aqueous solution 1~), 100 mg/Kg of 5-ASA, a 5-ASA-NOZ.HC1 amount corresponding to 100 mg/kg of 5-ASA, an amount of 5-ASA-N02.HN03 correspsonding to 100 mg/kg of 5-ASA.
The animals were treated by rectal route with the above compounds at zero time. After one hour the animals were treated with 0.5 ml of a 60 mg/ml solution of 2,4,6,trinitro-benzensulphonic acid in ethyl alcohol 50~r. After two hours the animals were treated again by rectal route with the same compounds and at 12 hour intervals up to a total of 6 administrations.
The tissular levels of the myeloperoxydase (MPO) enzym have been measured which is an inflammatory process marker in various tissues, among which the bony-articular one (C.
Rathakrishnan et A1., ~~Release of oxygen radicals by articular chondrocytes: A study of luminol-dependent chemiluminescence and hydrogen peroxide secretion~~ J. Bone Miner. Res. 7/10 1139-1148 1992).

The myeloperoxydase activity was measured by using a modified version of the experimental model described by Bra-dley et al. J. Invest. Dermatol. 78, 206-209, 1982. Samples of intestinal tissue were drawn from each animal, which were suspended in 0.1% of hexadecyltrimethylammonium bromide (50 mg/ml) at a pH 6 and homogenized for 15 seconds (Polytron°
PT-7 generator). The samples were frozen and then defrosted three times subsequently before being centrifuged (9, 000 g) for 2 minutes in an Eppendorf° Benchtop centrifuge. The myeloperoxydase activity was measured by adding ~ ~.1 of the surnatant to 200 ul of o-dianisidine (Sigma) reactant and measuring the optical density variation at 450 nm in a two minute time in a Microtitre Multiscan°. The reactant contained 0.0005% of hydrogen peroxide as substratum for the myelope-roxydase enzym. One unity of the myeloperoxydase activity was defined as the one capable to convert an hydrogen proxide micromole to water in one minute at 22°C. The results are re-ported in Table II and are expressed as unit number of the myeloperoxydase activity/tissue mg (wet).
From the table it is noticed that in the group treated with 5-ASA-N02.HN03 the myeloperoxydase activity is lower than that of the other groups.

Prevention of the ctastric damage induced by aspirin by administering Alendronate in comparison with Alendronate nitrate salt Three groups c~ 5 rats each were treated by oral route with gastric probe as indicated hereinafter:
- I group: treated with Alendronate (Alen.) at the dose of 80 mg/Kg.
- II group: 1 h before the Alendronate 80 mg/Kg dose, Asp irin (Asp.) was supplied per os at the dose of 125 mg/Kg.
- III group: 1 h before the Alendronate nitrate, (Alen .HN03) corresponding to the Alendronate 80 mg/Kg dose, Aspirin was supplied per os at the dose of 125 mg/Kg.
The evaluation of the gastric damage was carried out sacrificing the animals three hours after the treatment with Alendronate or Alendronate nitrate.
The results are reported in Table III and show that the administration of Alendronate nitrate reduces the level of the gastric damage from 4 to 5 times in comparison with the one noticed after the Alendronate supply.

TABLE I
Treatment Dose Gastric damage mg/K / .o. (% incidence) Control - 0 Piroxicam.HCl 100 100 Piroxicam.HN03 100 20 TABLE II
Treatment Myeloperoxydase activity (unit/mg tissue) carrier 111 t 19 5-ASA-N02.HC1 111 t 20 5-ASA-N02.HN03 35 13 TABLE III
Treatment Dose Gastric damage Alendronate (% incidence) mg/Kg/ .o.

Alen. 80 1.8 2.2 Alen. + Asp. 80 36.2 4.1 Alen.HN03 + Asp. 80 8.6 t 1.6

Claims (13)

1. Nitrate salts of compounds selected from the following classes:
Class F1) disodic Alendronate;
sodic Ibandronate (F1C) is disodic Pamidronate; (F1d) is sodic Risedronate;
Class F2A:
(F2AI) Tenoxicam;
(F2AII) Ampiroxicam;
(F2AIII) Lornoxicam;
(F2AIV) Piroxicam;
(F2AV);
(F2AVI) Meloxicam;
(F2AVII) Flufenamic acid;
(F2AVIII) Meclofenamic acid;
(F2AIX) Mefenamic acid';

(F2AX) Niflumic acid;
(F2AXI) Aceclofenac;
(F2AXII) Diclofenac (sodic salt);
(F2AXIII) Etodolac;
(FaAxIV) (F2AXV) Metotrexate (F2AXVI) Penicillamins; (F2AXVII) Class F2H:
(F2BI);
Tomoxiprols (F2BII) Droxicam;

Celecoxib;

Class F3:
(F3a) Pranlukast;
(F3b) Ibudilast;
(F3C) sodic salt Montelukast.
2. Nitrate salts according to claim 1 wherein the compounds are selected from the following ones:

- class F1: Alendronate;
- class F2A: Piroxicam, Diclofenac, Etodolac, Flu-fenamic acid;
- class F2B: Tomoxiprole;
- class F3: Pranlukast, Ibudilast.
3. Nitrate salts according to claims 1 and 2 wherein the compounds contain one or more -ONO2 groups covalently bound to the molecule by one of the following bivalent linking bridges:
- YO wherein Y is a C1-C20 alkylene linear or branched when possible, preferably from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene from 5 to 7 carbon atoms;
- Y1 selected from:
wherein n3 is an integer from 0 to 3;

wherein nf' is an integer from 1 to 6 preferably from 2 to 4;

wherein R1f = H, CH3 and of is an integer from 1 to 6; preferably from 2 to 4.
4. Nitrate salts according to claim 3 wherein the compounds containing -ONO2 groups covalently bound to the molecule by bivalent linking bridges are selected among the compounds of the F2A class and Montelukast of the F3 class.
5. Nitrate salts according to claims 1-4, containing one or more isomers of said compounds.
6. Nitrate salts according to claims 1-5, wherein the salts of said compounds contain at least one nitrate ion mole-/compound mole.
7. Pharmaceutical compositions of the nitrate salts accor-ding to claims 1-6.
8. Nitrate salts and pharmaceutical compositions according to claims 1-7 for use as a medicament.
9. Use of salts and compositions according to claim 10 for the preparation of medicament for the bony disorder tre-atment.
10. A process for preparing nitrate salts according to claims from 1 to 6, wherein, when the substance to be salified is available as a base or as a corresponding salt soluble in an organic solvent, which does not contain hydroxyl groups, the salt is prepared by dissolving the substance in the solvent at a concentration equal or higher than 10% w/v, adding the amount of concentrated nitric acid corresponding to the moles of salifiable aminic groups present in the compound, cooling during and after the addition at temperatures between 20°C and 0°C and recovering the product by filtration.
11. A process according to claim 10 wherein when the substance is not very soluble, or it is available as a not very soluble salt in the above mentioned solvents, the corresponding mixtures with hydroxylated solvents are used and precipitation is quickened by diluting the so obtained mixture, after the addition of nitric acid, with an apolar solvent.
12. A process according to claims 10-11 wherein when the starting product is salified with hydrochloric acid, the salt with nitric acid is prepared by directly adding silver nitrate to the compound solution, filtering the silver chloride, the solution is concentrated and cooled to recover the nitrate salt.
13. A process for preparing nitrate salts according to claims from 1 to 6 wherein when the starting product is a salt, the corresponding base can be liberated by a treatment with a sodium or potassium bicarbonate or carbonate saturated solution, or with a sodium or potassium hydroxide diluted solution, extracting the base by a suitable organic solvent, and following the methods to prepare the nitrate salts of claims 10 or 11.
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