NZ245547A - Salts of (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2- oxoethyl)-n-methylamino]carbonyl]cyclohexane-1- carboxylic acid with metals and organic bases; pharmaceutical compositions - Google Patents
Salts of (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2- oxoethyl)-n-methylamino]carbonyl]cyclohexane-1- carboxylic acid with metals and organic bases; pharmaceutical compositionsInfo
- Publication number
- NZ245547A NZ245547A NZ245547A NZ24554792A NZ245547A NZ 245547 A NZ245547 A NZ 245547A NZ 245547 A NZ245547 A NZ 245547A NZ 24554792 A NZ24554792 A NZ 24554792A NZ 245547 A NZ245547 A NZ 245547A
- Authority
- NZ
- New Zealand
- Prior art keywords
- salt
- carbonyl
- oxoethyl
- cyclohexane
- carboxylic acid
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- 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
- C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number £45547
24 5 5 4 7
. Priority DstG(s):
I
Complete Specification Filed:
Ciass: (§). /o^...^9^(^13.!<**;.
/9fci jLSt /i&$. i~.;
o^p^.lsv
> *••
Publication Date:..?...l..P.i..P...!.?.™.. P.O. Journal No: .\3\3.5X-.
Patents Form No. 5
NEW ZEALAND
PATENTS ACT 1953
COMPLETE SPECIFICATION
STABLE SALTS OF (+)-(lS,2R)-2-[[N-(2-HYDROXYLAMINO-2-OXOETHYL)-N-METHYL-AMINO]CARBONYL]CYCLOHEXANE-1-CARBOXYLIC ACID, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WE, LABORATORI GUIDOTTI SPA, an Italian company of Via Trieste, 40, 56100 Pisa, ITALY
hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:
(followed by page la)
245 54
This invention refers to novel salts of
(+)-(lS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexane-1-carboxylic acid with metal and organic bases having hypertensive activity, the process for their preparation and their use in pharmaceuticals, said salts being represented by the general formula (I)
wherein R and R', if taken together, represent a bivalent cation selected from calcium and other pharmaceutically acceptable bivalent metals, or, if R'=H, R represents sodium, potassium, choline or a monofunctional group derived from imidazole, lysine, diethylamine, arginine or histidine. The (+)-(lS,2R)-2-[[N-(2hydroxylamino-2-oxoethyl)-N-methy!-amino]carbonyl]cyclohexane-l
-carboxylic acid (1),(D.C.I. Idrapril) is a compound disclosed in the European Patent No. 337,348 as a novel ACE-inhibitory agent and therefore having antihypertensive activity.
This acid, when kept exposed to the air in the normal environmental conditions of humidity and temperature, is subject to autodecomposition processes which give rise to impurities obviously incompatible with regard to a therapeutical use. Such degradation processes are also accelerated by a temperature increase of the acid kept in the above conditions.
It has now been found and it is the main object of the present invention that the novel salts according to this invention, as defined above, do not undergo to the autodecomposition and degradation processes previously mentioned.
As it will be noted from the experimental data hereinafter reported, the salts of the invention, particularly if perfectly purified, are stable compounds in the normal
EN.2. patent office \J9 MAY 1995 received
245547
environmental conditions. Further the salts remain unchanged with time either kept as such or included (in a solid state) in a pharmaceutical preparation (tablets, pills, capsules, lyophilized compositions and the like) provided for their therapeutical use. The utilisation of these salts in drugs allows to avoid the costly protective methods otherwise necessary to store and transform into pharmaceutical preparations the aforementioned acid. The preparation of the compounds of the invention is based on a process characterized in that a compound selected from (1) ( + ) -(IS,2R)-2-[[N-(2-hydroxylamino-2oxoethyl)-N-methyl-amino] carbonyl]cyclohexane-l-carboxylic acid and (2) ( + )-(IS, 2R) -2-[[N-(2-benzyloxyamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-l-carboxylic acid, is reacted with a salt of sodium, potassium, or a monofunctional group derived from imadazole, lysine, diethylamine arginine or histidine, or pharmaceutically acceptable bivalent metals, as defined in the present invention, in water, an organic solvent or a mixture thereof, the reaction taking place, in the case of the starting product (2), with contemporaneous hydrogenolysis of the protecting benzyl group with hydrogen at atmospheric pressure, in the presence of a suitable hydrogenation catalyst, the process being completed by isolating the desired salt of the acid. The following synthesis schemes illustrate the process of the present invention
COOH
CO - N - CH - CO - NH - OBZ
CH
coon
CO - N - CH - CO - NH - OH
I 2
CH
3
I
*
I
ro cn cn
2 4 5 5 4 7
where Q is said hydroxide, or alkaline salt or calcium salt or an organic base. In the as above defined process, the preferred hydrogenation catalyst is charcoal-supported Pd, but PtC^.Rh/A^O^ and Ni-Raney can also be used.
As to the organic solvent, propanol, tetrahydrofuran and dioxane are also suitable besides methanol and ethanol.
The following examples, that only illustrate and do not limit the scope of the invention, explain the specific aspects and the chemical-physical properties of the compounds of the invention.
EXAMPLE 1
(+)-(lS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexane-1-carboxylic acid calcium salt.
To a vigorously stirred suspension of 15.2 g calcium hydroxide in water (152 mL), was added under nitrogen, a solution of 75 g of (+)-(lS,2R)-2-[[N-2-benzylhydroxyamino-2-oxoethyl)N-methylamino]carbonyl]cyclohexan e-1-carboxylic acid 2, dissolved in methanol (1150 mL) and stirring continued for 20 minutes under nitrogen at 20°C.
After an addition of 15 g 10% Pd/Charcoal suspended in 152 ml water, hydrogenation of the product at 20°C with an initial H2 pressure of 1 Atm, is carried out for 3 hours.
Once the hydrogen absorption ceased (about 5000 mL absorbed), the catalyst was filtered and washed with a water/methanol (1/1) mixture (300 mL) and the filtrate, combined with the washings, was concentrated under vacuum at 40°C until all the methanol had been removed.
The suspension thus obtained was treated twice with 200 ml methanol, removing thereafter, still under vacuum at 40°C, all the Solvent.
The final suspension was cooled for 20 hours at 0-4°C and the precipitate was filtered and washed on the filter with 70 ml precooled water at 0-4°C.
55 g of 3 (yield 85%) as an ivory solid, having the following chemical-physical characteristics, were obtained:
Melting point > 250°C
[<a]2° = + 35.3° (c= 1, H20)
Heavy metals < 30 ppm
Sulphuric ashes = 40.6% (on the product as obtained)
Ca (EDTA) = 11.7%
K.F. = 7.8%
2 A 5 5 4 7
Ethanol = 400 ppm
TLC: Stationary phase Merck F254 silicagel plates Mobile phase nBuOH/AcOH/F^O = 6/2/2 Unitary spot at Rf = 0.7 HPLC : Nucleosil Column Cj^5 jx (250x4.6)
Eluent CH3CN/H3P04 0.1% = 20/80 Flow rate 0.8 ml/min.
Wave lenght = 214 nm.
Injection of 20 ml 0.01% CH^CN/^O solution = 20/80
The chiral purity of the product is assayed by HPLC on chiral column:
chiral column AGP
Eluent CH3CN/buffer at pH = 4.1 = 1/99 Flow 0.7 ml/min Wave lenght = 214 nm
Injection 20 yu of 0.01% CH^CN/^O solution = 1/99 Chemical purity:total impurities = 0.5%
Optical purity > 98%
EXAMPLE 2
(+)-(IS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-l -carboxylic acid - calcium salt.
To a suspension of 15.2 g calcium hydroxide in 1500 mL water, under vigorous stirring and nitrogen flow, 50 g of
(+)-(lS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-l -carboxylic acid 1 were added and the mixture was further vigorously stirred for 60 minutes at 20°C.
The light suspension thus obtained was filtered (on paper) and the filtrate was concentrated under vacuum at 40°C to 200 mL.
After cooling at 0-4°C for 24 hours, the precipitated product was filtered and washed on filter with 50 mL of precooled water at 0-4°C.
48.2 g of 3 (yield 84%) were obtained as ivory solid with the following characteristic:
Melting point > 250°C
W2d° = +34.8° (c=l, H20)
Ca (EDTA) = 10.1% (on the product as obtained)
K.F. = 9.04%
2 4 5 5 4 7
TLC Stationary phase Merck F254 silicagel plates Mobile phase nBu0H/Ac0H/H20= 6/2/2 Unitary spot
HPLC: Analytical and chiral chromatography was carried out in the conditions set forth in Example 1.
Chemical purity: total impurities = 1.0%
Optical purity > 98%
EXAMPLE 3
(+)-(lS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-l -carboxylic acid sodium salt.
70 g of 2 were added, at 20°C under stirring, to 7.6 g sodium hydroxide dissolved in 95% ethanol (1050 mL).
This solution was added with 7g of 10% Pd/charcoal suspended in 35 mL water under nitrogen and hydrogenated at 20°C with an initial H2 pressure of 1 Atm, for 3 hours.
Once the hydrogen absorption ceased (4850 mL absorbed), the catalyst was filtered and washed twice with 95% ethanol (150 mL).
The filtrate combined with the washings was evaporated under vacuum at 30°C to small volume. The residue was added twice with 200 mL acetone and again concentrated to small volume, then diluted with acetone (200 mL) and the precipitated product was filtered and washed on filter with acetone (100 mL). 56 g of 4, were obtained as hygroscopic, white solid, with the following chemical-physical characteristics: ^
W3d° = + 26.0° (c=l, H20)
Heavy metals < 20 ppm
Sulphuric ashes = 19% (on the product as obtained)
K.F. = 2.5%
Ethanol = 1.1%
Acetone = 5.8%
TLC: Stationary phase Merck F254 silicagel plates
Mobile phase nBu0H/Ac0H/H20 = 6/2/2 Unitary spot R.f. = 0.7 HPLC: Analytical and chiral chromatography was carried out in the conditions set forth in Example 1.
Chemical purity: total impurities = 2.0 %
2 4 5 5 4 7
Optical purity > 95%
EXAMPLE 4
(+)-(lS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-l -carboxylic acid L-lysine salt.
21 g lysine dissolved in water (38 mL) were added, under stirring, to a solution of 2 in 95% ethanol (725 mL).
Under nitrogen, this solution was added with 5g 10% Pd/Charcoal and hydrogenated at 20°C with an initial H2 pressure of 1 Atm, for 3 hours.
Once the hydrogen absorption ceased (3600 mL H2 absorbed) the catalyst was filtered on paper and washed twice with absolute ethanol (150 mL).
The filtrate combined with the washings was concentrated to dryness under vacuum at 30°C and the residue was added twice with acetone (200 mL), thereafter removing the volatile portion under vacuum.
The resulting residue was added again with acetone (200 mL), was filtered and washed on filter with acetone (100 mL).
49 g of 5 were obtained as hygroscopic, white solid.
HPLC analysis was effected in the conditions of Example 1: Impurities = 4% total EXAMPLE 5
(+)-(lS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-I -carboxylic acid - potassium salt.
Following the same method as in example 4 with appropriate changings of reactants, a highly hygroscopic, white solid, with the following chemical-physical characteristics, was obtained:
TLC: Stationary phase Merck F254 silicagel plates Mobile phase nBu0H/Ac0H/H20 = 6/2/2 Unitary spot R.f. = 0.7
HPLC: Analytical and chiral chromatography, was carried out in the conditions of Example 1.
Chemical purity : total impurities = 4.0 %
Optical purity > 90%
EXAMPLE 6
(+)-(lS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-l -carboxylic acid imidazole salt.
Following the same method as in Example 4, with appropriate changings, a hygroscopic, resinous product was obtained.
24 5547
HPLC analysis was effected in the conditions of Example 1: Impurities = 10% The compound 1 and the compounds of Examples 1 and 3 having been obtained in solid form, and thus weighable and characterizable from the physical viewpoint, have been tested as regards relative stability at 60°C in air, in accordance with the following method.
2 g of substance are placed in a thermostatic stove at 60°C and, at prefixed times, a HPLC analysis is carried out to determine both purity and possible impurities of the compound.
Apparatus: Waters 600E Multisolvent delivery systemn
Tunable absorbance detector Waters 484 Injection loop 20 ja Integrato Waters 745 Data Module Nucleosil Column Cjg 5^u (250 x 4.6)
Mobile Phase Ch3CN/H3P04 0.01%=20/80 Flow rate 0.9 ml/min.
Detector: Wave length = 214 nm Sample preparation: Dissolve 20 mg of sample substance in 100 ml ^O/CH^N 80/20
^ injection
Retention time, under these conditions, is r.t. = 7.9 min.
Table 1 shows the results, and in the first column, the data for the acid (1), tested in the same way, are reported.
Compound
Compound 1 (Acid)
Kxample 1 (Ck salt)
Example 3 (Na sa!
Time
Purity%
Impurity^
Purity%
Impurity^
Purity%
Impurit
0
99.0
0.5
99.5
0.5
98.0
2.0
4 h
98.8
0.5
99.0
0.5
97.8
2.0
24 h
97.8
1.0
98.5
0.5
97.3
2.0
48 h
97.0
2.0
99.0
0.5
93.8
.0
72 h
94.7
3.4
98.5
0.5
88.0
8.0
6 days
91.0
6.4
99.0
0.5
85.3
.0
7 days
89.3
8.3
98.0
0.5
84.4
.0
8 days
86.6*
.4
99.0
0.5
82.3
16.0
9 days
84.6*
11.8
99.5
0.5
78.0
.0
14 days
67.3*
22.0
99.0
0.5
75.0
22.0
days
22.6*
64.4
99.5
0.5
60.0
36.0
* Melted sample ro -£>
Ol
CJ1
^3
24 5 5 4 7
- li -
The salts of the invention are also, within the suitable dosage ratios, practically comparable either for potency and for the activity lasting time of the acid 1.
Such pharmacological equivalence has been experimentally demonstrated by comparing acid (1) with the calcium salt of Example 1 as shown by the experimental results listed in Table 2.
TABLE 2
Inhibition of pressure
Pharmacokinetics in dog
response by Angiotensin I
at dosage of
in awake rat
-1
ED tyjmol unit Kg p.o.)
-1
8 jumol units Kg p
.o.
and 95% reliable limits
AUC* (>ig min/ml)
F(%)
Acid 1
2.83 (0.12-8.13)
82+ 12
i
27
Compound Ex. 1
3.06 (0.43-7.40)
189+ 56
62
♦Area under the curve (of the plasmatic concentrations of the drug)
The salts of this invention constitute the active ingredients for preparing pharmaceutical compositions both for oral and parenteral use.
Such compositions and preparations are made with the well-known pharmaceutical techniques and employing conventional excipients, carriers and solvents.
As regards the oral administration, dosages of from 25 to 150 mgs/day, and from 2.5-25 mgs/day for parenteral administration, are envisaged respectively.
245547
Claims (16)
1. Stable salts of ( + )-(IS, 2R)-2-[[N-(2- hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane -1-carboxylic acid, represented by the general formula (I) COO CO - N - CH - CO - NH - 0 2 CH ++ R R' wherein R and R', if taken together, represent a bivalent cation selected from calcium and other pharmaceutically acceptable bivalent metals, or if R'=H, R represents sodium, potassium, choline or a monofunctional group derived from imidazole, lysine, diethylamine, arginine or histidine.
2. Salts according to claim 1, characterized in that they possess ACE-inhibitory activity.
3. A process for the preparation of a salt of formula (I) as defined in claim 1, characterised in that (+)-(IS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-l-carboxylic acid which is protected with a benzyl group, is reacted with a salt of sodium, potassium or a pharmaceutically acceptable alkaline earth metal, as defined herein, in water, an organic solvent or a mixture thereof, in the presence of a hydrogenation catalyst, the process being completed by isolating the desired salt of formula (I). 2A5547 (U,J -13 - V UCT 1395 J
4. A process for the preparation of a salt orformula (I) as defined in claim 1, characterised in that the compound (+) -(IS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-l-carboxylic acid is reacted with a salt of sodium, potassium or a pharmaceutically acceptable alkaline earth metal as defined herein in water, an organic solvent of a mixture thereof, the process being completed by isolating the desired salt of formula (I).
5. A process according to claim 3, characterised in that the compound (+)-(1S,2R)-2-[[N-(2-benzyloxyamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-l-carboxylic acid is reacted with a salt of sodium, potassium or a pharmaceutically acceptable alkaline earth metal as defined herein while undergoing contemporaneous hydrogenolysis of the benzyl protecting group, in water, an organic solvent or a mixture thereof, the process being completed by isolating the desired salt of formula (I).
6. A process according to claim 3 or claim 5, characterised in that a reaction mixture of (+)-(IS,2R)-2-[[N-(2-benzyloxyamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-l-carboxylic acid and a salt selected from sodium, potassium, and a pharmaceutically acceptable alkaline earth metal as defined herein, undergoes hydrogenolysis with hydrogen at atmospheric pressure in the presence of a hydrogenation catalyst.
7. A process of any one of claims 3-6, characterized in that said alkaline earth metal is calcium. rgm. -14-
8. A process of claim 6, characterized in that said hydrogenation catalyst is charcoal supported palladium.
9. A process of any one of claims 3-6 whereby said organic solvent is selected from methanol, ethanol, 2-propanol, tetrahydrofuran and 1,4-dioxane.
10. A pharmaceutical composition, characterized in that it contains as active ingredient a salt according to claim 1, as well as the usual excipients and carriers.
11. A pharmaceutical composition according to claim 10, characterized in that it possess antihypertensive activity.
12. Salts according to claim 1 or claim 2, substantially as herein described.
13. Salts according to claim 1, substantially as described with reference to any one of the Examples.
14. A process according to any one of claims 3-9, substantially as herein described.
15. A process according to any one of claims 3-6, substantially as described with reference to any one of the Examples.
16. A pharmaceutical composition according to claim 10 or claim 11 substantially as herein described. LABORATORI GUIDOTTI SPA<-- BALDWIN, SON & CAREYS \\
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI913448A IT1252708B (en) | 1991-12-23 | 1991-12-23 | STABLE SALTS OF (+) - (1R, 2S) -2 ((N- (2-HYDROXYLAMINE-2-OSSOETHL) -N-METHYLAMINE) CARBONYL) CYCLOHEXAN-1-CARBOXYL, ACE INHIBITIVE ACTIVITY, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ245547A true NZ245547A (en) | 1995-12-21 |
Family
ID=11361409
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ245547A NZ245547A (en) | 1991-12-23 | 1992-12-21 | Salts of (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2- oxoethyl)-n-methylamino]carbonyl]cyclohexane-1- carboxylic acid with metals and organic bases; pharmaceutical compositions |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0575572A1 (en) |
| JP (1) | JPH06506002A (en) |
| CN (1) | CN1079474A (en) |
| AU (1) | AU657591B2 (en) |
| BG (1) | BG98050A (en) |
| BR (1) | BR9205652A (en) |
| CA (1) | CA2104372A1 (en) |
| CZ (1) | CZ379692A3 (en) |
| EE (1) | EE9400006A (en) |
| FI (1) | FI933685A (en) |
| HR (1) | HRP921454A2 (en) |
| HU (1) | HUT69287A (en) |
| IT (1) | IT1252708B (en) |
| LV (1) | LV10426B (en) |
| MA (1) | MA22749A1 (en) |
| MX (1) | MX9207543A (en) |
| NZ (1) | NZ245547A (en) |
| PL (1) | PL169086B1 (en) |
| PT (1) | PT101156A (en) |
| RU (1) | RU2079489C1 (en) |
| SI (1) | SI9200409A (en) |
| SK (1) | SK379692A3 (en) |
| TN (1) | TNSN92117A1 (en) |
| WO (1) | WO1993013056A1 (en) |
| YU (1) | YU110892A (en) |
| ZA (1) | ZA9210004B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1264860B1 (en) * | 1993-06-21 | 1996-10-17 | Guidotti & C Spa Labor | DERIVATIVES OF CIS- AND TRANS-2(((2-(HYDROXYAMINO)-2-OXOETHYL)- ALKYLAMINO)CARBONYL)CYCLOHEXINECARBOXYLIC ACIDS |
| US5639746A (en) * | 1994-12-29 | 1997-06-17 | The Procter & Gamble Company | Hydroxamic acid-containing inhibitors of matrix metalloproteases |
| FR2817241B1 (en) | 2000-11-30 | 2003-03-07 | Cebal | ALUMINUM TUBE WITH SPLITABLE END |
| CN101516191A (en) * | 2006-09-28 | 2009-08-26 | 默克公司 | Amine base salts of SAHA and polymorphs thereof |
| MX2022005016A (en) * | 2020-04-27 | 2022-05-16 | Carter Hoffmann LLC | Door movement system for cabinet. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1224627B (en) * | 1988-04-12 | 1990-10-04 | Guidotti & C Spa Labor | ACID STARCHES CYCLOMETHYLEN_1,2_DICARBOSSILS THERAPEUTIC ADAPTIVITY, PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
-
1991
- 1991-12-23 IT ITMI913448A patent/IT1252708B/en active IP Right Grant
-
1992
- 1992-12-12 CA CA002104372A patent/CA2104372A1/en not_active Abandoned
- 1992-12-12 HU HU9302389A patent/HUT69287A/en unknown
- 1992-12-12 EP EP92924726A patent/EP0575572A1/en not_active Withdrawn
- 1992-12-12 JP JP5511398A patent/JPH06506002A/en active Pending
- 1992-12-12 WO PCT/EP1992/002903 patent/WO1993013056A1/en not_active Application Discontinuation
- 1992-12-12 RU RU9293052414A patent/RU2079489C1/en active
- 1992-12-12 AU AU30871/92A patent/AU657591B2/en not_active Ceased
- 1992-12-12 BR BR9205652A patent/BR9205652A/en not_active Application Discontinuation
- 1992-12-21 NZ NZ245547A patent/NZ245547A/en unknown
- 1992-12-21 SK SK3796-92A patent/SK379692A3/en unknown
- 1992-12-21 CZ CS923796A patent/CZ379692A3/en unknown
- 1992-12-22 HR HR921454A patent/HRP921454A2/en not_active Application Discontinuation
- 1992-12-22 MA MA23040A patent/MA22749A1/en unknown
- 1992-12-22 SI SI9200409A patent/SI9200409A/en unknown
- 1992-12-23 PT PT101156A patent/PT101156A/en not_active Application Discontinuation
- 1992-12-23 PL PL92297118A patent/PL169086B1/en unknown
- 1992-12-23 ZA ZA9210004A patent/ZA9210004B/en unknown
- 1992-12-23 YU YU110892A patent/YU110892A/en unknown
- 1992-12-23 TN TNTNSN92117A patent/TNSN92117A1/en unknown
- 1992-12-23 MX MX9207543A patent/MX9207543A/en unknown
- 1992-12-23 LV LVP-92-358A patent/LV10426B/en unknown
- 1992-12-23 CN CN92113839A patent/CN1079474A/en active Pending
-
1993
- 1993-08-18 BG BG98050A patent/BG98050A/en unknown
- 1993-08-20 FI FI933685A patent/FI933685A/en not_active Application Discontinuation
-
1994
- 1994-05-23 EE EE9400006A patent/EE9400006A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX9207543A (en) | 1993-08-01 |
| FI933685A0 (en) | 1993-08-20 |
| CZ379692A3 (en) | 1993-09-15 |
| LV10426A (en) | 1995-02-20 |
| HUT69287A (en) | 1995-09-28 |
| CA2104372A1 (en) | 1993-06-24 |
| AU657591B2 (en) | 1995-03-16 |
| MA22749A1 (en) | 1993-07-01 |
| YU110892A (en) | 1996-01-08 |
| WO1993013056A1 (en) | 1993-07-08 |
| ITMI913448A0 (en) | 1991-12-23 |
| PL169086B1 (en) | 1996-05-31 |
| PT101156A (en) | 1994-06-30 |
| ZA9210004B (en) | 1993-12-13 |
| CN1079474A (en) | 1993-12-15 |
| SK379692A3 (en) | 1995-04-12 |
| TNSN92117A1 (en) | 1993-06-08 |
| BR9205652A (en) | 1994-05-03 |
| IT1252708B (en) | 1995-06-26 |
| EE9400006A (en) | 1995-12-15 |
| FI933685A (en) | 1993-08-20 |
| HU9302389D0 (en) | 1993-11-29 |
| AU3087192A (en) | 1993-07-28 |
| LV10426B (en) | 1995-08-20 |
| PL297118A1 (en) | 1993-09-06 |
| BG98050A (en) | 1994-04-29 |
| EP0575572A1 (en) | 1993-12-29 |
| ITMI913448A1 (en) | 1993-06-23 |
| JPH06506002A (en) | 1994-07-07 |
| RU2079489C1 (en) | 1997-05-20 |
| HRP921454A2 (en) | 1995-02-28 |
| SI9200409A (en) | 1993-09-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1187087A (en) | Derivatives of cis, endo-2-azabicyclo-[3.3.0]- octane-3-carboxylic acid, a process for their preparation, agents containing these compounds and their use | |
| US8318745B2 (en) | Crystalline forms of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride | |
| KR100197892B1 (en) | Novel phenylalkylaminoalcohol carbamates and process for preparing the same | |
| US7691894B2 (en) | Cyclohexanecarboxylic acid compound | |
| KR100388747B1 (en) | Indole derivatives | |
| NZ245547A (en) | Salts of (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2- oxoethyl)-n-methylamino]carbonyl]cyclohexane-1- carboxylic acid with metals and organic bases; pharmaceutical compositions | |
| US4134991A (en) | Derivatives of 2-(3-phenyl-2-aminopropionyloxy)-acetic acid | |
| US3740439A (en) | Treating hypertension with beta-aminoalkane carboxylic acids | |
| JPS63297377A (en) | Novel amino acid group containing 4-benzyl-1- (2h)-phthalazinone derivative, manufacture, antiasthmatic and antiallergic medicine | |
| KR100419355B1 (en) | Amorphous piretanide, piretanide polymorphs, process for their preparation and theire use | |
| US7163921B1 (en) | Peptide derivatives and medicinal compositions | |
| EP0767777B1 (en) | New salts of 2-[(2,6-dichlorophenyl)amine]phenylacetoxyacetic acid with organic basic cations | |
| CA2379370A1 (en) | Carboxylic acid derivatives of 3-hydroxy-4-oxo-1,4-dihydropyridine as iron chelators | |
| US20100016614A1 (en) | Process for the preparation of perindopril erbumine | |
| KR880001865B1 (en) | Process for preparing 4-(1-imidazolyl methyl)cinnamic acid hydro-chloride hydrate | |
| CZ286649B6 (en) | 2-(Aminomethyl)-3,4,7,9-tetrahydro-2H-pyrano/2,3-e/indol-8-one derivatives and pharmaceutical preparation in which they are comprised | |
| HUT74883A (en) | New process and intermediates for preparing naphthyridonecarboxylic acid salts | |
| JPS6136830B2 (en) | ||
| EP0252030B1 (en) | Derivatives of l-amino acyl l-carnitine, process for their preparation and pharmaceutical compositions having hepatoprotecting activity containing same | |
| EP0170549B1 (en) | 4,5,6,7-Tetrahydrofuro-or 1H-pyrrolo[2,3-c]pyridine derivatives, their preparation and therapeutical use | |
| CN115120568B (en) | Compound telithromycin hydrochloride sustained-release tablet and preparation method thereof | |
| JPH031319B2 (en) | ||
| EP0101633B1 (en) | Pyridinecarboxylic esters of dopamine and of its n-alkyl derivatives | |
| JPS62221684A (en) | 5- or 6-substituted beta-carboline-3-carboxylic acid ester, manufacture and antipsychotic | |
| EP0117089B1 (en) | Beta-adrenergic antagonist compounds and derivatives of beta-adrenergic antagonists |