GB1563469A - 1-phenoxy-3-t-butylaminopropan-2-ols - Google Patents
1-phenoxy-3-t-butylaminopropan-2-ols Download PDFInfo
- Publication number
- GB1563469A GB1563469A GB1217/78A GB121778A GB1563469A GB 1563469 A GB1563469 A GB 1563469A GB 1217/78 A GB1217/78 A GB 1217/78A GB 121778 A GB121778 A GB 121778A GB 1563469 A GB1563469 A GB 1563469A
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- GB
- United Kingdom
- Prior art keywords
- nitro
- butylaminopropan
- methylphenoxy
- compounds
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(54) 1-PHENOXY-3-T-BUTYLAMINOPROPAN-2-OLS (71) We, DR. L. ZAMBELETTI S.P.A., an Italian body corporate of Via
L. Zambeletti, 20021 -- Baranzate, Milan, do 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:- The present invention relates to l-phenoxy-3-t-butylaminopropan-2-ols and their salts, to processes for preparing such compounds, and to pharmaceutical compositions containing them.
According to the present invention we provide l-(2-nitro-methyl-phenoxy)-3-t- butylaminopropan-2-ols of formula (I)
and the pharmaceutically acceptable acid addition salts thereof. Preferably the methyl substituent on the phenoxy group is bonded to the 3- or 5-position of the benzene ring.
Propan-2-ols with a structure analogous to the compounds of the invention are described in Specification Nos. 1,069,341 and 1,069,345 and are said to have A- adrenergic blocking activity. This activity, but particularly the coronary dilator and sedative activity, are also described for other, analogous compounds in German
Auslegungsschrift 1,236,523. Moreover the compounds of formula (I) fall within the scope of claim I of the U.K. Patent No. 1,069,345.
It has now surprisingly been found that the compounds of formula (I) both in themselves and as their salts have the capacity of inhibiting platelet aggregation and thereby the formation of thrombi to such a degree as to allow the use of the compounds in the prevention and therapy of thrombosis. This activity, previously not described for the propan-2-ols of the above-mentioned patents, is greatest in the isomers of the compounds (I) wherein the methyl group is in the 3- or 5position, i.e. in l-(2-nitro-3-methylphenoxy)-3-t-butylamino-propan-2-ol and 1-(2nitro-5-methylphenoxy)-3-t-butylaminopropan-2-ol. However the 4- and 6-isomers also possess some activity.
According to the present invention, the compounds of formula I can be obtained by reacting the corresponding phenoxyepoxypropane of the formula (II)
(where the methyl group is bonded to the appropriate position of the benzene ring) with t-butylamine. The salts can then be obtained by conventional salification techniques.
In their turn, the compounds (II) can be obtained by treating the corresponding 2-nitromethylphenol with epichlorhydrin.
The anti-aggregation activity and acute toxicity of compounds of the present invention was determined. In the following tests and related discussion, the compounds are identified as follows:
A: 1 -(2-nitro-5-methyphenoxy)-3-t-butylaminopropan-2-ol hydrochloride.
B: 1-(2-nitro-3-methylphenoxy)-3-t-butylaminopropan-2-ol hydrochloride.
C: 1 -(2-nitro-4-methylphenoxy)-3-t-butylaminopropan-2-ol hydrochloride.
D: 1 -(2-nitro.6-methylphenoxy)-3-t-butylaminopropan-2-ol hydrochloride.
Anti-Aggregation Activity.
The anti-aggregation activity on platelets was evaluated in vitro and in vivo for guinea-pigs, and in vitro for man.
For the in vivo tests, guinea-pigs of weight 400 to 600 g were employed. The test compounds were administered intraperitoneously, either as a single treatment at the dose of 5 mg/kg or as a repeated treatment for 4 consecutive days at a dose of 2 mg/kg. Control animals were treated with physiological solutions.
Blood was withdrawn 15 minutes after and 120 minutes after each administration through intracardiac injection and mixed with 0.126 ml sodium citrate solution in the proportion of one part of this solution to nine parts of withdrawn blood.
Platelet aggregation was carried out with 0.8 micromoles/mi of adenosin-5diphosphate (ADP) and evaluated by reading the light transmission on a suitable photometer (ELVI-Aggregometer Mod. 840 "Aggregometer" being a registered trade mark).
For the test in vitro, the guinea-pig's blood or human blood was treated with the sodium citrate solution as mentioned above and with 0.8 micromoles/ml of
ADP, and then with 100 mcg/ml of the test compound. The light transmission and, consequently, the anti-aggregation activity were then determined by the abovementioned technique on the same apparatus.
The high anti-aggregation activity of the compounds of the invention are shown by the results in the following Tables 1 and 2.
TABLE 1
Anti-Aggregation Activity on Platelets in vitro
Guinea-pig Men Activity Transmission Activity Compound Transmission A 5% 92.6% 5% 93,7% B 33% 51.5% 18% C 47% 30.9% 307 62.5R D 49% 27.9% 407 507c Basis Value = 68 Basis Value = 80
TABLE 2
Anti-Aggregation Activity for Guinea-Pigs in vivo
After a single Administration After repeated administration Compound Transmission Activity Transmission Activity A 1 38sic 49.3inc 250/e 65.2% B 34% 54.6% 22% 69.4% C 70% 6.60/c 510/c 29.1% D 76% 0 % 46% 36.1% Basis Value = 75 Basis Value = 72
Acute Toxicity.
The acute toxicity of the test compounds was evaluated on mice ("Swissstrain") weighing 20 to 24 g. Before the test the mice were first kept for at least 10 days under standard conditions (temperature: 220C; relative humidity: ca.50%), and fed with a controlled diet (Altromin, Registered trade mark), and then they were left without feed for 15 hours, with water "ad limitum".
The mortality was determined on 10 animals/dose, 60 animals being used for each test compound. The LD, for each compound by intravenous administration as well as by oral administration was determined; the compounds were dissolved in distilled water and the maximum administered volumes were 0.1 mV10 g of body weight intravenously and 0.5 mV10 g of body weight per os.
Toxicity controls were carried out for the compounds of the invention.
The toxicity results are shown in the following Table 3.
TABLE 3 Mouse: LDso (mg/kg)
Compound Intravenously Orally A 47 377 B 37 211 C 60 407 D 33 328 The data in the Table 3 show that by intravenous administration the
Compound "D" is most toxic, followed by the Compounds "B", "A" and "C"; whereas, by oral administration, the most toxic compound is Compound "B", followed by Compounds "D", "A" and "C".
It is clear that taking into consideration the very low concentration at which the Compounds "A" to "D" show anti-aggregation activity, and at which their toxicity is undoubtedly small, therapeutic use of the compounds, particularly
Compounds "A" and "B", is possible.
The present invention accordingly provides a pharmaceutical composition which comprises a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier. The compounds can be administered in single doses varying between 1 and 10 mg in the case of parenteral administration e.g. from vials; or in single doses varying from 10 to 15 mg in the case of oral administration e.g. in the form of tablets or capsules.
The following Examples illustrate the invention.
Example 1.
a) 1 (2-nitro-5-methylphenoxy)-2,3-epoxyprnpane.
5 g of 2-nitro-5-methylphenol and 15 ml of epichlorhydrin were dissolved in 50 ml of methanol and the solution stirred and treated with 1.5 g of finely milled sodium hydroxide. Almost immediately a thick deep red-coloured suspension was formed which was then boiled while stirring for 8 hours. After this time the red solid had dissolved and the separation of sodium chloride was complete.
The reaction mixture was cooled, the precipitate filtered off, and the solution evaporated to dryness in vacuo. The thus obtained oil was dissolved in chloroform, the resultant solution washed a few times with water, and after drying over Na2SO4 the solution was evaporated to dryness. The oily residue typically spontaneously gave a crystalline light yellow solid, through trituration with diethyl ether gives more certain results. The solid had an M.p of 62 to 63 C. The identity of the compound was confirmed by analytical data and an NMR spectrum.
b) l-(2-nitro-5-methylphenoxy)-3-t-butylaminopropan-2-ol hydrochloride (Com
pound "A").
5 g of the l-(2-nitro-5-methylphenoxy)-2,3-epoxypropane prepared as in (a) and 10 ml of t-butylamine in 10 ml of methanol were refluxed for three hours. The resultant reddish solution was evaporated to dryness in vacuo to give a solid residue which was washed with ether. The solid base thereby obtained had an M.p of 88"C.
The base was suspended in 20 ml of absolute ethanol; 10 ml of ethanol saturated with hydrogen chloride were added and the mixture boiled for a few minutes until completion of dissolution.
The solution was then filtered through charcoal and the hydrochloride precipitated by cooling, yielding 5.2 g of white-yellowish bulky crystals of m.p. 215 to 2160C. Analytical data and an NMR spectrum confirmed the identity of the compound.
Example 2.
a) l-(2-nitro-3-methylphenoxy)-2,3-epoxypropane.
A mixture of 5 g of 3-methyl-2-nitrophenol, 15 ml of epichlorhydrin and 2 ml of piperidine was heated for 6 hours at 950 to 1000C with stirring. After evaporation off in vacuo of the excess epichlorhydrin the oily residue was dissolved in chloroform and the solution stirred fox about one hour with 50 ml of a solution of sodium hydroxide (20%).
The chloroform layer was separated, washed several times with water, dried over sodium sulphate and evaporated to dryness to give an oily residue which may be used, as it is, for the subsequent step (b).
b) 1-(2-nitro-3-methylphenoxy)-3-t-butylaminopropan-2-ol hydrochloride (Com
pound "B").
A solution of 6 g - of the 1-(2-nitro-3-methylphenoxy)-2,3-epoxypropane prepared in step (a) and 20 ml of t-butylamine in 30 ml of methanol was refluxed for 4 hours. The reaction mixture was evaporated to dryness in vacuo and the residue dissolved in diethyl ether. The solution was then weakly acidified with diethyl ether saturated with hydrogen chloride. A transparent oil precipitated and rapidly solidified. The solid was filtered off and crystallised from isopropyl alcohol to give crystals of M.p 1850C and 187"C. Analytical data and an NMR spectrum confirmed the identity of the compound.
Examples 3 and 4.
By the same method I (2-nitro-4-methylphenoxy)-34-butylaminopropan-2-ol hydrochloride (Compound "C"), m.p. = 1660 to 168"C and 1-(2-nitro-6methylphenoxy)-3-t-butylaminopropan-2-ol hydrochloride (Compound "D"), m.p. = 152" to 1530C were prepared.
Claims (9)
1. A 1-(2-nitro-methylphenoxy)-3-t-butylaminopropan-2-ol of formula (I)
and pharmaceutically acceptable acid addition salts thereof.
2. A propan-2-ol derivative according to Claim 1, wherein the methyl substituent on the phenoxy group is bonded to the 3- or 5-position of the benzene ring.
3. 1-(2-nitro-5 1 (2-nitro-5-methylphenoxy)-3-t-butylaminopropan-2-ol hydrochloride.
4. 1 (2-nitro-3-methylphenoxy)-3-t-butylaminopropan-2-ol hydrochloride.
5. A process for preparing a compound of formula (I), characterised in that the corresponding phenoxyepoxypropane (II),
wherein the methyl group is bonded to the appropriate position of the benzene ring, is reacted with t-butylamine.
6. A process according to Claim 5 substantially as described in Example 1 or 2.
7. A propan-2-ol derivative of formula I as defined in Claim 1 when prepared by a process according to Claim 5 or 6.
8. A pharmaceutical composition comprising a propan-2-ol derivative of formula I as defined in Claim 1, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier or diluent.
9. A pharmaceutical composition according to Claim 8 wherein the propan-2ol derivative is as claimed in Claim 2.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT4100177 | 1977-01-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1563469A true GB1563469A (en) | 1980-03-26 |
Family
ID=11249971
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB1217/78A Expired GB1563469A (en) | 1977-01-12 | 1978-01-12 | 1-phenoxy-3-t-butylaminopropan-2-ols |
Country Status (8)
Country | Link |
---|---|
JP (1) | JPS53111023A (en) |
AT (1) | ATA20678A (en) |
BE (1) | BE862680A (en) |
DE (1) | DE2758868A1 (en) |
ES (1) | ES465872A1 (en) |
FR (1) | FR2377372A1 (en) |
GB (1) | GB1563469A (en) |
NL (1) | NL7800215A (en) |
-
1977
- 1977-12-30 DE DE19772758868 patent/DE2758868A1/en active Pending
-
1978
- 1978-01-06 NL NL7800215A patent/NL7800215A/en not_active Application Discontinuation
- 1978-01-06 BE BE2056575A patent/BE862680A/en unknown
- 1978-01-10 ES ES465872A patent/ES465872A1/en not_active Expired
- 1978-01-10 FR FR7800567A patent/FR2377372A1/en not_active Withdrawn
- 1978-01-11 JP JP232378A patent/JPS53111023A/en active Pending
- 1978-01-12 AT AT20678A patent/ATA20678A/en not_active IP Right Cessation
- 1978-01-12 GB GB1217/78A patent/GB1563469A/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
ATA20678A (en) | 1979-01-15 |
ES465872A1 (en) | 1979-01-01 |
FR2377372A1 (en) | 1978-08-11 |
BE862680A (en) | 1978-05-02 |
NL7800215A (en) | 1978-07-14 |
DE2758868A1 (en) | 1978-07-13 |
JPS53111023A (en) | 1978-09-28 |
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Legal Events
Date | Code | Title | Description |
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CSNS | Application of which complete specification have been accepted and published, but patent is not sealed |