IE56128B1 - 3-amino-1-phenoxy-2-propanol derivatives - Google Patents
3-amino-1-phenoxy-2-propanol derivativesInfo
- Publication number
- IE56128B1 IE56128B1 IE2487/83A IE248783A IE56128B1 IE 56128 B1 IE56128 B1 IE 56128B1 IE 2487/83 A IE2487/83 A IE 2487/83A IE 248783 A IE248783 A IE 248783A IE 56128 B1 IE56128 B1 IE 56128B1
- Authority
- IE
- Ireland
- Prior art keywords
- chloro
- propanol
- addition salt
- dimethoxyphenoxy
- formula
- Prior art date
Links
- JZEHWMUIAKALDN-UHFFFAOYSA-N 1-amino-3-phenoxypropan-2-ol Chemical class NCC(O)COC1=CC=CC=C1 JZEHWMUIAKALDN-UHFFFAOYSA-N 0.000 title abstract 3
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 5
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 150000002924 oxiranes Chemical class 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 230000036772 blood pressure Effects 0.000 description 9
- 241000700159 Rattus Species 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000003292 diminished effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229960001317 isoprenaline Drugs 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000001871 Tachycardia Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 230000006794 tachycardia Effects 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 102100032392 Circadian-associated transcriptional repressor Human genes 0.000 description 2
- 101710130150 Circadian-associated transcriptional repressor Proteins 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 208000006218 bradycardia Diseases 0.000 description 2
- 230000036471 bradycardia Effects 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 230000002057 chronotropic effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000035487 diastolic blood pressure Effects 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- 210000002837 heart atrium Anatomy 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229940105631 nembutal Drugs 0.000 description 2
- 229960001412 pentobarbital Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000000213 tachycardiac effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 101100440696 Caenorhabditis elegans cor-1 gene Proteins 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 230000000059 bradycardiac effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 230000001955 cumulated effect Effects 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- -1 methoxyphenoxy Chemical group 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100001160 nonlethal Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 210000002385 vertebral artery Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
- C07C217/32—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/34—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
-
- 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
- A61P9/06—Antiarrhythmics
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (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)
Abstract
1. Claims for the contracting states : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE : 3-amino-1-phenoxy-2-propanol derivative, characterized in that it is selected from the group constituted by (i) the 3-alkylamino-1-(2-chloro-3,5-dimethoxyphenoxy)-2- propanols responding to the general formula see diagramm : EP0110746,P12,F1 in which R is CH(CH3 )2 or C(CH3 )3 ; and (ii) their addition salts. 1. Claims for the contracting state : AT Use of a 3-amino-1-phenoxy-2-propanol derivative, selected from the group constituted by (i) the 3-alkylamino-1-(2-chloro-3,5-dimethoxyphenoxy)- 2-propanols responding to the general formula : see diagramm : EP0110746,P13,F1 in which R is CH(CH3 )2 or C(CH3 )3 ; and (ii) their non toxic addition salts for manufacturing a drug.
Description
LABORATOIRE L. LAFON, A FRENCH BODY CORPORATE, OF 1, RUE GEORGE MEDERIC, 94701 MAISONS-ALFORT, FRANCE.
The present invention relates, as novel industrial products, to derivatives of 3-amino-l-phenoxy-2-propnnol, namely the 3-alky1 ami no-1-(2-chloro-3f5-dimethoxyphenoxy)2-propanols of formula (1) below and their Salts. It also relates to their use in therapeutics and the process of preparation of these novo] products.
It is known, particularly from French Patents No. 364/M, No. 4O61M and No. 70.13806 and U£iP No. 3 203 992, that in general, the derivatives belonging to the family of 5-ami no-1-phcnoxy-2-prop IS short.
It has just been found surpr ΐ s ί ngl.y that the 3 -a I kyl am t no- 1 - ( 2-chloro-3,5-d Ltnethoxyphenoxy) -2-propanols according to the invention do not have the above-indicated drawbacks, are from the therapeutic point of view more effective than (i) 1 - ( 3,5-d inicthoxyphenoxy )-3-isopropy la* mino-2-propanol of USM NO.3047M and No. 4Ο61Μ» and (ii) 1-(3,5-diinethnxyphenoxy)-3-tertinbutylamino-2-propanol of French Patent No. 7θ·138θύ, and arc at least as interesting as propanolol, a A -blocking reference substance • 1 winch is structurally different.
The derivatives of -2-propanol according to the invention in that they are selected from· 3-amino-I-phenoxyare characterized 3-nlkyJar» i no- 1- (2-chloro-3,5-d i methoxy plienoxyj-2-propanol* of the general formula (i) (I) (ii) in tyhich R is C!l(Cil^)^ or C(CH^)^; and, their Addition salts.
Prom the practical point of view, the preferred 5 products according' to the invention arc 1-(2-chloro-3,5d i methoxy phenoxy ) -3-ter tiobuty 1 a mi no-2-propanol and its addition salt.s, particularly the hydrochloride. Tests in animals and in man have shown that the 3-tertiobutylaHuno derivative and its salts arc more active than the 10 3-i sopropy 1 am ino der.ivat.ive and its salts.
By addition salts, is meant here the acid addition salts obtained hy the reaction of a free base of formula (l) with an inorganic or organic acid, and the ammonium salts* Among the acids useful for salifying the bases 15 of formula if), may be mentioned particularly hydrochloric, hydrobromic, nitric, sulfuric, formic, acetic, propionic, oxalic, fumaric, maleic, succinic, benzoic, cinnamic, mandelic, citric, malic, tartaric, aspartic, p-t.olucnesu 1 fonic and methancsul fonic acids. _ compounds enabling the ammonium salts to be obtained, may be mentioned particularly ICIi^ and CICII^ . The acid addition salts, particularly the hydrochlorides, are the addition salts preferred in therapeutics.
The derivatives of 3-amirio-t-phcnoxy25 2-propanol according to tin? invention may be prepared by a method known in itself by the application of conventional reaction mechanisms. The process that is recommended comprises two steps, namely a) the reaction of 2-chloro-3>5-dimethoxyphenol of formula glutamic , Anions the with the epi chlorhydrin ( III) in the presence of pyridine, to obtain the 1-(2-chloro3,5~d iniethoxyphenoxy) -2,3-epoxypropane (XV) amine (V) lower nii2r (where R is i-C* H« or t-C. II rt Jin a 3 / 4 9 alcohol, particularly a C j -C" alcohol, preferably ethanol or methanol· The best mode for operating consists, in step a), of reactin'; I ntole of II with 4 to 10 moles of III lor 2 to Sh at a temperature of between 100 and 120C, the epi chiorhydrin III serving as a solvent and pyrjdin as catalyst and, in step h), reacting 1 mole of epoxide IV with 8 to 12 moles of amine V in the presence of ethanol, at the reflux temperature of the reaction medium for at least 0.5h.
A certain number of compounds according to the Invention have been indicated in non-limiting manner in Table I below.
TABLE Ε Product Code Number Melting Point Example 1(b) CKL 41058 t-c4n9 2l6eC Example 2(a) -t_C4H9 85«C Example 3(b) CRL 41045i-C3,*7 206®C Example 4(a) - 97°C Notes : (a) : free base (b) : Iivdrochl oride The 3-a 1 Uylftmino-1-(2-cliIoro-3* 5-dimethoxyphenoxy)-2-propano Is of fot'nmla (I) and their addition salts arc useful as ^-blocking medicaments· There is recommended according to the invention a therapeutic composition which is characterized in that it comprises in association with a physiologically acceptable excipient, at least one compound of formula (I) above or one of its non-toxic addition salts as ^-blocking agent· In addition, the compounds according to the Invention, particularly the free bases, take part aa intermediates of synthesis in the preparation of other substances as indicated in French Patent Application No· S2-17935 filed by Applicant on the same day as that for the present invention. nt hep advant .mil «bar.ut erist ics of the invention will be better understood on reading the Following description <»f examples of the preparation, which are in no way limiting but given purely by way of illustration. > i)j:SCjnPT7<)\ OF PKFFKKKEJ) E.'iPUblME.vr^ p;:i.ρΛιΖat11»·<_ Ί Preparat i_«»n of I - ( 2-c.h h>ro-3 > 3 ··?! i mcthoxyphenoxy )-3I er t i obut y 1 an i nn-2-propanol bydrneb1 or i do.
(I'xample I; Code Xo, CEI. 41 1) 2-cbloro-3>5-d imcthnxyphonol Into λ solution kept at a temperature comprised between 35 and 40°C and constituted by 75 % (0.487 mole) of 31 5-d i niet-hoxyphonol and 4θθ ml of CO , , are introduced bv fractious, in 2.5b, an amount of 7Ο·5 g (0-528 mole) I *> o'" \-ch I orosucc » n i hi i dr . ft. i at .: t riiipcr a tu re of about 7,,nC » , removed by filtration and dryness under reduced pressure, thus obtained is purified by then wash in? of the distillate obtained SO. 5 X (yield 61,6 5.') phenol. EP. j (Kofler) = 57"C. s then floated for O.25h . Tlir precipitate formed the filtrate brought to The evaporation residue d i st iI 1 at ion under vacuum with water. There are of 2-chioro-J,5-dimethoxy2 ) )-( 2-eh I oro-3 , S^diim^tlmxyplicnoxy) - 2,3-epoxypropane There is heated towards 115QC For 4h a solution 25 of 40 (0.212 mole) of 2-rhloro-3,5-dimethoxyphenol in 133 ml (1.697 mole) of epicbJorhydrin in the presence of 0.25 ml of pyridine. The reaction medium is taken to dryness, the residue taken up again with ethyl acetate so anil the ethyl acetate pha.se is washed successively with sodium hydroxide and water. After drying over anhydrous sodium sulfate and evaporation of the solvent, a thick brown nil is obtained. This oil is purifil'd by crystallization in jsopropanol to give 36.5 g (yield 70.4%) of 1-(2-chloro-3,5-dimethoxyphenoxy)-2,3-cpoxypropane which is in the form of a chocolate brown colored powder.
Ml*. _ (Koller) - y6’C. i n s t 3) 41 058 Under reflux Cor 1 hour then* is heated a solution of 3*> g (0.147 mole) of 1 - ( 2-ch I oro-j , 5-d i methoxyphenoxy) 2,3-epoxy propane and 107· 5 K (1.4/2 i;:ole) of fcertiobutylamine in 15‘1 ml of anhydrous ethanol. The reaction medium is taken to dryness and the residue so obtained purified bv crystallization in diisopropyl ether to obtain 7 .'IP. t Uofler) = ?5°C. j nsf.
The free base so obtained is treated under reflux in anhydrous ethanol with hydrochloric ethanol. Λ orecipίLate is formed which is isolated to collect 36.3 g (y inld = 69.75*) of UJiL 41 θ5$ which is in the form of a slightly beige powder soluble to 12.,5 fi/l in water. IIP. .(Kdfler) - 210°C.
I list ρςι paratjo?; tt Preparation of 1-(2-chioro-3> 5-d imotboxyphenoxy)-3-isopropyl am i no-2-propaneI Ji v tlrocb 1 ori tic .
(Example 3; Code No. CKL 41 015) By proceeding as indicated in stage 3) of preparation 1, but replacing the Lorbiobutylaniine by isopropylamine, CKL 41 045 is obtained. '^inst (Kofler) - 2O6°C.
Below are summarized a part of the tests which have been undertaken with CKL 41 0.58 (product of Example 1). In these tests and except for indication to the contrary, CKL .)1 Ο58, suspended in an aqueous solution of arable gum for concentrations higher than or equal to 3 g/1, and .J,o and 1) in solution in distilled water for concentrations less than 3 g/l, was administered Intrapcritoneally in a volume of 20 ml,'kg in tho male mouse and 5 ml/kg in the male rat.
TOKfCITY Tn tlic male mouse by the I.P. route, the (maximum non-lethal dose) is higher than 64 m g/kg the Ι,Π.θ (dose at which 30/ of the animals die) is of the order of 128 mg/kg. The Ci OVERALL nr.HAVinil AM) REACTIVITIES Batches of 3 animals were observed before, then 1.5 min, 30 min, lh, 21i, 3h and 24h after the adniinistration of CRL 41 by the I.P. route. It is observed, that in flu: mouse - doses of 0.5 mg/kg;, 2 mg/kg and 8 mg/kg do not cause distinct synptooms; - the dose of 3- mg/kg leads to an (inconstant sedation (in 2 animals out of 3) and fleeting (3θ min), a dyspnoea (in 2 animals out ol' 3) for 15 to 3θ min; and in the rat doses of 0,25 mg/kg, 1 mg/kg and 4 mg/kg do not cause distinct symptoms; - the dose of 16 mg/kg gives a fleeting sedation (30 min) and depresses respiration (in 2 animals out of 3) for 30 min.
STUDY OF THE CARDIOVASCULAR PROPERTIES Λ - ALTSTilETIZED DOG Three dogs(average weight : 13*6 kg) anesthetized with nembutal received CliL 41 058 intraduodenally in successive doses of 0-5 mg/kg, 1 mg/kg, 2.5 mg/kg, 5 m?;/kg and 10 mg/kg. The blood pressure (it is recalled 2) l.h.Π. I i,:ih fig ct)rre.sponds to about 1.333 * J0~ Pa), the pulse rate, the femoral artery flow rate, the vertebral artery flow rate, the rectal, temperature, wort* noted .m CUE 41 05S is bradycardiac from the dose of 0.5 my,/up without any distinct action on the blood pressure. It .is not a vertebral vasodilator. The increase in the femoral flow rate is present only in one dog out of three of which the control flow rate was low (24 ml/min)· in the two other dogs, the flow rate diminishes. The rectal and cutaneous temperatures varied little. The color of th»· skin and that of the bile were not modified, ΐς The effects of ».oprenal i ne tested after the cumulated do .e of Id mg/kg of CRL 41 053 were much reduced: 3/Ug/kg of i soprena 1 ine caused the diastolic blood pressure to pass to 11»» 1.111 II;; instead of 4$ »»»»> H& and the pulse rate to 110 beat/min instead of 245 beat/ialn as control.
In two dogs where the isoprenalinc dose was increased to lOOytv g/kg, the tachycardiac effect for this dose was less than the tachycardiac effect of 0.3yiv g/kg of the isoprcnaline control· The hypertension with noradrenal in was also reduced : at the dose of 1/t** g/kg of noradrenalin, the systolic blood pressure passed to 221 mm llg instead of 230 iniii II;» as control.
B - LsOLATU) GU1XKA-PTG A'fRTA right atria isolated from the guinea pig ςο were used to determine the ρΛ9 of the CRL 41 0.58 with respect to the chronotropic effect of isoprcnalinc; after 15 m.in contact, the average of the pA^ was 3.21 ί 0.272.
On these atria, the inotropic and chronotropic effect itself of the CRL 41 058 was also evaluated; no average could be made, the concentrations and order of aduinistralion of the concentrations being variable.
)() IS The CRL -Π 058 possesses an ino* and chrono* effect which is maximum at the first concentration used whatever it -S -6 is (3 x 10 Lo 10 M). On the other hand, if, for example, the concentration of 10 & >i is administered after lower concentrations which have been stimulating, this concentration of 10 ° ?i is ino and chrono (this phenomenon Could allow the supposition of a liberation of catechol a in . nos ) · ARLSTIii’.TT ZI.D KAT rmotonsive rats were anesthetized with pentobarbital (75 mg/kg I.P.) and given atropine (1 mg/kg I.F.). Their* carotid blood pressure was measured and their heart rate by integration of the blood pressure. A jugular vein vas catheterized for the injections. If necessary, anesthesia was maintained by sub-cutaneous injection of pentobarbital. 1) Determination of the effective /J-blocking dose — — — — —p-— ————— — —— ———— — — eats received CRL 41 058 intravenously, at successive doses of 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg and possibly 30 mg/kg. The dose which blocks tachycardia induced hy 0.03 to 0.3 yUSAff T-V. isoprenaline (dose necessary to obtain an increase of the to 50 brat/min) was determined. It the? dose involved is 1 mg/kg T.V. 2) Duration of-blocking effect rats received 1 mg/kg of CRL 41 05$ intravenously. It was observed that : - the diastolic blood pressure was not modified, it remained around 91 mm JJg; and - the heart rate passed, in 5 min, from 345 to 290 beat/min (namely the maximum bradycardia was obtained in the time 20 min : 280 beat/min (namely -19%). After 90 inin, the heart rate was at 3θ7 bcat/min (namely —11%)* In addition, the dose of 0.03 ^.fi/kg I.V„ of isoprenaline caused the passing of : heart rate of is found that * - the blood pressure from 91 to 65 mm Hg (namely -26 mm Hg) ; after 1 mg/kg I.V. of CRL 41 058, the variation in blood pressure was +8 mm Hg (-69$ with respect to the control variation) at 5 min and during the 2h of observation; and - the heart rate from 345 to 3S4 beat/min (namely *39 heat/min); the tachycardia, completely inhibited by the CKI. 41 05? at time 5 min, resumed 50f’ of its value at t imc 20 min; it was restored to 92% of its value at time 60 π in.
Finally, in 5 control rats receiving a physiological serum in place of the product, it was observed that: the blood pressure remained constant; the hypotension with isoprenaline diminished by 40% in the 1$ course of the test; and - the heart rate diminished by 28 beat/min following injections of nembutal necessary for maintaining the anesthesia; the tachycardia with isoprenaline remained constant during the -h observation. 0 - WOKEN RAT genetically hypertensive rats, with an implanted femoral artery catheter, received CRL 41 058 at the dose of 20 mg/kg P-0.
The blood pressure passed from 191 to 167 mm Hg 25 at time 6h (-13%; statistically significant variation). The heart rate diminished from 5 min, it passed from 382 to 322 beat/min (-15%; statistically significant variation); the maximum bradycardia was reached at 2h (305 beat/min, namely -20%; statistically significant variation), it then diminished to be, at 7b, 322 beat/min, namely -15/j statistically significant variation). 24h after administration of CRL 41 058, it was observed that the blood pressure had resumed its control value, the heart rate being again 330 beat/min (namely -13%; statistically significant variation). j I· - CONCIJJSJOS It results from the tests summarized above that CRL 4] O5S is a vrrj .xond /¾ -block i.ng agent.
Clinical assays have confirmed in man the interest ς of the β* -blocking effect of CRL 41 OSS at the daily dose of 40 to 50 r.i*x (distributed in 2 to 3 administrations) for 2 to 6 weeks·
Claims (9)
1. Λ 3-nmino-l-phenoxy-2-propanol derivative which is selected from: (i) a 3-aBqrlandno-l- (2-chloro-3,5^dimethoxyphenoxy)-2-propanol of the general formula (ii ) CI) and,
2. 1 -( 2-Chloro-3,5-dimethoxyphenoxy )-3- tertiobutyl10 ami.no-2«propanol or a non-toxic addition salt thereof.
3. - 1-(2-Chloro-3,5-dimethoxylphenoxy)-3- isopropylamino-2-propanol or a non-toxic addition salt thereof.
4. · A pharmaceutical composition comprising in association with a physiologically acceptable excipient, a pharma15 ceutically effective amount of at least one 3-alkylamino1-(2-chloro-3,5-dimethoxyphenoxy)-2-propanol of formula 1 according to Claim 1 or a non-toxic addition salt thereof.
5. · Λ method for preparing a compound according to Claim 1 comprising the following steps a) reacting the 2-chloro-3,5“dimethoxyphenoi of the formula ^11 rc (II) CH 0 with cpichlorhydrin (111), in the presence of pyridine to obtain the l-(2-chloro25 3.5-dimethoxyphenoxy)-2,3-epoxypropane of the formula j (JV) b) reacting epoxide IV thus an amine of the formula NH,!< wherein R is CII(CH Λ ) ο οι a Cj-C^-alkanol. obtained with (V) of compound to S hours at C(CH , ). 4 J , in in which step 11 with 4 to • a temperature p b) comprises mol a of amine b.
6. Λ method according to Claim 5, a) comprises reacting 1 mol 10 nobs of compound Til for 2 of between 100¾ and 12O°C, and st reacting I mol o f epoxide IV with 8 to 1 V in the presence of ethanol at the reflux temperature of the reaction medium for at least 0-5 hour·
7. . A 3-alkylamino-l- (2-chloro--3, 5-dimethc«yphenoxy) -2-propanol of the general formula I given and defined in Claim 1 or an addition salt thereof, which is any one of those specifically hereinbefore mentioned.
8. A method for preparing a 3-cdkylandno-l-(2-chloro-3,5-dinethoxyphenoxy)-2-propanol of the general formula I given and defined in Claim 1 or an addition salt thereof, substantially as hereinbefore described and exemplified·
9. A 3-aIkylamino-l- (2-chloro-3, S-dimsthoxyphenoxy) -2-propanol of the general formula I given and defined in claim 1 or an addition salt thereof, whenever prepared by a method claimed in a preceding claim.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8217934A FR2534908A1 (en) | 1982-10-26 | 1982-10-26 | NOVEL 3-AMINO-1-PHENOXY-2-PROPANOL DERIVATIVES, THERAPEUTIC USE AND PREPARATION METHOD |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE832487L IE832487L (en) | 1984-04-26 |
| IE56128B1 true IE56128B1 (en) | 1991-04-24 |
Family
ID=9278614
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2487/83A IE56128B1 (en) | 1982-10-26 | 1983-10-24 | 3-amino-1-phenoxy-2-propanol derivatives |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0110746B1 (en) |
| JP (1) | JPS5995244A (en) |
| AT (1) | ATE20339T1 (en) |
| AU (1) | AU565183B2 (en) |
| CA (1) | CA1227220A (en) |
| CS (1) | CS235985B2 (en) |
| DE (1) | DE3364087D1 (en) |
| DK (1) | DK156566C (en) |
| ES (1) | ES526737A0 (en) |
| FI (1) | FI78903C (en) |
| FR (1) | FR2534908A1 (en) |
| GR (1) | GR77581B (en) |
| HU (1) | HU188975B (en) |
| IE (1) | IE56128B1 (en) |
| IL (1) | IL70061A0 (en) |
| MA (1) | MA19937A1 (en) |
| MX (1) | MX155997A (en) |
| NZ (1) | NZ206050A (en) |
| OA (1) | OA07575A (en) |
| SU (1) | SU1223841A3 (en) |
| ZA (1) | ZA837922B (en) |
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| CN113968792A (en) * | 2020-07-24 | 2022-01-25 | 郭峰 | Novel method for synthesizing 2-chloro-5-aminophenol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR4061M (en) * | 1963-07-19 | 1966-05-09 |
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1982
- 1982-10-26 FR FR8217934A patent/FR2534908A1/en active Granted
-
1983
- 1983-10-21 CA CA000439481A patent/CA1227220A/en not_active Expired
- 1983-10-24 IE IE2487/83A patent/IE56128B1/en not_active IP Right Cessation
- 1983-10-24 MA MA20157A patent/MA19937A1/en unknown
- 1983-10-25 MX MX199210A patent/MX155997A/en unknown
- 1983-10-25 NZ NZ206050A patent/NZ206050A/en unknown
- 1983-10-25 GR GR72781A patent/GR77581B/el unknown
- 1983-10-25 SU SU833657054A patent/SU1223841A3/en active
- 1983-10-25 DE DE8383402068T patent/DE3364087D1/en not_active Expired
- 1983-10-25 AT AT83402068T patent/ATE20339T1/en not_active IP Right Cessation
- 1983-10-25 EP EP83402068A patent/EP0110746B1/en not_active Expired
- 1983-10-25 ZA ZA837922A patent/ZA837922B/en unknown
- 1983-10-25 ES ES526737A patent/ES526737A0/en active Granted
- 1983-10-25 AU AU20566/83A patent/AU565183B2/en not_active Ceased
- 1983-10-26 HU HU833674A patent/HU188975B/en not_active IP Right Cessation
- 1983-10-26 IL IL70061A patent/IL70061A0/en unknown
- 1983-10-26 DK DK490983A patent/DK156566C/en not_active IP Right Cessation
- 1983-10-26 FI FI833921A patent/FI78903C/en not_active IP Right Cessation
- 1983-10-26 OA OA58146A patent/OA07575A/en unknown
- 1983-10-26 CS CS837863A patent/CS235985B2/en unknown
- 1983-10-26 JP JP58199309A patent/JPS5995244A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5995244A (en) | 1984-06-01 |
| AU565183B2 (en) | 1987-09-10 |
| DK156566C (en) | 1990-02-12 |
| HU188975B (en) | 1986-05-28 |
| FI78903C (en) | 1989-10-10 |
| DK490983D0 (en) | 1983-10-26 |
| EP0110746B1 (en) | 1986-06-11 |
| NZ206050A (en) | 1987-04-30 |
| OA07575A (en) | 1985-03-31 |
| FR2534908A1 (en) | 1984-04-27 |
| FI833921A0 (en) | 1983-10-26 |
| ES8406062A1 (en) | 1984-07-01 |
| CS235985B2 (en) | 1985-05-15 |
| DK156566B (en) | 1989-09-11 |
| FI833921L (en) | 1984-04-27 |
| DK490983A (en) | 1984-04-27 |
| ES526737A0 (en) | 1984-07-01 |
| CA1227220A (en) | 1987-09-22 |
| FI78903B (en) | 1989-06-30 |
| AU2056683A (en) | 1984-05-03 |
| MX155997A (en) | 1988-06-13 |
| IL70061A0 (en) | 1984-01-31 |
| EP0110746A1 (en) | 1984-06-13 |
| GR77581B (en) | 1984-09-24 |
| IE832487L (en) | 1984-04-26 |
| MA19937A1 (en) | 1984-07-01 |
| DE3364087D1 (en) | 1986-07-17 |
| ATE20339T1 (en) | 1986-06-15 |
| ZA837922B (en) | 1984-06-27 |
| SU1223841A3 (en) | 1986-04-07 |
| FR2534908B1 (en) | 1985-03-08 |
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| MM4A | Patent lapsed |