JPH0140828B2 - - Google Patents
Info
- Publication number
- JPH0140828B2 JPH0140828B2 JP55108382A JP10838280A JPH0140828B2 JP H0140828 B2 JPH0140828 B2 JP H0140828B2 JP 55108382 A JP55108382 A JP 55108382A JP 10838280 A JP10838280 A JP 10838280A JP H0140828 B2 JPH0140828 B2 JP H0140828B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- carbon atoms
- compounds
- hydrogen
- 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.)
- Expired
Links
- 150000001875 compounds Chemical class 0.000 claims description 47
- 125000004432 carbon atom Chemical group C* 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 150000002431 hydrogen Chemical group 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- CBTITARLOCZPDU-UHFFFAOYSA-N 1h-indole-2-carbonitrile Chemical compound C1=CC=C2NC(C#N)=CC2=C1 CBTITARLOCZPDU-UHFFFAOYSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 235000010290 biphenyl Nutrition 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000011282 treatment Methods 0.000 description 5
- -1 2-amino-1-hydroxyethyl group Chemical group 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 102000015007 alpha-adrenergic receptor activity proteins Human genes 0.000 description 2
- 108040006816 alpha-adrenergic receptor activity proteins Proteins 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- UORJNBVJVRLXMQ-UHFFFAOYSA-N aprobarbital Chemical compound C=CCC1(C(C)C)C(=O)NC(=O)NC1=O UORJNBVJVRLXMQ-UHFFFAOYSA-N 0.000 description 2
- 102000015005 beta-adrenergic receptor activity proteins Human genes 0.000 description 2
- 108040006818 beta-adrenergic receptor activity proteins Proteins 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000000496 cardiotonic agent Substances 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 210000003191 femoral vein Anatomy 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000002861 ventricular Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000000579 2,2-diphenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(C1=C([H])C([H])=C([H])C([H])=C1[H])C([H])([H])* 0.000 description 1
- WANDYUHWUAJSBK-UHFFFAOYSA-N 4-(oxiran-2-ylmethoxy)-1h-indole-2-carbonitrile Chemical compound C1=CC=C2NC(C#N)=CC2=C1OCC1CO1 WANDYUHWUAJSBK-UHFFFAOYSA-N 0.000 description 1
- BYBYHCOEAFHGJL-UHFFFAOYSA-N 4-[3-[4-(diphenylmethyl)-1-piperazinyl]-2-hydroxypropoxy]-1H-indole-2-carbonitrile Chemical compound C=1C=CC=2NC(C#N)=CC=2C=1OCC(O)CN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 BYBYHCOEAFHGJL-UHFFFAOYSA-N 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010054211 Cardiac discomfort Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010021333 Ileus paralytic Diseases 0.000 description 1
- 201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000036747 functional refractory period Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 125000005059 halophenyl group Chemical group 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 210000005246 left atrium Anatomy 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 201000007620 paralytic ileus Diseases 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000008359 toxicosis Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
æ¬çºæã¯ïŒâã¢ããããããã·ã¢ãªãŒã«èªå°
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R1ã¯æ°ŽçŽ ãŸãã¯ã¡ãã«ã§ããã
R2ã¯ã¡ãã«ãççŽ ååæ°ïŒãïŒåã®ã¢ã«ã³ã
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ïœ åºââCOâRhã§ãããããã§ïŒ¢ã¯åº
The present invention relates to 3-aminopropoxyaryl derivatives, their preparation and pharmaceutical compositions containing them. According to the invention, the formula where R 1 is hydrogen or methyl, R 2 is methyl, alkoxycarbonyl having 2 to 5 carbon atoms, carbamoyl or cyano, and R is a group -B-CO-R h , where and B is the base
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Rhã¯ççŽ ååïŒã11åã®ããšãã«ã¢ã«ãã«
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ã«ã§ããæãã¯
ïœ åº[Formula], where R 1 is hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl monosubstituted with halogen of atomic number 9 to 35, and R h is hydrogen, alkyl of 1 to 4 carbon atoms, or phenyl monosubstituted with halogen of atomic number 9 to 35, and R h is phenylalkyl or diphenylalkyl having 13 to 17 carbon atoms, or b group
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Roããã³Rpã¯ççŽ ååæ°13ã17åã®ãžããš
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ïœ åºââCOâRhãäžã«å®çŸ©ãããšããã§ã
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ïœ åº[Formula], where R n is -COR o or -R p , where R o and R p are diphenylalkyl having 13 to 17 carbon atoms; Aminopropoxyaryl derivatives or pharmaceutically acceptable salts thereof are provided. One group of compounds of the invention has the general formula p where R 1 and R 2 are as defined above and R p is a group âBâCOâR h , as defined above; b group
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Rpâ²ã¯åºCompounds of the formula p', where R o is as defined above, are Another group of compounds of the invention are compounds of the general formula p ' where R 1 and R 2 are as defined above and R p â² is a group
ãåŒãã§ãããããã§Rp
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Ra 2ã¯ã¡ãã«ãççŽ ååæ°ïŒãïŒåã®ã¢ã«ã³ã
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Raã¯
ïœ åºâBaâCOâRa hãããã§
Baã¯åºA compound of the formula: wherein R p is as defined above, and including the conditions of the foregoing proviso. Another group of compounds of the invention are those of the general formula a where R 1 is as defined above, R a 2 is methyl, alkoxycarbonyl of 2 to 5 carbon atoms or cyano, and R a is a group -B a -CO-R a h , where B a is the base
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Ra iã¯æ°ŽçŽ ãã¡ãã«ãŸãã¯ããããšãã«ã§ã
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Ra hã¯ãã³ãžã«ãŸãã¯ãžããšãã«ã¡ãã«ã§ã
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ïœ åº[Formula], where R a i is hydrogen, methyl or halophenyl, and R a h is benzyl or diphenylmethyl; b group
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Ra nã¯âCORa oãŸãã¯âRa pã§ãããããã§Ra o
ã¯ãžããšãã«ã¡ãã«ã§ããããããŠRa pã¯ãžã
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Rbã¯
ïœ åºBbâCOâhãããã§
Bbã¯[Formula] Here, R a n is -COR a o or -R a p , where R a o
is diphenylmethyl, and R a p is diphenylmethyl or 2,2-diphenylethyl. Another group of compounds of the invention are those of formula b where R 1 and R 2 are as defined above and R b is a group B b âCOâ h , where B b is
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Rhã¯äžã«å®çŸ©ãããšããã§ããããããã¯
ïœ åº[Formula] where R b i is hydrogen or alkyl of 1 to 4 carbon atoms, and R h is as defined above, or b group
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ä»ã®äºçŸ€ã«ãããŠãRbã¯åºwhere R n is -COR o or -R p , where R o and R p are as defined above. It is. It is a compound of In one subgroup, R h in formula b is diphenylalkyl. In other subgroups R 2 is cyano. In other subgroups, R 1 is hydrogen.
In other subgroups, R b is the radical
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ïœ åºBbâCOâRb hãããã§
Bbã¯äžã«å®çŸ©ãããšããã§ããããããŠ
Rb hã¯ççŽ ååæ°13ã17åã®ãžããšãã«ã¢ã«
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ïœ åº[Formula]. Another group of compounds of the invention are those of formula c where R 1 and R 2 are as defined above and R c is a group B b âCOâR b h , where B b is as defined above and R b h is Diphenylalkyl having 13 to 17 carbon atoms, b group
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Rb oãã³Rb pã¯Rb hã«ã€ããŠäžã«ç€ºããæå³ãæ
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ä»ã®äºçŸ€ã«ãããŠãRcã¯åº[Formula] where R b n is -COR b o or -R b p , where R b o and R b p have the meanings given above for R b h , is a compound of . In one subgroup, R 2 in formula c is other than hydrogen. In other subgroups, R 2 is cyano.
In other subgroups, R c is the base
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[Formula]. In other subgroups, R 1 is hydrogen. R 1 is preferably hydrogen. R 2 is preferably alkoxycarbonyl, carbamoyl or cyano, especially cyano. R is preferably a group
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ãã°ãRxã¯åŒ[Formula]. R i is preferably hydrogen or alkyl, especially hydrogen. R h , R o and/or R p are diphenylalkyl.
R n is preferably -R p . Phenyl alkyl preferably has 7 to 7 carbon atoms.
9, especially 7 or 8 carbon atoms. When it is more than 8, the alkylene moiety is preferably in particular in the α-position, e.g.
Part - CαH (CH 3 ) CH 2 -, -Cα (CH 3 ) 2 CH 2 -
or branched, as in -Cα(CH 3 ) 2 (CH 2 ) 2 -. Diphenylalkyl preferably has 13 carbon atoms
~15, especially 13 carbon atoms. The phenyl rings are preferably attached to the same carbon atom. The rings are preferably attached to a carbon atom in the Ï-position, eg 3-diphenylpropyl. Diphenylalkyl is preferably diphenylmethyl. Alkyl and/or alkoxy preferably has 1 or 2 carbon atoms, especially 1 carbon atom.
Alkoxycarbonyl preferably has 2 carbon atoms
Or three, especially two. If it is based on more than two carbon atoms, it is preferably branched at position alpha to the carbonyl moiety, as in isopropoxycarbonyl. The halogen is preferably chlorine or bromine, especially chlorine. According to the invention, the compounds of the invention have the formula where R 1 and R 2 are as defined above and R x is a group capable of reacting with a primary or secondary amine to form a 2-amino-1-hydroxyethyl group. , with a suitable compound of the formula R--H, in which R is as defined above, and optionally the resulting compound of the formula is reacted singly in free or salt form. It can be obtained by a method consisting of separating. This amination method is based on the analogous 3-amino-2-
It can be carried out by conventional methods for the production of hydroxypropoxyaryl compounds. For example, R x is the formula
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RxãA group of the formula or a derivative of this group, for example a group of the formula -CH(OH)-CH 2 Y, where Y is chlorine, bromine or R y -SO 2 -
O--, where R y can be phenyl, tolyl or lower alkyl. Y is especially chlorine. This reaction is preferably carried out in isopropanol or a suitable ether such as dioxane. Excess amine can be used as a solvent if necessary. Alternatively, the reaction can be carried out in the form of a fusion melt. A suitable reaction temperature is approximately 20
to about 200°C, conveniently the reflux temperature of the reaction mixture when a solvent is present. The free form of the compounds of the invention can be prepared in the conventional manner by
It can be converted into salt form and vice versa. Suitable acids for the formation of acid addition salts include maleic acid, malonic acid or fumaric acid. In the compounds of the invention, for example, the carbon atom at the 2-position of the 3-aminopropoxy side chain is asymmetrically substituted. Thus, the compounds of the invention can exist in the form of racemates or individual optical isomers. The preferred optical isomer has the S configuration at this asymmetrically substituted carbon atom of the 3-aminopropoxy side chain. Individual optical isomers can be obtained, for example, by using optically active starting materials or by fractional crystallization using optically active acids. The compounds used as starting materials can be obtained by conventional methods. In particular, compounds of formula In the formula, R 1 and R 2 are as defined above. The compounds of formula are preferably reacted in anionic form. formula a where R i and R h are as defined above, a compound of formula where S is a protecting group, for example a benzyl group, is reacted with hydroxylamine, the resulting oxime is reduced, the resulting amine is suitably monoacylated, and optionally subsequently the group R i can be obtained by introducing into a monoacylated derivative produced by N-alkylation and finally removing the protecting group S from the resulting derivative. formula b where R o is as defined above, a compound of formula where S' is a protecting group, for example benzyl, can be obtained by suitably acylating the compound and deprotecting the resulting acyl derivative, for example by debenzyl. Unless the preparation of a particular starting material is specifically described, the preparation of this starting material can be carried out in a conventional manner. The invention is further illustrated by the following examples. In these examples, all temperatures are uncorrected. Example 1 4-[3-(4-diphenylmethylpiperazin-1-yl)-2-hydroxypropoxy]-1H-indole-2-carbonitrile 4g of 4-(2,3-epoxypropoxy)-
1H-indole-2-carbonitrile and 3.7 g of 1-diphenylmethylpiperazine are dissolved in methanol and the solvent is evaporated to dryness. 70 residue
Heat to â for 10 minutes. After cooling to room temperature, the resulting yellow oil is dissolved in ethanol and 1 equivalent of Romain is added. After adding ether to the ethanol solution, crystallization begins. The title compound in the form of hydrogen malonate salt is obtained in the form of crystals containing ethanol (mp 124 °C [decomposition]; after removal of ethanol mp 140
(°C; melting point of methanesulfonate form: 188°C; melting point of free base form: 163-164°C). R x
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For example, in normally tonic Numal anesthetized dogs, the increase in left ventricular contractility is approximately
Observed with intravenous doses of 0.2 to about 2 mg/Kg and intraduoduole doses of about 0.02 to about 2 mg/Kg. The test method is as follows: Dogs of both sexes weighing 10-15 Kg are used. 65
Numal in an intravenous dose of mg/Kg is used as anesthetic. Mount the animal in supine position on the operating table. After the usual preparations, a heparinized catheter is introduced into the left ventricle along the right carotid artery under radiologic control, and the pressure transfer is applied to the donor.
Record with membrane (Gould Statham p23Gb). The increase in pressure as a function of time is calculated and recorded with an HSE-physiodifferentiator.
The left ventricular pressure increase is a measure of the heart's contractile force. The magnitude of the pressure difference is expressed in mmHg/sec. Maintain a constant appropriate body temperature (approximately 36-37°C). After a control period of approximately 40 minutes, the test substance is injected into the femoral vein and its effect observed on recorded or calculated parameters. The compounds are therefore indicated for use as cardiotonic agents, for example for the treatment of heart failure. The compound of Example 1 is preferred in this application. The applied daily dose is about 1 mg to about 500 mg,
1 in unit dosage form containing about 0.25 mg to about 250 mg.
It is convenient to administer in divided doses 2 to 4 times a day or in delayed release form. An example of a daily dosage is 10-500 mg. The compounds also exhibit antiarrhythmic activity as shown in standard tests.
For example, the compound is described by N. Reuter and E Heeg.
According to the principle of [ Arch.Pharmakol. 268 (1971) 323-333], the functional refractory period in the left atrium of the guinea pig is 10 -6 ~
Extend at a concentration of 10 -4 molar. The compounds are therefore suitable for use as antiarrhythmic agents, for example in the treatment of heart rhythm disorders.
disorder). The compounds also exhibit α-adrenoceptor blocking activity as shown in standard tests. For example, inhibition of alpha-adrenoceptors occurs in isolated spirals and strips of the dog's femoral vein.
strip) (E. MUšller-Schweinitzer and E. Stušmer, Br. J. Pharmacol. [1974] 51 ,
441-446), can be observed at bath concentrations of about 10 -7 molar to about 10 -5 molar. Therefore, the compound is an α-adrenoceptor.
Use as a blocker is indicated, for example for the prophylaxis and treatment of disorders relating to paralysis of the intestine motility of the intestines, such as paralytic ileus. The compounds also have β-adrenoceptor blocking activity as shown in standard tests. For example, an isolated spontaneously sliding guinea pig atrium (K. Saameli, Helv. Physiol. Acta 25
[Method of 1967/CR219-CR221], the positive inotropic effect of adrenaline
inotropic effect) is suppressed from approximately 10 -9 mol to approximately 10 -6
observed at molar bath concentrations. The compounds are therefore suitable for use as β-adrenoceptor blockers, for example in coronary artery diseases, such as angina pectoris, in conditions resulting from sympathetic overstimulation, such as neurogenic cardiac discomfort. (nervous
heart ailment), myocardial infarction (myocardial infarction)
in fact), for the treatment of interval migraine, and for the prevention and treatment of glaucoma and thyreotoxicosis.
toxicosis). The applied daily dose is about 0.1 mg to about 1000 mg,
1 in unit dosage forms containing about 0.025 mg to about 500 mg.
It is convenient to administer in divided doses 2 to 4 times a day or in delayed release form. An example of daily dosage is
It is 0.1-100 mg. Generally, the 2(S) optical isomer of the compound is β
-More active as an adrenoceptor blocker than the 2(R) optical isomer. Before carrying out the aforementioned in vitro tests to demonstrate activity, it may be necessary to convert compounds with a substituent in the 2-position of the 3-aminopropoxy side chain to the corresponding free hydroxy compound. . Use as a cardiotonic agent is a preferred mode of use of the compound. The compounds can be administered in the form of pharmaceutically acceptable salts. Such salt forms exhibit similar activity to the free form and are easily prepared by conventional methods. The invention also provides a pharmaceutical composition comprising a compound of the invention in free form or in pharmaceutically acceptable salt form and a pharmaceutical carrier or diluent. Such compositions can be in the form of solutions or tablets, for example.
Claims (1)
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ãã®è£œè¬åŠçã«èš±å®¹ãããå¡©ã®è£œé æ¹æ³ã[Claims] 1 formula where R 1 is hydrogen or methyl, R 2 is methyl, alkoxycarbonyl having 2 to 5 carbon atoms, carbamoyl or cyano, and R is a group -B-CO-R h , where and B is a group [formula], where R i is phenyl monosubstituted with hydrogen, alkyl having 1 to 4 carbon atoms, or halogen having atomic number 9 to 35, and R h is a carbon phenylalkyl of 7 to 11 atoms or diphenylalkyl of 13 to 17 carbon atoms, or b group [formula], where R n is -COR o or -R p , where: A 3-aminopropoxyaryl derivative or a pharmaceutically acceptable salt thereof, wherein R o and R p are diphenyl alkyl having 13 to 17 carbon atoms. 2 4-[3-(4-diphenylmethylpiperazin-1-yl)-2-hydroxypropoxy]-
The compound according to claim 1, which is 1H-indole-2-carbonitrile or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2, which is a 2(S) optical isomer. 4 formula In the formula, R 1 is hydrogen or methyl, R 2 is methyl, alkoxycarbonyl of 2 to 5 carbon atoms, carbamoyl or cyano, and R X is a group [formula] or a group [formula], where Y is chlorine, bromine or R y âSO 2 âO, where R y is phenyl, tolyl or lower alkyl, is a compound of the formula RâH where R is a group âBâCOâR h , where B is a group [formula], where R i is hydrogen, alkyl having 1 to 4 carbon atoms, or phenyl monosubstituted with halogen having atomic number 9 to 35, and R h is phenylalkyl of 7 to 11 carbon atoms or diphenylalkyl of 13 to 17 carbon atoms; or b group [formula], where R n is -COR o or -R p , where R o and R p are diphenylalkyl of 13 to 17 carbon atoms, and optionally the resulting compound in free form or as a salt. Formulas characterized by isolation in the form A method for producing a 3-aminopropoxyaryl derivative or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and R are as defined above.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH736679 | 1979-08-10 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP63241170A Division JPH01230516A (en) | 1979-08-10 | 1988-09-28 | Drug containing 3-aminopropoxyaryl derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5632455A JPS5632455A (en) | 1981-04-01 |
JPH0140828B2 true JPH0140828B2 (en) | 1989-08-31 |
Family
ID=4323999
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP10838280A Granted JPS5632455A (en) | 1979-08-10 | 1980-08-08 | 33aminopropoxyaryl derivative |
Country Status (2)
Country | Link |
---|---|
JP (1) | JPS5632455A (en) |
ZA (1) | ZA804848B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3131146A1 (en) * | 1981-08-06 | 1983-02-24 | Boehringer Mannheim Gmbh, 6800 Mannheim | NEW HETEROARYLOXYPROPANOLAMINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
JP2578095B2 (en) * | 1985-11-07 | 1997-02-05 | äžè±éå·¥æ¥æ ªåŒäŒç€Ÿ | Adiabatic multiple fuel valve side injection combustion system |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2337461A1 (en) * | 1973-07-24 | 1975-02-06 | Boehringer Mannheim Gmbh | NEW INDOLDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
EP0000485A1 (en) * | 1977-07-08 | 1979-02-07 | Ciba-Geigy Ag | Piperidino-propanols, their preparation and pharmaceutical compounds containing them |
-
1980
- 1980-08-08 ZA ZA00804848A patent/ZA804848B/en unknown
- 1980-08-08 JP JP10838280A patent/JPS5632455A/en active Granted
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2337461A1 (en) * | 1973-07-24 | 1975-02-06 | Boehringer Mannheim Gmbh | NEW INDOLDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
EP0000485A1 (en) * | 1977-07-08 | 1979-02-07 | Ciba-Geigy Ag | Piperidino-propanols, their preparation and pharmaceutical compounds containing them |
Also Published As
Publication number | Publication date |
---|---|
ZA804848B (en) | 1982-03-31 |
JPS5632455A (en) | 1981-04-01 |
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