NZ229540A

NZ229540A - N-hetero-ring-substituted chroman derivatives

Info

Publication number: NZ229540A
Application number: NZ229540A
Authority: NZ
Inventors: Gunther Hausler; Rolf Gericke; Hanns Wurziger; Manfred Baumgarth; Ingeborg Lues; Rolf Bergmann; Peyer Jacques De
Original assignee: Merck Patent Gmbh
Priority date: 1988-06-16
Filing date: 1989-06-14
Publication date: 1991-03-26
Also published as: AU626549B2; NO174391C; AU3644089A; DK296789A; FI92824B; DK296789D0; IL90613A0; FI892948A0; KR910000711A; FI92824C; EP0346724A1; NO892494D0; PT90864A; JPH0240375A; HUT56096A; PT90864B; FI892948A; NO892494L; NO174391B

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £29540 NOW AMENDED 22 95 4 0 Priority Oate(s): . I b.'.fct III. » • • • *b • • •••Ti • r>«J •» Complete Specification Filed: Cfa: .wSJ*. 'W'' Publication Date: P.O. Journal, No: .... Q?r......... AMENDED under Section «f the Patents Act 1953 from ?£> I u[ oit. >V Af ASSISTANT COMMISSIONER^ OF PATENTS N.Z. No. NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION CHROMAN DERIVATIVES •. vi n r \ \4JUN\989 . { We, MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG, a German company of Frankfurter Strasse 250, D-6100 Darmstadt, Federal Republic of Germany, 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:- - 1 - (Followed by 1A) 4 20 25 IA Mlj.uK Pub—11 riilnnilti 221)540 Chroman derivatives The invention relates to new chroman derivatives of the formula I wherein X-Y is >cS:R8-, XZH-CO- or >CH-CHR8- and, if the 10 radical R5 is neither completely nor partially hydrogenated, also >CRA-CR3Ra- or > CH-CRa(OA) R1 is A, R2 and R8 are each H or A, R1 and R2 together are also alkylene having 3-6 C atoms, 15 R3 is OH or OAc, R" is H, R3 and R* together are also a bond, r5 is a pyridyl-oxy, pyridazinyl-oxy, pyrimidinyl-oxy, pyrazinyl-oxy, oxo-dihydro-pyridyl-oxy, oxo-dihydro-pyridaziriyl-oxy, oxo-dihydro-pyrimidinyl-oxy, oxo-dihydro-pyrazinyl-oxy, lH-2-pyridon-l-yl, lH-4-pyridon-l-yl, 1H-4-pyridazinon-l-yl, lH-6-pyridazinon-l-yl, 1H-2-, 1H-4- or lH-6-pyrimidinon-l-yl, 1H-2-pyrazinon-l-yl, 3H-2-pyrrolinon-l-yl, 5H-2-pyrrolinon-l-yl, lH-2-quinolon-l-yl, 2H-1-isoquinolon-2-yl, 2H-l-phthalazinon-2-yl, 3H-4-quinazolinon-3-yl or lH-2-thiopyridon-l-yl radical which is unsubstituted or monosubstitu-ted or disubstituted by A, F, CI, Br, I, OH, 30 OA, OAc, N02, NH2, AcNH, HOOC and/or AOOC, it being also possible for these radicals to be completely or partially hydrogenated, R6 and R7 are each H, A, HO, AO, CHO, ACO, ACS-s^HOgc, - 2 - 229540 AOOC, AO-CS/ ACOO, A-CS-O, hydroxyalkyl having 1-6 C atoms, mercaptoalkyl having 1-6 C atoms, N02/ NH2, NHA, NA2, CN, F, CI, Br, I, CF3/ ASO, AS02, AO-SO, A0-S02, AcNH, AO-CO-NH, H2NSO, 5 HANSO, A2NSO, H2NS02, HANS02, A2NS02, H2NCO, HANCO, A2NCO, H2NCS, HANCS, A2NCS, ASONH, AS02NH, AOSONH, A0S02NH, ACO-alkyl, nitroalkyl, cyano-alkyl, A-C(=NOH) or A-C(=NNH2) , R7 is also pyridyl, pyridazinyl, pyrimidinyl or 10 pyrazinyl, A is alkyl having 1-6 C atoms, alkyl is alkylene having 1-6 C atoms and Ac is alkanoyl having 1-8 C atoms or aroyl having 7-11 C atoms, 15 and to salts thereof. In particular, the invention relates to compounds of the above formula I wherein <D X-Y is >C-CRa-, >CH-CO- or >CH-CHR8 and, if R5 is a 1H-4-pyridon-l-yl, lH-4-pyridazinon-l-yl, lH-4-pyrimidinon-l-20 yl, lH-2-quinolon-l-yl, 2H-l-isoquinolon-2-yl, 2H-1-phthalazinon-2-yl or 3H-4-quinazolinon-3-yl radical which is unsubstituted or monosubstituted or disubstituted by A, F, CI, Br, I, OH, OA, OAc, N02, NH2, AcNH, HOOC and/or AOOC (it being also possible for these radicals to be 25 completely or partially hydrogenated) and/or if R7 is pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, X-Y is also >CR*-CR3R8-, or, if the radical R5 is neither completely nor partially hydrogenated, X-Y is also >CH-CRfl(OA)-. 30 Similar compounds are known from EP-A1 76,075 and EP-A1 173,848. The invention was based on the object of finding new compounds with valuable properties, especially compounds which can be used for the preparation of 35 medicaments. It has been found that the compounds of the formula (I) and their physiologically acceptable salts possess valuable pharmacological properties and a: 22 95 4 - 3 - tolerated. Thus they display an effect on the cardiovascular system, in which connection a selective attack on the coronary system can be observed as a rule at fairly low doses and a hypotensive effect on the coronary system 5 can be observed at fairly high doses. Effects occurring on the coronary system are, for example, reduction in resistance and increase in flow, while the effect on the heart rate remains low. The compounds also display a relaxing action on various smooth muscle organs (the 10 gastrointestinal tract, the respiratory system and the uterus). The effects of the compounds can be determined by means of methods known per se, such as are indicated, for example, in EP-A1 76,075, EP-A1 173,848 or AU-A 45,547/85 (Derwent Farmdoc No. 86,081,769) and by K.S. 15 Meesmann et al., Arzneimittelforschung 25. (11), 1975, 1770-1776. Examples of suitable experimental animals are mice, rats, guinea-pigs, dogs, cats, monkeys or pigs. The compounds can therefore be used as active compounds for medicaments in human and veterinary medi-20 cine. They can also be used as intermediate products for the preparation of further active compounds for medicaments . In the formulae indicated A is an alkyl group, preferably unbranched, which has 1-6, preferably 1-4 and 25 especially 1, 2 or 3, C atoms, specifically preferably methyl and also preferably ethyl, propyl, isopropyl, butyl and isobutyl, and also preferably sec.-butyl, tert.-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methylpentyl). 30 If R1 and R2 together are alkylene, the alkylene group is preferably unbranched and is specifically preferably -(CH2)n-, in which n is 3, 4, 5 or 6. The group "alkyl" is preferably -CH2- or -CH2CH2-. 35 Ac is preferably alkanoyl having 1-6, in par ticular 1, 2, 3 or 4, C atoms, specifically preferably formyl or acetyl and also preferably propionyl, butyryl, isobutyryl, pentanoyl or hexanoyl and also preferably benzoyl, o-, m- or p-toluyl, 1-naphthoyl or 2-naphthoyl. - 4 - 229540 20 The group X-Y is preferably >CR*-CR3R8-, specifically preferably >CH-CRa(0H)- or >C=CR0-, and particularly preferably >CH-CH0H- or >C=CH-; it is also preferably 0 /°\ 5 >9-CRa- (especially >C-CH-), >CH-C0-, >CH-CHR8- (especi ally CH-CH2-) or =CH-CRa(OA) - [in particular >CH-CH(OA)-]. R1 and R2 are preferably each alkyl, especially each, methyl or ethyl and preferably each methyl. 10 R3 and R* are preferably together a bond. If RA is H, R3 is preferably OH, O-CHO or 0-C,QCH3. R5 is preferably lH-2-pyridon-l-yl, 2-hydroxy-4-pyridyl-oxy or 6-hydroxy-3-pyridazinyl-oxy, furthermore 2-, 3- or 4-pyridyl-oxy, 3-hydroxy-lH-15 6-pyridazinon-l-yl or lH-4-hydroxy-2-pyridon-l-yl, and also preferably unsubstituted lH-2-pyrazinon-l-yl, 1H-6-pyridazinon-l-yl, 4,5-dihydro-lH-6-pyridazinon-l-yl, 1H- 2-pyrimidinon-l-yl,lH-6-pyrimidinon-l-yl, 3H-pyrrolinon-1-yl, 5H-pyrrolinon-l-yl or lH-2-thiopyridon-l-yl. R5 is also preferably unsubstituted lH-4-pyridon-l-yl, 1H-4-pyridazinon-l-yl, lH-4-pyrimidinon-l-yl, lH-2-quinolon- 1-yl, 2H-l-isoquinolon-2-yl, 2H-l-phthalazinon-2-yl or 3H-4-quinazolinon-3-yl. If R5 is a substituted pyridone or thiopyridone ring, this ring is preferably monosubstituted in the 3-, 4- or 5-position or disubstituted in the 3-position and the 5-position. Particularly preferred substituents are OH, N02 and NH2, and also AOOC, OA, CI, Br and NHCOCH3; particularly preferred substituted radicals R5 are specifically 4-hydroxy-, and also 3-, 5- and 6-hydroxy-, 3-, 4-, 5- or 6-methoxy-, 3-, 4-, 5- or 6-acetoxy-, 3-, 5- or 6-chloro-, 3-nitro- or 5-nitro-, 3-amino- or 5-amino-, 3-carboxy- or 5-carboxy-, 3-methoxy-carbonyl- or 5-methoxycarbonyl-, 3-ethoxycarbonyl- or 5-yfl f aTJ^ ethoxycarbonyl-, 3-acetamido- or 5-acetamido-, 3,5^. JJ * dichloro-, 3,5-dibromo-, 3-chloro-5-nitro-, 3-nitro-fi* - chloro-, 3-bromo-5-nitro-, 3-nitro-5-bromo-, 3,5-dinitrl L3 ' JANl99fl 3-chLoro-5-am.i.no-, 3-dm ina-5-chlorc-, 3-bromo-5-amirio-^^- . q 3-amino-5-bromo-, 3-chloro-5-acetamido-, 3-acetamido-5-chloro-, 3-bromo-5-acetamido- and 3-acetamido-5-bromo-lH- 2-pyridon-l-yl or -lH-2-thiopyridon-l-yl, 1H-4-hydroxy-40 6-pyridazinon-l-yl, lH-5-hydroxy-6-pyridazinon-l-yl, 1H- 25 30 - 5 - 22 9 5 4 0 3-, 1H-4- or lH-5-methoxy-6-pyridazinon-l-yl, 1H-3-, 1H- 4- or lH-5-ethoxycarbonyl-6-pyridazinon-l-yl, 1H-4-, 1H- 5- or lH-6-hydroxy-2-pyrimidinon-l-yl, 1H-2-hydroxy-6-pyrimidinon-l-yl or lH-4-hydroxy-6-pyrimidinon-l-yl. R5 can also preferably be: 3,4-dihydro-lH-2-pyridon-l-yl, 2,3-dihydro-6H-2-pyridon-l-yl, 5,6-dihydro-lH-2-pyridon-l-yl, 2-piperidinon-l-yl, 2,3-dihydro-lH-6-pyridazinon-l-yl, 1,2-dihydro-5H-6-pyridazinon-l-yl, 4,5-dihydro-lH-6-pyridazinon-l-yl, 2,3,4,5-tetrahydro-lH-6-pyridazinon-l-yl, 3,4-dihydro-lH-2-pyrimidinon-l-yl, 1,6-dihydro-3H-2-pyrimidinon-l-yl, 5,6-dihydro-lH-2-pyrimidi-non-l-yl, 3,4,5,6-tetrahydro-lH-2-pyrimidinon-l-yl, 2,3-dihydro-lH-6-pyrimidinon-l-yl, 1,2-dihydro-5H-6-pyrimidi-non-l-yl, 4,5-dihydro-lH-6-pyrimidinon-l-yl, 2,3,4,5-tetrahydro-lH-6-pyrimidinon-l-yl, 3,4-dihydro-lH-2-pyrazinon-l-yl, 1,6-dihydro-3H-2-pyrazinon-l-yl, 5,6-dihydro-lH-2-pyrazinon-l-yl, 3,4,5,6-tetrahydro-lH-2-pyrazinon-l-yl-2-pyrrolidinon-l-yl, 3,4-dihydro-lH-2-thiopyridon-l-yl, 2,3-dihydro-6H-2-thiopyridon-l-yl or 5,6-dihydro-lH-2-thiopyridon-l-yl. The symbols in R6 and R7 are preferably as follows s A: methyl, also ethyl; AO: methoxy, also ethoxy; ACO: acetyl, also propionyl; ACS: thioacetyl, also thiopropionyl; AOOC: methoxycarbonyl, also ethoxycarbonyl; AO-CS: methoxy-thiocarbonyl, also ethoxy-thiocar- bonyl; ACOO: acetoxy, also propionoxy; ACSO: thio(no)acetoxy, also thio(no)propionoxy; hydroxyalkyl: hydroxymethyl or 1-hydroxyethyl or 2- hydroxyethyl; mercaptoalkyl: mereaptomethyl or 1-mereaptoethyl or 2- mercaptoethyl; NHA: methylamino, also ethylamino; NA2: dimethylamino, also diethylamino; ASO: methylsulfinyl, also ethylsulfinyl; AS02: methylsulfonyl, also ethylsulfonyl; 22 9 5 4 0 - 6 - i 15 AO-SO: methoxy-sulfinyl, also ethoxy-sulfinyl; methoxy-sulfonyl, also ethoxy-sulfonyl; acetamido, also formamido, propionamido or benzamido; methoxycarbonylamino, also ethoxycar-bonylamino; methylaminosulfinyl, also ethylaminosul-f inyl dimethylaminosulfinyl, also diethylamino-10 sulfinyl; methylaminosulfonyl, also ethylaminosul-fonyl; dimethylaminosulfonyl, also diethylamino-sulfonyl; N-methylcarbamoyl, also N-ethylcarbamoyl; N,N-dimethylcarbamoyl, also N,N-diethyl-carbamoyl; N-methyl-thiocarbamoyl, also N-ethyl-thiocarbamoyl; N,N-dimethyl-thiocarbamoyl, also N,N-diethyl-thiocarbamoyl; methylsulfinylamino, also ethylsulfinyl-amino; methylsulfonylamino, also ethylsulfonyl-2 5 amino; methoxysulfinylamino, also ethoxysul-finylamino; methoxysulfonylamino, also ethoxysul-fonylamino; 30 ACO-alkyls 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3- oxopentyl; nitromethyl, 1-nitroethyl or 2-nitroethyl; cyanomethyl, 1-cyanoethyl or 2-cyanoethyl; 1-oximinoethyl, also 1-oximinopropyl; 35 A-C(= NNH2) : 1-hydrazonoethyl, also 1-hydrazonopropyl. The radical R7 can also be 2-, 3- or (preferably) 4-pyridyl, and also 3-pyridazinyl, 4-pyridazinyl, 2-, 4-or 5-pyrimidinyl or pyrazinyl. The radicals R6 and R7 are preferably in the 6- 20 A0-S02: Ac-NH; AO-CO-NH: HANSO: A2NS0 s HANS02: A2NS02: HANCO: A2N0C: HANCSs A2NCS s ASONH: AS02NH: AOSONHs A0S02NH: ACO-alkyls nitroalkyl: cyanoalkyl: A-C(= NOH): A-C(= NNHZ) : - 7 - 22 9 5 4 0 position and 7-position of the chroman system. They can, however, also be in the 5-position and 6-position, 5-position and 7-position, 5-position and 8-position, 6-position and 8-position and also the 7-position and 8-position. One of the radicals R6 and R7 is preferably H, while the other is different from H. This other radical is preferably in the 6-position, but is also in the 5-, 7- or 8-position, and is preferably CN or N02, and also preferably CHO, ACO (especially acetyl), AOOC (especially methoxycarbonyl or ethoxycarbonyl), ACOO (especially acetoxy), and also preferably F, CI, Br, I, CF3, H2NCO, H2NCS, NH2 or 4-pyridyl. The radical R8 is preferably H and also preferably methyl or ethyl. Accordingly, the invention relates particularly to compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following formulae la to Ii, which correspond to the formula I and in which the radicals not designated in detail have the meaning indicated in the formula I, but in which, however: R1 and R2 are each A; R1 and R2 are each CH3; R1 and R2 together are alkylene having 3-6 C atoms; R5 is lH-2-pyridon-l-yl, 2-pyrrolidinon-1-yl, 2-hydroxy-4-pyridyl-oxy or 6-hydroxy-3-pyridazinyl-oxy; R5 is 1H-2-pyridon-1-yl,2-hydroxy-4-pyridyl- oxy- or 6-hydroxy-3-pyridazinyl-oxy; R is 1H-2-pyridon-1-yl• -.1^2 R and R are each CH0 and 5 3 R is 1H-2 pyridon-1-yl, 2-pyrrolidinon-1-yl, 2-hydroxy-4-pyridyl-oxy or 6-hydroxy-3-pyridazinyl-oxy; in la in lb in Ic in Id in Ie in If in Ig - 8 - 22 9 5 4 0 in Ih R1 and R2 are each CH3 and R5 is lH-2-pyridon-l-yl, 2-hydroxy-4-pyridyl- oxy or 6-hydroxy-3-pyridazinyl-oxy; in Ii R1 and R2 are each CH3 and 5 R5 is lH-2-pyridon-l-yl. Further preferred compounds are those of the formulae I' and la' to Ii', which correspond to the formulae I and la to Ii, but in which in each case -X-Y-is additionally =C-CR8 (OH) -. 10 Further preferred compounds are those of the formulae I" and la" to Ii", which correspond to the formulae I and la to Ii, but in which in each case -X-Y- is additionally =C=CR8-. Further preferred compounds are those of the 15 formulae I, I', I'', la to Ii, la' to Ii' and la'' to Ii'' in which, additionally, in each case (a) R6 is different from hydrogen and R7 is H; (b) R6 is different from hydrogen and is in the 6-20 position and R7 is H; (c) R6 is N02, CN, CHO, ACO, HOOC, AOOC, ACOO, F, CI, Br, I, CF3, H2NCO, H2NCS or NH2 and R7 is H; 25 (d) R6 is N02, CN, CHO, ACO, HOOC, AOOC, ACOO, F, CI, Br, I, CF3, H2NCO, H2NCS or NH2 and is in the 6-position and R7 is H; (e) R6 is N02, CN, CHO, CH3C0, CH3OOC, C2H5OOC or CH3COO 30 and - 9 - 900540 R7 is H; (f) R6 is NO2, CN, CHO, CH3CO, CH3OOC, C2H5OOC or CH3COO and is in the 6-position and R7 is H; 5 (g) R6 is N02 or CN and R7 is H; (h) R6 is N02 or CN and is in the 6-position and R7 is H; (i) R6 is CN and 10 R7 is H; (j) R6 is CN and is in the 6-position and R7 is H. Compounds which are particularly preferred are those of the formulae I, I', I'', la to Ii, la' to Ii' 15 and la'' to Ii'' and those of the remaining groups of compounds characterized above as preferred in which Ra is additionally H. In other respects the radicals R1 to R8, A, "alkyl" and Ac have the meanings indicated in formula I 20 in the preceding and following text, unless anything to the contrary is expressly indicated. The invention also relates to a process for the preparation of chroman derivatives of the formula I, characterized in that, in order to prepare compounds of 25 the formula I wherein X-Y is >CR4-CR3Ra- or >CH-CHR8-, a 3,4-epoxychroman of the formula Ila or a chroman derivative of the formula lib Ila lib wherein E is CI, Br, I or a reactive esterified OH group and 30 R1, R2, R6, R7 and R8 have the meaning indicated ifnr-formula I, is reacted with a compound of the formula III - 10 - 221)540 r5-h iii wherein r5 has the meaning indicated in formula i or with a reactive derivative thereof, and/or a compound of the formula I wherein X-Y is >CH-CRs(0H)- is dehydrated or alkylated and/or a compound of the formula I wherein X-Y is >C=CR8- is epoxidized and/or A a compound of the formula I wherein X-Y is >C-CH- is isomerized into a compound of the formula I wherein X-Y is >CH-C0- by treatment with an acid catalyst and/or one or more of the radicals R3, R5, R6 and/or R7 in a compound of the formula I are converted into other radicals R3, R5, R6 and/or R7 and/or a basic compound of the formula I is converted into one of its acid addition salts by treatment with an acid. In other respects the compounds of the formula I are prepared by methods known per se, such as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie ("Methods of Organic Chemistry"), Georg-Thieme-Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., Mew York; and also in the patent applications indicated above), specifically under reaction conditions which are known and suitable for the reactions mentioned. In this connection it is also possible to make use of variants which are known per se but not mentioned here in detail. If desired, the starting materials can also be formed in situ by a process in which they are not isolated from the reaction mixture, but are immediately reacted further to give the compounds of the formula I. The compounds of the formula I are preferably prepared by reacting compounds of the formula Ila or lib with compounds of the formula III, preferably in the presence of an inert solvent at temperatures between about 0 and 150°. As a rule, the starting materials Ila, lib and III are known. Insofar as they are not known, they can be prepared by methods known per se. Thus the startinc /af 3 I JANI99J 229540 -11- materials of the formula Ila can be obtained by reacting 2-hydroxyacetophenones of the formula 2-HO-R6R7C6H2-COCH3 with ketones of the formula R1-CO-R2 to give corresponding 4-chromanones of the formula IVa 10 IVa -X-Y- = -C0-CH2-IVb -X-Y- = -CO-C(=CH-R9) -IVC -X-Y- = -CHOH-CHR8-IVd -X-Y- = -CH=CR8-IVe -X-Y- = -CHBr-CR8 (OH) - if appropriate, a condensation reaction with aldehydes of the formula R9-CHO (R9 = alkyl having 1-5 C atoms) to give 3-alkylidene-4-chromanones of the formula IVb, reduction, for example by means of NaBH4, to give 4-chromanols of 15 the formula IVc, dehydration, for example by means of p- toluenesulfonic acid, to give chromenes of the formula IVd and oxidation, for example by means of 3-chloroper-benzoic acid. The last-mentioned oxidation can also be carried out in several stages. Thus it is possible, for 20 example by means of N-bromosuccinimide in aqueous solution, first to prepare the bromohydrins of the formula Ve and then to eliminate HBr from these by means of a base, for example sodium hydroxide solution. The chromenes of the formula IVd can also be 25 obtained by a condensation reaction between salicylal-dehydes of the formula 2-HO-R6R7-C6H2-CHO and ketones of the formula R1-CO-CH2-R8 to give hydroxyketones of the formula 2-HO-R6R7C6H2-CH=CR8-CO-Rx, reacting the latter with organolithium compounds of the formula R2-Li and subse-30 quent hydrolysis to give diols of the formula 2-HO- R6R7C6H2-CH=CR8-CR1R2-OH and cyclization of the latter with the elimination of water. Starting materials of the formula Ila (R8=H) can also be obtained by reacting propargyl chlorides of the 35 formula HC^C-CR^-Cl with phenols of the formula R6R7C6H3OH to give phenol ethers of the formula - 12 - 22 95 4 0 R^CgHaO-CR^-OCH, cyclization of the latter to give 2H-chromenes corresponding to formula I, but in which the group -CH=CH- replaces the group -XR5-Y-, adding on HOBr to give the bromohydrin of the formula IVe (Re=H) and 5 dehydrobrominat ion. Suitable "reactive esterified OH groups" in the compounds of the formula lib are, in particular, esters with alkylsulfonic acids (wherein the alkyl group contains 1-6 C atoms) or with arylsulfonic acids (wherein 10 the aryl group contains 6-10 C atoms). Compounds of the formula lib can be obtained from the 4-chromanols of the formula IVc by reacting the latter with an inorganic acid halide, such as PC13, PBr3, S0C12 or S0Br2, or with a sulfonyl chloride, such as 15 methanesulfonyl or p-toluenesulfonyl chloride. Suitable reactive derivatives of III are the corresponding salts, for example the Na or K salts, which can also be formed in situ. Different products of formula I can be formed by the 20 reaction of II with III, dependent in particular from the structure of the starting materials and from the reaction conditions. For instance, the formation of compounds of formula I 5 containing an oxygen bridge (R = unsubstituted or sub-25 stituted pyridyl-oxy, pyridazinyl-oxy, pyrimidinyl-oxy, pyrazinyl-oxy, oxo-dihydro-pyridyl-oxy, oxo-dihydro-pyridazinyl-oxy, oxo-dihydro-pyrimidinyl-oxy or oxo-dihydro-pyrazinyl-oxy) is favored if the compound III contains at least one OH group as substituent in addition 30 to the lactame or lactime group and/or if the reaction is carried out under relatively mild conditions, f.e. in the presence of a weak base such as pyridine in an alcohol. 22 9 5 4 0 - 13 - For instance, from 2,2-dimethyl-3,4-epoxy-6-cyano-chromane ("lie") and 1H-2-pyridone with NaH in DMSO there are formed predominantly 2,2-dimethyl-4-(1H-2-pyridon-1-yl) 6-cyano-2H-chromene ("A") and 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-6-cyano-3-chromanol ("B"), whereas with pyridine in ethanol there is formed "B" together with a small amount of 2,2-dimethyl-4—(2-pyridyl—oxy)—6-cyano-3-chromanol. From 2,4-dihydroxypyridine (= 4-Hy-droxy-lH-2—rpyridone) and lie in pyridine/ethanol there are formed 2,2-dimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-cyano-3-chromanol together with a small amount of 2,2-dimethyl-4-(4-hydroxy-1H-2—pyridon-1-yl)-6-cyano-3-chromanol. In each single case optimal reaction conditions can be worked out easily. The reaction products can be separated and isolated without difficulties, f.e. by crystallization and/or chromatography. It is preferable to carry out the reaction in the presence of a base. Examples of suitable bases are alkali metal hydroxides, carbonates, alcoholates, hydrides or amides or alkaline earth metal hydroxides, carbonates, alcoholates, hydrides or amides, such as NaOH, KOH, Ca(0H)2, Na2C03, K2C03, Na methylate, ethylate or tert.-butylate, K methylate, ethylate or tert.-butylate, NaH, KH, CaH2, NaNH2 or KNH2, and also organic bases, such as triethylamine or pyridine, which can also be used in excess and then can at the same time act as the solvent. Suitable inert solvents are, in particular, alcohols, such as methanol, ethanol, isopropanol, n-butanol or tert.-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methylglycol or ethylglycol), ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; nitriles, such as acetonitrile; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate; amides, such as dimethylformamide (DMF), dimethylacetamide or hexamethylphosphoric tri- - 14 - 22 9 5 4 0' amide; sulfoxides, such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons, such as methylene dichloride, chloroform, trichloroethylene, 1,2-dichloroethane or carbon tetrachloride; or hydrocarbons, such as benzene, 5 toluene or xylene. Mixtures of these solvents with one another are also suitable. The epoxide II can also be prepared in situ, for example by the action of a base on the corresponding bromohydrin Ve. 10 A compound of the formula I wherein -X-Y- is =CH-CR8(OH)- can be converted into a compound of the formula I wherein -X-Y- is =CH=CR8- by treatment with a dehydrating agent. This is effected, for example, by the action of one of the bases indicated, for example NaOH, KOH or NaH, in 15 one of the solvents indicated, for example tetrahydrofuran, dioxane or DMSO, at temperatures between 0 and 150°. It is also possible to alkylate a compound of the formula I wherein -X-Y- is =CH-CR8(OH)-, when a 3-alkoxy compound of the formula I wherein -X-Y- is =CH-CR8(OA)-20 is formed. Alkylation is preferably carried out using corresponding alkyl halides or sulfonates of the formula A-E, for example A-Cl, A-Br, A-1, A-OSOaA or A-0S02aryl, such as methyl chloride, bromide, iodide, methanesul-fonate or benzenesulfonate, or using dialkyl sulfates of 25 the formula A^C^, for example dimethyl sulfate or diethyl sulfate, preferably in the presence of one of the inert solvents indicated, such as toluene or DMF, and/or in the presence of one of the bases indicated, such as K2C03 or K tert.-butylate, at temperatures between 0 and 120°. If 30 further OH groups are present in the molecule at the same time, these can also be alkylated at the same time. Compounds of the formula I wherein -X-Y- is =C=CR8- can be epoxidized, when epoxides of the formula I 0^ 35 wherein -X-Y- is =C-CR8- are formed. It is preferable to carry out epoxidation using a derivative of hydrogen peroxide, preferably a per-acid, such as perbenzoic acid or 3-chloroperbenzoic acid, in an inert solvent, such as methylene dichloride, at temperatures between 0 and 60°. - 15 - 220 Epoxides of the formula I wherein -X-Y- is 0 x/-CR8- can be converted into the isomeric ketones of the formula I wherein -X-Y- is >CH-CO- by treatment with acid catalysts, preferably with mineral acids, such as HC1, HBr or H2S04, in inert solvents, such as dioxane, at temperatures between 0 and 120°, It is also possible to convert one or more of the radicals R3, R5, R6 and/or R7 in a compound of the formula I into other radicals R3, R5, R6 and/or R7. For example, it is possible to replace an H atom by a halogen atom by means of halogenation or by a nitro group by means of nitration and/or to reduce a nitro group to an amino group and/or to alkylate or acylate an amino or hydroxyl group and/or to convert a cyano group (for example by means of HC1 in water/methanol at 20-100°) into a carboxyl group or (for example by means of Raney nickel in water/acetic acid/pyridine in the presence of sodium phosphate) into a formyl group or (for example by means of KOH in tert.-butanol) into a carbamoyl group or (for example by means of H2S in pyridine/ triethylamine) into a thiocarbamoyl group and/or to convert a substituted or unsubstituted lH-2-pyridon-l-yl radical (for example by means of P2S5 or by means of Lawesson reagent in toluene) into the corresponding 1H-2-thiopyridon-l-yl radical. Nitration can be carried out under customary conditions, for example using a mixture of concentrated HN03 and concentrated H2S04 at temperatures between 0 and 30°. If at least one of the substituents R6 and R7 is an electronegative group, such as CN or N02, the nitration takes place mainly on the radical R5; in other cases mixtures in which the nitro groups can be on the radical R5 or on the chroman ring are obtained as a rule. Analogous considerations apply to halogenation, which can be carried out, for example, by means of elementary chlorine or bromine in one of the customary inert solvents at temperatures between about 0 and 30°. A primary or secondary amino group and/or an - 16 - 22 9 5 4 0 group can be converted into the corresponding secondary or tertiary amino group and/or alkoxy group by treatment with alkylating agents. Examples of suitable alkylating agents are compounds of the formulae A-Cl, A-Br or A-I or 5 correspnding sulfuric acid or sulfonic acid esters, such as methyl chloride, bromide or iodide, dimethyl sulfate or methyl p-toluenesulfonate. It is also possible, for example, to introduce one or two methyl groups by means of formaldehyde in the presence of formic acid. The 10 alkylation is preferably carried out in the presence or absence of one of the inert solvents mentioned, for example DMF, at temperatures between about 0° and about 120°, and a catalyst can also be present, preferably a base, such as potasium tert.-butylate or NaH. 15 Suitable acylating agents for acylating amino or hydroxyl groups are preferably the halides (for example chlorides or bromides) or anhydrides of carboxylic acids of the formula Ac-OH, for example acetic anhydride, propionyl chloride, isobutyryl bromide, formic/acetic 20 anhydride or benzoyl chloride. It is possible to add a base, such as pyridine or triethylamine, in the course of the acylation. Acylation is preferably carried out in the presence or absence of an inert solvent, for example a hydrocarbon, such as toluene, a nitrile, such as aceto-25 nitrile, an amide, such as DMF, or an excess of a tertiary base, such as pyridine or triethylamine, at temperatures between about 0° and about 160°, preferably between 20° and 120°. It is also possible to carry out formylation using formic acid in the presence of pyri-30 dine. A base of the formula I can be converted into the appropriate acid addition salt by means of an acid. Acids suitable for this reaction are, in particular, those which afford physiologically acceptable salts. Thus it is 35 possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrogen halide acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, - 17 - 22 9 5 4 0 araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic or 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonico-tinic acid, methanesulfonic or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphtha-lenemonosulfonic and naphthalenedisulfonic acids and laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to purify the compounds of the formula I. The compounds of the formula I can have one or more chiral centres. They can therefore be obtained in the course of their preparation as racemates or, if optically active starting materials are used, also in an optically active form. If the compounds have two or more chiral centres, they can then be obtained in the course of the synthesis as mixtures of racemates from which the individual racemates can be isolated in a pure form, for example by recrystallization from inert solvents. Thus, for example, compounds of the formula I wherein R1 is R2, R3 is OH and R4 is H have two chiral centres; in the course of preparation by reacting Ila with III, however, only a racemate having the substituents R3 = OH and R5 in the trans-position is formed very predominantly. Resulting racemates can, if desired, be resolved into their enantiomers mechanically or chemically by methods known per se. Thus diastereomers can be formed from the race-mate by reacting the latter with an optically active resolving agent. Examples of suitable resolving agents for basic compounds of the formula I are optically active acids, such as the D-forms and L-forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, camphor-sulfonic acids, mandelic acid, malic acid or lactic acid. Carbinols (I, R3 = OH) can also be esterified by means of - 18 - 22 9 5 4 0 chiral acylating agents, for example D-a-methylbenzyl isocyanate or L-a-methylbenzyl isocyanate and can then be resolved (cf. EP-A1 120,428). The different forms of the diastereomers can be separated in a manner known per se, for example by fractional crystallization, and the enantiomers of the formula I can be liberated from the diastereomers in a manner known per se. Resolution of enantiomers is also possible by means of chromatography on optically active supporting materials. The compounds of the formula I and physiologically acceptable salts thereof can be used for the production of pharmaceutical formulations, particularly by a non-chemical route. In this regard they can be brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, if appropriate, in combination with one or more further active compounds. The invention—also relates to agents^in particular pharmaceutical formulations, containing at least one compound of the formula I and/or a physiologically acceptable salt thereof. These formulations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral) or parenteral administration or for topical application and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc, lanolin or petroleum jelly. Tablets, coated tablets, capsules, syrups, elixirs or drops are employed, in particular, for oral use, suppositories are employed for rectal use, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants are employed for parenteral use and ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example in alcohols, such as ethanol or isopropanol, acetonitrile, DMF, dimethyl-acetamide, 1,2-propanediol or mixtures thereof with one 22954 - 19 - another or with water) or powders are employed for topical use. The new compounds can also be lyophilized and the resulting lyophilizates can be used, for example, for the preparation of injection preparations. Liposomal formulations are also suitable, particularly for topical use. The formulations indicated can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and flavourings and/or aroma substances. They can, if desired, also contain one or more further active compounds, for example one or more vitamins. The compounds of the formula I and physiologically acceptable salts thereof can be administered to humans or animals, in particular mammals, such as monkeys, dogs, cats, rats or mice, and can be used in the therapeutic treatment of the human or animal body and also in combating diseases, in particular in the therapy and/or prophylaxis of disorders of the cardiovascular system, in particular decompensated cardiac insufficiency, angina pectoris, arrhythmia, peripheral or cerebral vascular diseases and also illness states associated with high blood pressure and also diseases associated with changes in the non-vascular muscular system, for example asthma or incontinence of the bladder. In this regard the substances according to the invention are, as a rule, administered analogously to known anti-angina agents or hypotensive agents, for example nicorandil or cromakalim, preferably in dosages between about 0.01 and 5 mg, in particular between 0.02 and 0.5 mg, per dosage unit. The daily dose is preferably between about 0.0001 and 0.1, in particular between 0.0003 and 0.01 mg/kg of body weight. The particular dose for each intended patient depends, however, on a wide variety of factors, for example on the effectiveness of the particular compound employed, on the age, body weight, the general state of health and the sex, on the diet, on the time and route of administration and on the 22954 - 20 - speed of excretion, the combination of medicaments and the severity of the particular disease for which the therapy is used. Oral administration is preferred. The compounds of the formula I and their salts are also suitable, particularly in the case of topical use, for the treatment of alopecia, including androgenic alopecia and Alopecia areata. The pharmaceutical formulations used especially for this purpose are those which are suitable for topical treatment of the scalp and which are mentioned above. They contain about 0.005 to 10, preferably 0.5 to 3, % by weight of at least one compound of the formula I and/or at least one of its salts. In other respects these compounds can be used against alopecia analogously to the instructions in WO 88/00822. In the following examples "customary working up" means as follows: If necessary, water is added, the mixture is extracted with an organic solvent, such as ethyl acetate, the phases are separated and the organic phase is dried over sodium sulfate, filtered and evaporated and the product is purified by chromatography and/or crystallization. In the preceding and following text all temperatures are quoted in °C. Example 1 A mixture of 21.5 g of 2,2,3-trimethyl-3,4- epoxy-6-cyanochroman, 9.5 g of 1H-2-pyridone ("pyri-done"), 3 g of an 80% dispersion of NaH in paraffin oil and 600 ml of DMSO is stirred for 16 hours at 20°, poured into water and extracted with ethyl acetate. The extract is evaporated and the residue is chromatographed over silica gel. 2,2,3-Trimethyl-4-(lH-2-pyridon-l-yl)-6-cyano-2H-chromene (m.p. 212°) is eluted with methylene dichloride and then 2,2,3-trimethyl-4-(lH-2-pyridon-l-yl)-6-cyano-chroman-3-ol (m.p. 185-186°) is eluted with ethyl acetate. Preparation of the starting material: (a) A mixture of 81 g of 3-acetyl-4-hydroxybenzonitrile, 48 ml of acetone, 11.8 ml of pyrrolidine and 300 ml - 21 - 229540 of toluene is allowed to stand for 1 hour at 20° and is then boiled under a water separator for 2 hours and cooled. Customary working up gives 2,2-dimethyl-6-cyano-4-chromanone/ m.p. 119-120°. (b) A solution of 24 g of the chromanone, 12 g of paraformaldehyde and 24 ml of piperidine in 300 ml of ethanol is heated at 70° for 3 hours and is evaporated. The residue is taken up in 1:1 methylene dichloride/petroleum ether and the solution is filtered through silica gel and the filtrate is evaporated to give 2,2-dimethyl-3-methylene-6-cyano-4-chromanone as an unstable oil. (c) 6 g of NaBH4 are added to a solution of 25 g of the above chromanone in 500 ml of methanol, and the mixture is stirred for 1 hour at 20° and evaporated. Customary working up gives 2,2,3-trimethyl-6-cyano-4-chromanol, mixture of isomers, oily. (d) A solution of 27 g of the above mixture and 1.2 g of p-toluenesulfonic acid in 400 ml of toluene is boiled under a water separator for 3 hours. The mixture is evaporated, the residue is dissolved in 1:1 methylene dichloride/petroleum ether, the solution is filtered through silica gel and the filtrate is evaporated again to give 2,2,3-tri-methyl-6-cyano-2H-chromene, m.p. 55°. (e) A solution of 6.4 g of m-chloroperbenzoic acid in 40 ml of methylene dichloride is added dropwise, with stirring, to a solution of 6.8 g of the above chromene in 100 ml of methylene dichloride. The mixture is stirred for a further 16 hours and filtered, dilute sodium hydroxide solution is added and the mixture is worked up in the customary manner to give 2,2,3-trimethyl-3,4-epoxy-6-cyano-chroman, m.p. 118°- The following are obtained analogously 2,2-dimethyl-4-(lH-2-pyridon-l-yl)-6-cyano-2H-chromene ("A"), m.p. 146-148° 2,2-dimethyl-4-(lH-2-pyridon-l-yl)-6-cyano-3-chromanol ("B"), m.p. 224° - 22 - 22954 2 ,2-dimethyl-4- (lH-5-chloro-2-pyridon-l-yl) -6-cyano-2H-chromene, m.p. 185-188° 2,2-dimethyl-4-(lH-5-chloro-2-pyridon-l-yl)-6-cyano-3-chromanol, m.p. 268-270° 5 2,2-dimethyl-4-(lH-3-hydroxy-2-pyridon-l-yl)-6-cyano-2H- chromene 2 ,2-dimethyl-4- (lH-3-hydroxy-2-pyridon-l-yl) -6-cyano-3-chromanol, m.p. 262-265° 2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-y1)-6-cyano-2H-10 chromene 2 ,2 -dimethyl-4 - (1H-4 -hydroxy-2 -pyridon- 1-yl) -6-cyano-3-chromanol, m.p. 256 - 25 7° 2,2-dimethyl-4-(lH-5-hydroxy-2-pyridon-l-yl)-6-cyano-2H-chromene 15 2 ,2-dimethyl-4- (1H-5-hydroxy-2-pyridon-1-yl) -6-cyano-3 chromanol, m.p. 256.5-258° 2,2-dimethyl-4-(1H-3-methoxy-2-pyridon-1-yl)-6-cyano-2H chromene 2 ,2-dimethyl-4- (lH-3-methoxy-2-pyridon-l-yl) -6-cyano-3 20 chromanol, m.p. 245-248° 2,2-dimethyl-4-(lH-3-acetoxy-2-pyridon-l-yl)-6-cyano-2H chromene 2 ,2-dimethyl-4- (lH-3-acetoxy-2-pyridon-l-yl) -6-cyano-3 chromanol, m.p. 260-263° 25 2,2-dimethyl-4-(lH-3-nitro-2-pyridon-l-yl)-6-cyano-2H chromene, m.p. 148-150° 2,2-dimethyl-4- (lH-3-nitro-2-pyridon-l-yl) -6-cyano-3 chromanol, m.p. 240-242° 2,2-dimethyl-4-(lH-5-nitro-2-pyridon-l-yl)-6-cyano-2H 30 chromene, m.p. 214-216° 2 ,2-dimethyl-4- (lH-5-nitro-2-pyridon-l-yl) -6-cyano-3 chromanol, m.p. 249-251° 2,2-dimethyl-4-(lH-3-amino-2-pyridon-l-yl)-6-cyano-2H chromene 35 2 ,2-dimethyl-4- (lH-3-amino-2-pyridon-l-yl) -6-cyano-3 chromanol, m.p. 213-215° 2,2-dimethyl-4-(lH-5-amino-2-pyridon-1-yl)-6-cyano-2H chromene, m.p. 180° 2,2-dimethyl-4-(lH-5-amino-2-pyridon-l-yl) -6-cyano-3 22 9 5 4 0 - 23 - chromanol, m.p. 260-264° 2, 2-dimethyl-4- (1H-2-pyridon-1-yl) -6-nitro-2H-chromene, m.p. 158° 2 , 2-dimethyl-4- (lH-2-pyridon-l-yl)-6-nitro-3-chromanol, 5 m.p. 229-231° 2,2-dimethyl-4-(1H-2-pyridon-1-y1)-6-acetyl-2H-chromene, m.p. 148-150° 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-6-acetyl-3-chromanol, m.p. 257-269° 10 2/2-dimethyl-4-(lH-2-pyridon-l-yl)-6-methoxycarbonyl-2H- chromene, m.p. 126-127° 2, 2-dimethyl-4- (lH-2-pyridon-l-yl)-6-methoxycarbonyl-3-chromanol, m.p. 267-267.5° 2, 2-dimethyl-4- (1H-2-pyridon-1 -yl) -6-ethoxycarbonyl-2H-15 chromene, 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-6-ethoxycarbonyl-3-chromanol, m.p. 213° 2 , 2-tetramethylene-4-(lH-2-pyridon-l-yl)-6-cyano-2H-chromene, m.p. 181-183° 20 2,2-tetramethylene-4-(lH-2-pyridon-l-yl)-6-cyano-3- chromanol, m.p. 227-230° 2 , 2-pentamethylene-4-(lH-2-pyridon-l-yl)-6-cyano-2H-chromene, m.p. 202-204° 2 , 2-pentamethylene-4-(lH-2-pyridon-l-yl)-6-cyano-2H-25 chromanol, m.p. 240-242° 2,2-dimethyl-4-(lH-2-pyridazinon-l-yl)-6-cyano-2H-chromene, m.p. 136-138° 2,2-dimethyl-4-(lH-2-pyridazinon-l-yl)-6-cyano-3-chroma-nol, m.p. 216-218° 30 2,2-dimethyl-4-(4,5-dihydro-lH-6-pyridazinon-l-yl) -6-cyano-2H-chromene 2,2-dimethyl-4- (4,5-dihydro-lH-6-pyridazinon-l-yl) -6-^ cyano-3-chromanol, m.p. 163-164.5° 2,2-dimethyl-4-(1H-3-ethoxycarbonyl-6-pyridazinon-l-yl)-35 6-cyano-2H-chromene 22 9 5 4 0 - 24 - 2,2-dimethyl-4-(lH-3-ethoxycarbonyl-6-pyridazinon-l-yl)-6-cyano-3-chromanol, m.p. 259-260.5° 2,2-dimethyl-4-(lH-2-pyrimidinon-l-yl)-6-cyano-2H-chrom-ene 5 2,2-dimethyl-4-(lH-2-pyrimidinon-l-yl)-6-cyano-3-chroman- ol/ m.p. 250-252° 2,2-dimethyl-4- (lH-4-hydroxy-2-pyrimidinon-l-yl) -6-cyano-2H-chromene, m.p. 278-279.5° 2,2-dimethyl-4- (lH-4-hydroxy-2-pyrimidinon-l-yl) -6-cyano-10 3-chromanol, no m. p. below 300° 2,2-dimethyl-4-(lH-6-pyrimidinon-l-yl)-6-cyano-2H-chrom-ene 2,2-dimethyl-4- (lH-6-pyrimidinon-l-yl) -6-cyano-3-chroman-ol/ m.p. 207-208° 15 2,2, 3-trimethyl-4- (1H-2-pyridon-1-yl) -6-cyano-2H-chrom ene , m.p. 200° 2,2,3-trimethyl-4- (1H-2-pyr idon-1-yl) -6-cyano-3-chromanol 2,2, 3-trimethyl-4- ( 2-pyrrolidon-1-yl) -6-cyano-2H-chrom-ene, m.p. 186° 20 2,2,3-trimethyl-4- (2-pyrrolidon-l-yl) -6-cyano-3-chromanol 2 , 2-dimethyl-4-(2-pyrrolidon-l-yl)-6-(4-pyridyl)-2H-chromene 2,2-dimethyl-4-(2-pyrrolidon-l-yl)-6-(4-pyridyl)-3-chromanol, m.p. 238-239° 25 2 ,2-dimethyl-3-ethyl-4-(1H-2-pyridon-1-yl) -6-cyano-2-H- chromene 2 ,2-dimethyl-3-ethyl-4- (lH-2-pyridon-l-yl) -6-cyano-3-chromanol. Example 2 30 A mixture of 20.1 g of lie, 11.2 g of 3,6-pyrida zinediol, 12 ml of pyridine and 600 ml of ethanol is boiled for 72 hours. About 300 ml are distilled off and the residue is cooled and unreacted 3,6-pyridazinediol is filtered off and the filtrate is evaporated. The result- 35 ing 2,2-dimethyl-4-(6-hydroxy-3— pyridazinyloxy)- - 25 - 22 95 4 0 6-cyano-3-chromanol is recrystallized from isopropanol, m.p. 255-256°. In addition, a small amount of 2,2-dimethyl-4-(3-hydroxy-1H-6-pyridazinon-1-yl)-6-cyano-3-chromanol is formed, m.p. 260-262°. The following are obtained analogously using the corresponding compounds of the formula R5-H: 2,2 -dimethyl - 4 - (1H-4 -pyr idon- 1-yl) -6 -cyano- 3 -chromanol, m.p. 301° 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-cyano-3-chromanol, m.p. 249-249.5° (from ethanol; in addition, a small amount of 2,2-dimethyl-4-(4-hydroxy-1H-2-pyridon-1-yl)-6-cyano-3-chromanol is formed, m.p. 256-257°, from acetone) 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-nitro-3-chromanol, m.p. 224-226° 2 ,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-acetoxy-3-chromanol, m.p. 251 -—252° 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-thiocar-bamoyl-3-chromanol, m.p. 242° 2,2-dimethyl-4-(1H-3,5-dichloro-4-pyridon-l-yl)-6-cyano-3-chromanol, m.p. > 250° 2,2-dimethyl-4- (IH-2-methoxy-4-pyridon-1-yl) -6-cyano-3-chromanol, m.p. 200-202° 2,2-dimethyl-4- (1H-4-pyr imidinon-1-yl) -6-cyano-3-chroman-ol, m.p. 308-310° 2 / 2—dimethyl—4— (2H—1—isocjuinolon—2—yl) —6—cyano—3—chromanol, m.p. 135° 2,2-dimethyl-4- (2H-l-phthalazinon-2-yl) -6-cyano-3-chromanol, m.p. 205° 2 , 2-dimethyl-4-(IH-2-pyridon-1-yl)-6-(4-pyridyl)-3-chromanol, m.p. 216-218°. 2,2,3-trimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-cyano-3-chromanol, m.p. 240°. 20 - 26 - 22 9 5^) 9 5 4 Example 3 1.2 g of 80% NaH are added to a solution of 2.66 g of 2,2-dimethyl-4-bromo-6-cyano-chroman (m.p. 89-92°; obtainable by reducing 2,2-dimethyl-6-cyano-4-chromanone 5 with NaBH4 in CH30H to give oily 2,2-dimethyl-6-cyano-4- chromanol and reacting the latter with PBr3 in toluene at 20°) and 2 g of lH-2-pyridone in 70 ml of dimethyl sulfoxide, and the mixture is stirred for 3 days at 20°. Customary working up gives 2,2-dimethyl-4-(lH-2-pyridon-10 1-yl)-6-cyano-chroman, m.p. 159°. The following are obtained analogously using the corresponding compounds of the formula R5-H: 2,2-dimethyl-4-(lH-4-pyridon-l-yl)-6-cyano-chroman, m.p. 141-142° (with 4-hydroxypyridine = 1H-4-pyridone) 15 2,2-dimethyl-4-( 6-hydroxy-3-pyridazinyloxy)-6-cyano- chroman, m.p. 221-224° (with 3,6-pyridazinediol = 3-hydroxy-1H-6-pyridazinone). Example 4 A mixture of 10 g of "B", 3 g of sodium hydroxide and 350 ml of dioxane is boiled for 20 minutes. The mixture is cooled and filtered; evaporating the filtrate gives "A", m.p. 146-148°. The corresponding 3-hydroxychromans are obtained analogously by dehydration: 25 2,2, 3-trimethyl-4- (lH-2-pyridon-l-yl) -6-cyano-2H-chrom- ene, m.p. 212° 2,2-dimethyl-4-(lH-4-pyridon-l-yl)-6-cyano-2H-chromene, . m.p. 211° 2,2-dimethy1-4-(1H-3,5-dichloro-4-pyridon-l-yl)-6-cyano-30 2H-chromene, m.p. 298-299° 2 , 2-dimethyl-4- (2H-l-isoquinolon-2-yl )-6-cyano-2H-chro-mene, m.p. 171-172° 2 , 2-dimethyl-4-(lH-2-pyridon-l-yl)-6-(4-pyridyl)-2H-chromene, m.p. 175-176°. 22 9 5 4 9 27 - Example 5 9.5 g of K2C03 and 6 ml of dimethyl sulfate are added to a solution of 3.13 g of 2,2-dimethyl-4-(1H-3-hydroxy-6-pyridazinon-l-yl)-6-cyano-chroman-3-ol in 160 5 ml of DMF, the mixture is stirred for 16 hours and poured onto ice and worked up in the customary manner to give 2,2-dimethyl-3-methoxy-4-( lH-3-methoxy-6-pyridazinon-l-yl)-6-cyano-chroman, m.p. 190-192°. The following is obtained analogously 10 2,2-dimethyl-3-methoxy-4- (lH-2-pyridon-l-yl) -6-cyano- chroman. m.p. 169-171°. Example 6 A solution of 0.5 g of 3-chlorperbenzoic acid in 5 ml of methylene dichloride is added dropwise at 20° and 15 with stirring, to a solution of 298 mg of 2,2-dimethyl- 4-(lH-2-pyridon-l-yl)-6-nitro-2H-chromene in 8 ml of methylene dichloride, the mixture is stirred for 16 hours at 20°, a further 0.5 g of 3-chloroperbenzoic acid in 5 ml of methylene dichloride is added, stirring is con- 2° tinued for a further 2 days, the mixture is filtered and the filtrate is worked up in the customary manner to give 2, 2-dimethyl-3, 4-epoxy-4- (IH-2-pyridon-1-yl) -6-nitro-chroman, m.p. 130-132°. The following are obtained analogously by 25 epoxidation of the corresponding chromenes: 2,2-dimethyl-3,4-epoxy-4- (lH-2-pyridon-l-yl) -6-cyano-chroman, m.p. 130-131° 2,2-dimethyl-3,4-epoxy-4-(IH-2-pyridon-1-yl) -6-carbamoyl-chroman, m.p. 162-164° 30 2,2-dimethyl-3 ,4-epoxy-4-(IH-2-pyridon-1-yl) -6-acetoxy- chroman. 22 9 5 4 0 - 28 - Example 7 HCl is passed into a boiling solution of 12.5 g of 2,2-dimethyl-3,4-epoxy-4-(IH-2-pyridon-1-yl)-6-cyano-chroman in 100 ml of dioxane for 45 minutes, the mixture 5 is cooled and the precipitated 2,2-dimethyl-4-(1H-2- pyridon-l-yl)-6-cyano-3-chromanone is filtered off and washed with dioxane and then with ether, m.p. 188-190°. The following are obtained analogously by isomer-ization of the corresponding epoxides: 10 2,2-dimethyl-4-(lH-2-pyridon-l-yl)-6-nitro-3-chromanone 2 ,2-dimethyl-4- (1H-2-pyridon-1-yl) -6-carbamoyl-3-chroman-one 2,2-dimethyl-4-(lH-2-pyridon-l-yl) -6-acetoxy-3-chroman-one, m.p. 137-139°. 15 Example 8 A mixture of 2 g of "B", 11.7 ml of formic acid and 3.3 ml of acetic anhydride is allowed to stand for 16 hours at 20° and is then heated at 40-42° for 2 hours. Evaporation and customary working up gives 2,2-dimethyl-20 3-formyloxy-4-(lH-2-pyridon-l-yl)-6-cyano-chroman, m.p. 203.5-204°. Example 9 A mixture of 1 g of "B" and 5 ml of acetic anhydride is boiled for 1 hour. The mixture is cooled and 25 worked up in the customary manner to give 2,2-dimethyl-3-acetoxy-4-(IH-2-pyridon-1-yl)-6-cyano-chroman, m.p. 228-228.5°. 22 95 40 I - 29 - Example 10 2.96 g of "B" are suspended in 100 ml of water and 3.2 g of bromine are added dropwise at 10-20% with stirring. The substance dissolves and 2,2-dimethyl-4-(1H-3,5-dibromo-2-pyridon-l-yl)-6-cyano-chroman-3-ol is precipitated and is filtered off, m.p. 207-209°. Example 11 2.78 g of "A" are dissolved in a mixture of 10 ml of concentrated nitric acid (68%; density 1.41) and 12 ml of concentrated sulfuric acid, the mixture is stirred for 3 hours at 20° and poured onto ice; filtering off the product and washing it with water gives a mixture of 2,2-dimethyl-4-(lH-3-nitro-pyridon-l-yl)-6-cyano-2H-chromene and 2,2-dimethyl-4-(lH-5-nitro-pyridon-l-yl)-6-cyano-2H-chromene, which can be separated by chromatography. Example 12 A solution of 1 g of 2,2,3-trimethyl-4-(1H-3-nitro-2-pyridon-l-yl)-6-methoxycarbonyl-chroman-3-ol in 25 ml of methanol is hydrogenated at 20° and under 1 bar over 0.5 g of 5% Pd-C until absorption ceases. The mixture is filtered and the filtrate is evaporated to give 2,2,3-trimethyl-4-(lH-3-amino-2-pyridon-l-yl)-6-methoxycarbonyl-chroman-3-ol. Example 13 A solution of 1 g of 2,2,3-trimethyl-4-(1H-3-amino-2-pyridon-l-yl)-6-cyano-2H-chromene in 15 ml of HCOOH and 1 ml of pyridine is boiled for 19 hours and evaporated. Customary working up gives 2,2,3-trimethyl-4-(lH-3-formamido-2-pyridon-l-yl)-6-cyano-2H-chromene. Example 14 A mixture of 1 g of 2,2,3-trimethyl-4-(lH-5-amino-2-pyridon-l-yl)-6-cyano-2H-chromene, 10 ml of acetic anhydride and 10 ml of pyridine is allowed to stand at 20° for 16 hours. The mixture is evaporated and purification of the residue by chromatography gives 2,2,3-trimethyl-4-(lH-5-acetamido-2-pyridon-l-yl)-6-cyano-2H-chromene. Example 15 HCl is passed into a boiling solution of 1 g of - 30 - 119 5 4 0 "A" in 50 ml of methanol and 2 ml of water for 14 hours, with stirring. The mixture is allowed to cool and to stand overnight. The precipitated 2,2-dimethyl-4-(lH-2-pyridon-l-yl)-2H-chromene-6-carboxylic acid is filtered 5 off, m.p. 281-284°. Example 16 A mixture of 2.78 g of "A", 31 g of Na3P04.12 H20, 28 ml of pyridine, 28 ml of water, 67 ml of acetic acid and 25 g of Raney Ni (water-moist) is stirred for 3 hours 10 at 20°. The mixture is filtered and customary working up gives 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-6-formyl-2H-chromene, m.p. 160-162°. Example 17 2.78 g of "A" are dissolved in 40 ml of tert.-15 butanol, and 5.6 g of powdered KOH are added, with stirring. Boiling for 1 hour and customary working up gives 2,2-dimethyl-4-(lH-2-pyridon-l-yl)-6-carbamoyl-2H-chromene . Example 18 20 H2S is passed into a solution of 2.78 g of "A" in a mixture of 20 ml of pyridine and 10 ml of triethylamine at 20° for 5 hours, the mixture is evaporated and the residue is worked up in the customary manner to give 2,2-dimethyl-4-(lH-2-pyridon-l-yl)-6-thiocarbamoyl-2H-chrom-25 ene, m.p. 254-257°. Example 19 A mixture of 310 mg of "B", 808 mg of Lawesson reagent and 50 ml of toluene is boiled under N2 for 1 hour. Customary working up gives 2,2-dimethyl-4-(1H-2-30 thiopyridon-1-yl)-6-cyano-chroman-3-ol. 2 , 2-Dimethyl-4- (lH-2-thiopyridon-l-yl) -6-cyano-2H-chromene is obtained analogously from "A". The following examples relate to pharmaceutical formulations containing compounds of the formula I or 35 physiologically acceptable salts thereof: Example A Tablets A mixture of 1 kg of 2,2-dimethyl-4-(lH-2-pyri-don-l-yl)-6-cyano-2H-chromene ("A"), 400 kg of lactose, 120 kg of potato starch, 20 kg of talc and 10 kg of </div>

Claims

<div id="claims" class="application article clearfix printTableText"> 22 9 5 4 0 - 31 - magnesium stearate is compressed in a customary manner to give tablets so that each tablet contains 0.1 mg of active compound. Example B Coated tablets 5 Tablets are compressed analogously to Example A and are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and dyestuff. Example C Capsules 1 kg of 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyloxy) 10 6-cyano-3-chromanol ("B") is filled into hard gelatine capsules in a customary manner so that each capsule contains 0.5 mg of active compound. Example D Ampoules A solution of 100 g of 2,2-dimethyl-4-(6-15 hydroxy-3-pyridazinyloxy)-6-cyano-3-chromanol in 2,000 1 of twice-distilled water is filtered under sterile conditions and filled into ampoules. Each ampoule contains 0.1 mg of active compound. Tablets, coated tablets, capsules or ampoules 20 containing one or more of the other active compounds of the formula I and/or physiologically acceptable salts thereof can be obtained analogously. Example E Solution for topical application (against alopecia) 25 500 g of "A" (or "B") are dissolved in a mixture of 5.2 kg of 1,2-propanediol and 15 1 of ethanol, and the mixture is made up to 25 1 with ethanol, filtered under sterile conditions and filled into bottles. Example F Gel 30 0.45 g of Carbopol 934 P (= carboxyvinyl polymer) is mixed with 40 ml of twice-distilled water and 27 ml of ethanol, a solution of 0.5 g of "A" (or "B") and 0.45 g of diisopropanolamine in 10 ml of 1,2-propanediol and 13 ml of ethanol is added and mixed thoroughly, and the 35 mixture is made up to 100 ml with water and again mixed thoroughly. The resulting gel contains 0.5% by weight of active compound. - X - 7 29540 \ liMNMataiiMtMUMMt <iQQ B a ■ m a ii a n t. WHAT//WE CLAIM IS:

1. Chroman derivatives of the formula I .5 R6 I wherein 0V 1 \ a a X-Y is >C-CR8-, >CH-C0- or >CH-CHR0- and, if the radical R5 is neither completely nor partially hydrogenated, also >CR4-CR3R8- or >CH-CRa(0A)-, R1 is A, R2 and R8 are each H or A, R1 and R2 together are also alkylene having 3-6 C atoms, R3 is OH or OAc, R4 is H, R3 and R4 together are also a bond, R5 a pyridyl-oxy, pyridazinyl-oxy, pyrimidinyl-oxy, pyrazinyl-oxy, oxo-dihydro-pyridyl-oxy, oxo-dihydro-pyridazinyl-oxy, oxo-dihydro-pyrimidinyl-oxy, oxo-dihydro-pyrazinyl-oxy, 1H-2-pyridon-1-yl, lH-4-pyridon-l-yl, 1H- 4-pyridazinon-l-yl, IH-6-pyridazinon-l-yl, 1H-2-, 1H-4- or IH-6-pyr imidinon-1-yl, 1H-2-pyrazinon-l-yl, 3H-2-pyrrolinon-l-yl, 5H-2-pyrrolinon-l-yl, lH-2-quinolon-l-yl, 2H-1-isoquinolon-2-yl, 2H-l-phthalazinon-2-yl, 3H-4-quinazolinon-3-yl or lH-2-thiopyridon-l-yl radical which is unsubstituted or monosubstitu-ted or disubstituted by A, F, CI, Br, I, OH, OA, OAc, N02, NH2, AcNH, HOOC and/or AOOC, it being also possible for these radicals to be completely or partially hydrogenated, - X - NOW AMENDED 229540 and R7 are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO-CS, ACOO, A-CS-O, hydroxya'lkyl having 1-6 C atoms, mercaptoalkyl having/l-6 C atoms, N02, NH2, NHA, NAa, CN, F, CI, B/, I, CF3, ASO, AS02, AO-SO, A0-S02f ACNH, AO-CO-NH, H2NSO, HANSO, A2NSO, H2NS02, HANSOj7, A2NS02, H2NCO, HANCO, AjNCO, H2NCS, HANCS, A2'NCS, ASONH, AS02NH, AOSONH, A0S02NH, ACO-alkyl,/ nitroalkyl, cyano-alkyl, A-C(=NOH) or A-C(=NNH2), is also pyridyl, pyridazinyl, pyrimidinyl or A alkyl Ac pyrazinyl, / is alkyl having 1-6 G atoms, is alkylene having ,j!-6 C atoms and'' is alkanoyl having 1-8 C atoms or aroyl having 7-11 C atoms, and salts thereof.

2. Compounds of th^e' formula I acp ording to Claim 1 wherein - and, if R is a 1H- P\ 8 / X-y is >C-CR -, yZHjCO- or >CH-CHR 4-pyridon-1-yl, lH-/4-pyridazinon-l-yl, lH-4-pyrimidinon-1-yl, lH-2-quinolon-l-yl, 2H-l7-/xsoquinolon-2-yl, 2H-1-phtJialazinon-2-yl or 3H-4-quinazolinon-3-yl radical which i^s unsubstituted or monosubstituted or disubstituted by A, F, CI, Bif/l, OH, OA, OAcf, N02, NH2, AcNH, HOOC and/or AOOC (it being also possible for these radicals to be completely/ or partiallyyhydrogenated) and/or if R7 is pyridyl,/pyridazinyl, pyrimidinyl or pyrazinyl, X-Y is also >^R*-CR3R8-, or, ttt the radical R5 is neither completely nor partially hydrogenated, X-Y is also >CH-C*Ra (OA) -. '_'f_ 229540 AS AMENDED R8 and R' are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO-CS, ACOO, A-CS-O, hydroxyalkyl having 1-6 C atoms, mercaptoalkyl having 1-6 C atoms, N02, NH2, NHA, NAa, CN, p, CI, Br, I, CF3, ASO, AS02/ AO-SO, A0-S02, AcNH, AO-CO-NH, H2NSO, HANSO, AjNSO, H2NS02, HANS02, AjjNSO^ HjNCO, HANCO, A^NCO, H2NCS, HANCS, A^NCS, ASONH, AS02NH, AOSONH, A0S02NH, ACO-alkyl, nitroalkyl, cyano-alkyl, A-C (=NOH) or A-C (=NNH2) , R7 is also pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, A is alkyl having 1-6 C atoms, alkyl is alkylene having 1-6 C atoms and Ac is alkanoyl having 1-8 C atoms or aroyl having 7-11 C atoms, and salts thereof, with the proviso that in the radical >CR4-CR3R8- R8 is H. 2. Compounds of the formula I according to Claim 1 wherein 0v I \ . X-Y is >C-CR -, ;>CH-CO- or XH-CHR3- and, if R5 is a 1H- 4-pyridon-1-yl, lH-4-pyridazinon-1-yl, lH-4-pyrimidinon-1-yl, lH-2-quinoIon-1-yl, 2H-l-isoquinolon-2-yl, 2H-1-phthalazinon-2-yl or 3H-4-quinazolinon-3-yl radical which is unsubstituted or monosubstituted or disubstituted by A, F, CI, Br, I, OH, OA, OAc, N02, NH2, AcNH, HOOC and/or AOOC (it being also possible for these radicals to be completely or partially hydrogenated) and/or if R7 is pyridyl, pyridazinyl, pyrimidinyl. or pyrazinyl, X-Y is also >CR*-CR3R8-, or, if the radical R5 is neither completely nor partially hydrogenated, X-Y is also >CH-CRa (OA) -. ■» ' > V* -2 - 229540

3. a) 2,2-Dimethyl-4-(IH-2-pyridon-1-yl)-6-cyano- chroman-3-01 ; b) 2,2-Dimethyl-4-(lH-2-pyridon-l-yl)-6-cyano-2H-chromene; c) 2,2-Dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-3-chromanol.

4. Process for the preparation Qf chroman deriva- as defined in claim 1 tives of the formula IJ, characterized in that, in order to prepare compounds of the formula I wherein X-Y is > CR4- CR3R8- or ^CH-CHR8-, a 3,4-epoxychroman of the formula Ila or a chroman derivative of the formula lib wherein Ila lib E is CI, Br, I or a reactive esterified OH group and R1, R2, R6, R7 and R8 have the meaning indicated in formula 1/ is reacted with a compound of the formula III R5-H III wherein R5 has the meaning indicated in formula I or with a reactive derivative thereof, and/or a compound of the formula I wherein X-Y is >CH- CR8(OH)- is dehydrated or alkylated and/or a compound of the formula I wherein X-Y is >C=CR8- is epoxidized and/or O / \ a compound of the formula I wherein X-Y is >C-CH- is isomerized into a compound of the formula I wherein X-Y is >CH-CO- by treatment with an acid catalyst and/or one or more of the radicals R3, R5, R6 and/or R7 in a compound^ of the formula I are converted into other radicals R3, R5, R6 and/or R7 and/or a basic compound of the formula I is converted into one of its acid addition salts by tre ment with an acid. 4 <£> A - 229540

5. Process for the preparation of pharmaceutical formulations, characterized in that a compound of the /as defined in clain 1, and/or a physiologically acceptable salt thereof is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or auxiliary and, if appropriate, in combination with one or more further active compounds.

6. Pharmaceutical formulation characterized in. that .as definea in claim i it contains at least one compound of the formula IJand/or a physiologically acceptable salt thereof. ,as defined in claim 1

7. The use of compounds of the formula l|for the preparation of a medicament. i as defined, in claim 1

8. The use of compounds of the formula l|for the preparation of a medicament for the treatment of alopecia. tas defined in claim 1

9. The use of compounds of the formula l|in comba- ing diseases in non-human animals.

10. A compound according to claim 1 substantially as herein described or exemplified.

11. A process according to claim 4 substantially as herein described or exemplified.

12. A process according to claim 5 substantially as herein described or exemplified.

13. A pharmaceutical formulation according to claim 6 substantially as herein described or exemplified. </div>