CA1340960C - Chroman derivatives - Google Patents

Chroman derivatives

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Publication number
CA1340960C
CA1340960C CA000554945A CA554945A CA1340960C CA 1340960 C CA1340960 C CA 1340960C CA 000554945 A CA000554945 A CA 000554945A CA 554945 A CA554945 A CA 554945A CA 1340960 C CA1340960 C CA 1340960C
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Prior art keywords
dimethyl
pyridon
formula
compound
cyano
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French (fr)
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Gunther Hausler
Rolf Gericke
Hanns Wurziger
Manfred Baumgarth
Inge Lues
Jacques De Peyer
Rolf Bergmann
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Chroman derivatives of the formula I
(see formula I) have an action on the cardiovascular system. In formula I R1 is alkyl having 1-6 carbon atoms and R2 is hydrogen or alkyl having 1-6 carbon atoms or R1 and R2 together form an alkylene group of 3-6 carbon atoms. R3 is OH or OAc, wherein Ac is formyl or alkanoyl of 2-6 carbon atoms or amyl having 7-11 carbon atoms and R4 is H, or R3 and R4 together form a bond. R5 is a nitrogen-containing heterocyclic group and R6 and R7 are hydrogen or a substituent, suitable substituents including hydroxy, alkoxy, alkyl, formyl and alkanoyl.

Description

Chroman derivatives The invention relates. to new chroman derivatives of the formula I
RS

R
wherein R1 is A, R2 is H or A, R1 and R2 together are also alkylene having 3-6 C ai:oms, R3 is ()H or OAc, R4 i s H

, R3 and R4 together are also a bond, R5 is a 1H-2-pyridon-1-yl, 1H-6-pyridazin-on-'I-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl, 1H-2-pyrazinon-1-yl or 'IH-2-thiopyridon-1-yl radical which is unsubstituted or monosubstituted or disubstituted by A, F, Cl, Br, I, OH, OA, OAc, N02, NH2, AcNH, HOOC and/or A00(:, it being also possible for these radicals to be partially hydrogenated, R6 and R7 are each H, A, H0, A0, CHO, ACO, ACS, HOOC, A00(:, AO-CS, AC00, A-CS-0, hydroxyalkyl having 1-6 C atoms, mercaptoalkyl hav-ing 1-6 C atoms, N02, NH2, NHA, NA2, CN, F, Cl, Br, I, CF3, ASO, AS02, AO-S0, AO-502, AcNH, AO-CO-NH, H2NS0, HANSO, A2NS0, H2NS02, HANS02, A2NS02, H2NC0, HAN'CO, A~,NCO, H2NCS, HANCS, A2NCS, ASONH, AS02NH, AOSONH, AOS02NH, 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl, nitro-(C1-C2)-alkyl, cyano-(C1-C2)-alkyl, A-C(=NOH) or A-C (=D1NH2 ) , A is alkyl having 1-6 C atoms, and Ac is alkanoyl having 1-8 C atoms or aroyl having 7-11 C at:oms, and also to salts thereof.
Similar compounds have been disclosed in EP-A1-76,075 and EP-A1-173,848.
The invention was based on the problem of finding new compounds having valuable properties, particularly compounds which can be used for the preparation of medicaments.
It has been found that t:he compounds of formula I and their physiologically acceptable salts possess valuable pharmacological properties and are well tolerated. Thus they exhibit an action on the: cardiovascular system in which, as a rule, a selective attack: on the coronary system can be observed at fairly low closes and a hypotensive effect can be observed at fairly high doses. Examples of effects on the coronary system are a decrease in resistance and increase in flow, while the effect on the heart rate remains small. The compounds also have a relaxing action on various smooth muscle F

~34o~so - 2a -organs (the gastro-intestinal tract, the respiratory system and the uterus). The action of the compounds can be measured by means of methods which are 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.
Messmann et al., Arzneirnittelforschung 25 (11), 1975, 1770 1776. Examples of: suitable experimental animals are mice, rats, guinea-pigs, dogs,. cats, monkeys or pigs.
The compound can therefore be used as active compounds for medicaments in human and veterinary medicine. Tfiey can also be used as intermediate products for the prepara-tion of further active compounds for medicaments.
In the formulae indicated, A is an alkyl group which is preferably unbranched and has 1-6, preferably 1-4 and es-pecially 1, 2 or 3, C atoms, specifically preferably methyl, and also preferably ethyl,~propyl, isopropyl, butyl or iso-butyl, and also preferably sec.-butyl, tert.-butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methyl-pentyl).
If R1 and R2 together are alkylene, the alkylene group is preferably unbranched and is specifically preferably -(CH2)n-wherein n is 3, 4, 5 o.c. 6_ Ac is preferably ,alkanoyl having 1-6, in particular 1, 2, 3 or 4, C atoms, ~~pecifically preferably formyl or acetyl, and also preferabi'-y propionyl, butyryl, isobutyryl, pen-tanoyl or hexanoy~~, and also preferably benzoyl, o-, m-or p-toluyl, 1-naphthoyl or 2-naphthoyl.
R1 and R2 are preferably each alkyl, particularly each methyl or ethyl and prefE~rably each methyl.
R3 and R4 are prefierably, together, a bond. If R4 is H, R3 is preferably OH, 0-CHO or 0-COCH3.
RS is preferably unsubstituted 1H-2-pyridon-1-yl, 1H-2-pyrazinon-1-yl or 1H-4-Ihydroxy-2-pyridan-1-yl and also pre-ferably unsubstituted lli-6-pyridazinon-1-yl, 4;5-dihydro-1H-5-pyridazinon-'I-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimid-inon-1-yl or 1H-2--thiopyridon-1-yl. If RS is a substituted pyridone or thiopyridone ring, this ring is preferably monosubstituted in the 3-, 4- or 5-position or is disubsti-tuted in the 3-position and the 5-position. Substituents F
which are particularly preferred are OH, N02 and NH2,,,and also AOOC, OA, Cl, Br and NHCOCH3, substituted radicals R5 which are particularly preferred are specifically 4-hydroxy-, and also 3-, 5- and 6-hydroxy-, 3-, 4-, 5- or b-methoxy-, 3-, 4-, 5- or 6-acetoxy-, 3-, 5- or 6-chloro-, 3-vitro- or 5-vitro-, 3-amino- or 5-amino-, 3-carboxy- or 5-carboxy-, 3-methoxycarbonyl- or 5-methoxycarbonyl-, 3-ethoxycarbonyl- or 5-ethoxycarbonyl-, 3-acetamido- or 5-acetamido-, 3,'.i-dichloro-, 3,5-dibromo-, 3-chloro-5-vitro-, 3-vitro-5-chlo;-o-, 3-bromo-5-vitro-, 3-vitro-5-bromo-, 3,5-dinitro-, :3-chloro-5-amino-, 3-amino-S-chloro-, 3-bromo-5-amino-,, 3-amino-5-bromo-, 3-chloro-5-acetamido-, 3-acetamido-5~-chloro-, 3-bromo-5-acetamido- and 3-acetamido-5-bromo-1H-2-pyridon-1-yl or -1H-2-thiopyridon-1-yl, 1H-3-, 1H-4- or 1H-5-hydroxy-b-pyridazinon-1-yl, 1H-3-, 1H-4- or 1H-5-ethoxycarbonyl-b-pyridazinon-1-yl, 1H-4-, 1H-5- or 1H-b-hydroxy-2--pyrimidinon-1-yl, or 1H-2-hydroxy-b-pyrimid-inon-1-yl or 1H-4-hydroxy-b-pyrimidinon-1-yl.
RS can also preferably be: 3,4-dihydro-1H-2-pyridon-1-yl, 2,3-dihydro-6H--2-pyridon-1-yl, 5,6-dihydro-1H-2-pyridon-1-yl, 2,3-dihydro-1H-b-pyridazinon-1-yl, 1,2-dihydro-5H-6-pyridazinon-1-yl, 3,4-dihydro-1H-2-pyrimidinon-1-yl, 1,6-dihydro-3H-2-pyrimidinon-1-yl, 5,6-dihydro-1H-2-pyrimidino-1-yl, 2,3-dihydro-1H-6-pyrimidinon-1-yl, 1,2-dihydro-5H-6-pyrimidinon-1-yl, 4,5-dihydro-1H-b-pyrimidinon-1-yl, 3,4-dihydro-1H-2-pyrazinon-1-yl, 1,6-dihydro-3H-2-pyrazinon-1-yl, 5,6-dihydro-1H--2-pyrazinon-1-yl, 3,4-dihydro-1H-2-thio-pyridon-1-yl, 2,3-dihydro-6H-2-thiopyridon-1-yl or 5,6-di-hydro-1H-2-thiopyridon-1-yl.
In Rb and R7 the symbols are preferably as follows:
A: methyl and also ethyl;
A0: methox~~ and also ethoxy;
ACO: acetyl and also propionyl;
ACS: thioaceatyl and also thiopropionyl;
AOOC: methox~~carbo~nyl and also ethoxycarbonyl;

-5- ~3~o9so AO-CS: met:hoxythiocarbonyl and also ethoxythiocarbonyl;
AC00: ace~toxy and also propionoxy;

ACSO: th~io(no)acetoxy and also thio(no)propionoxy;

hydroxy-S alkyl: hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl;

mercapto-alkyl: mercaptomethyl, 1-mercaptoethyl or 2-mercaptoethyl;

NHA: met:hylamino and also ethylamino;

NA2: dimethyl;amino and also diethylamino;

ASO: met:hylsulfinyl and also ethylsuLfinyl;

ASO2: met:hylsulfonyl and also ethylsulfonyl;

AO-S0: me t:hoxysulfinyl and also ethoxysulfinyl;

AO-S02: m~et:hoxysulfonyl and also ethoxysulfonyl;

Ac-NH: acetamido and also formamido, propionamido or , benzamido;

AO-CO-NH: met:hoxyc;srbonylamino and also ethoxycarbonylamino;

HANSO: met:hylaminosulfinyl and also ethylaminosulfinyl;

A2NS0: dimethyl~aminosulfinyl and also diethylamino-ZO sul f inyl,;

HANS02: met:hylaminosulfonyl and also ethylaminosul-fonyl;

AZNS02: dimethylaminosulfonyl and also diethylaminosul-fonyl;

HANCO: N-methylcarbamoyl and also N-ethylcarbamoyl;

A2NOC: N,N-dimethylcarbamoyl and also N,N-diethyl-ca rbamoyl. ;

HANCS: N-methyl~thiocarbamoyl and also N-ethylthio-carbamoyl.;

A2NCS: N,N-dimethylthiocarbamoyl and also N,N-diethyl-th iocarbamoyl;

ASONH: methylsul.finylamino and also ethylsulfinyl-amino;

AS02NH: methylsul.fonylamino and also ethylsulfonyl-amino;

AOSONH: methoxysulfinylamino and also ethoxysulfinyl-amino;

134o9so _ _ b AOS02NH: methoxysulfonylamino and also ethoxysulfnnyl-amino;
nitroalkyl: nitromethyl,. 1-nitroethyl or 2-nitroethyl;

cyano-alkyl: cyanomethyl,. 1-cyanoethyl or 2-cyanoethyl;
A-C(=NOH): 1-oximinoeth~yl_ and also 1-oximinopropyl;
A-C(=NNH2): 1-hydrazonoe~thyl and also 1-hydrazonopropyl.
The radicals Rb and R7 are preferably in the 6-position and 7-position of the chroman system. They can, however, also be in the 5- and b-, 5- and 7-, 5- and 8-, 6- and 8-position and in the 7- and 8-position.
One of the radicals R6 and R7 is preferably H, while the other is different from H. This other radical is prefer-ably in the 6-position, but can also be in the S-, 7- or 8-position, and is preferably CN or N02, and also prefer-ably CHO, ACO (particularly acetyl), AOOC (particularly methoxycarbonyl or ethoxycarbonyl) or AC00 (particularly acetoxy), and also preferably F, Cl, Br, I, CF3, H2NC0, H2NCS or NH2.
Accordingly, the invention relates particularly to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings men-tioned above. Soms~ preferred groups of compounds can be expressed by means of the formulae Ia to Ii below, which correspond to the formula I and in which the radicals not indicated in detail. have the meaning indicated in the for-mula I, but in which in Ia: R1 and R2 arcs each A;
in Ib: R1 and R2 area each CH3;
in Ic: R1 and R2 together are alkylene having 3-6 C atoms;

134p960 in Id: R5 is 1H-c'_-pyridon-1-yl, 1H-2-pyrazinon-1-y-l, 1H-6-pyridazinon-1-yl., 4,5-dihydro-1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl, 1H-2-thiopyridon-1-yl, 3-, 4-, 5- or 6-hydroxy-, 3-, 4-, 5- or 6-methoxy-, 3-, 4-, 5-- or b-acetoxy-, 3-, 5- or 6-chloro-, 3-nitro- or 5-nitro-, 3-amino- or 5-amino-, 3-carboxy-- or 5-carboxy-, 3-methoxycarbonyl-or 5-methoxycarbonyl-, 3-ethoxycarbonyl- or 5-ethoxycarbonyl-, 3-acetamido- or S-acetamido-, 3,5-dichloro-, 3,5-dibromo-, 3-chloro-5-nitro-, 3-vitro-5-~chloro-, 3-bromo-S-vitro-, 3-nitro-5-bromo-, 3,5-dinitro-, 3-chloro-5-amino-, 3-amino-5-~chloro-, 3-bromo-5-amino-, 3-amino-5-bromo-, 3-~chloro-5-acetamido-, 3-acetamido-5-chloro-, '_~-bromo-5-acetamido- or 3-acetamido-5-bromo-1E1-2-pyridon-1-yl or -1H-2-thiopyrid-on-1-yl, 1'H-3-, 1H-4- or 1H-5-hydroxy-b-pyrid-azinon-1-yl, 1H-3-, 1H-4- or 1H-5-ethoxycar-bonyl-6-pyridazinon-1-yl, 1H-4-, 1H-5- or 1H-6-hydroxy-2-pyrimidinon-1-yl or 1H-2-hydroxy-6-pyrimidinon-1-yl or 1H-4-hydroxy-b-pyrimid-inon-1-yl;
in Ie: R5 is 1H-f.-pyridon-1-yl, 1H-2-pyrazinon-1-yl or 1H-4-hydroxy-2-pyridon-1-yl;
in If: R5 is 1H-f.-pyridon-1-yl;
in Ig: R1 and R2 are each CH3 and R5 is 1H-2.-pyridon-1-yl, 1H-2-pyrazinon-1-yl, 1H-6-pyridlazinon-1-yl, 4,5-dihydro-1M-6-pyridazinc~n-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-:35 pyrimidina~n-1-yl, 1H-2-thiopyridon-1-yl, 3-, 4-, 5- or 6-hydroxy-, 3-, 4-, 5- or 6-methoxy-, 3-, 4-, 5- or 6-acetoxy-, 3-, 5- or b-chloro-, 3-vitro- o~r 5-vitro-, 3-amino- or 5-amino-, -8_ 3-carboxy-- or 5-carboxy-, 3-methoxycarbonyl-or 5-methoxycarbonyl-, 3-ethoxycarbonyl- or 5-ethoxyc<3rbonyl-, 3-acetamido- or 5-acetamido-, 3,5-dichloro-, 3,5-dibromo-, 3-chloro-5-nitro-, 3-vitro-5--chloro-, 3-bromo-5-vitro-, 3-nitro-5-bromo-, 3,5-dinitro-, 3-chloro-5-amino-, 3-amino-5--chloro-, 3-bromo-5-amino-, 3-amino-~-bromo-, 3--chloro-5-acetamido-, 3-acetamido-5-chloro-, a-bromo-5-acetamido- or 3-acetamido-5-bromo-1H-2-pyridon-1-yl or -1H-2-thiopyrid-on-1-yl, 'IH-3-, 1H-4- or 1H-5-hydroxy-b-pyrid-azinon-1-yl, 1H-3-, 1H-4- or 1H-5-ethoxycar-bonyl-6-pyridazinon-1-yl, 1H-4-, 1H-5- or 1H-6-hydroxy--2-pyrimidinon-1-yl or 1H-2-hydroxy-6-pyrimidinon-1-yl or 1H-4-hydroxy-6-pyrimid-inon-1-yl;;
in Ih: R1 and R'~ are each CH3 and R5 is 1H--2-pyridon-1-yl, 1H-2-pyrazinon-1-yl or 1H-4-hydroxy-2-pyridon-1-yl; and in Ii: R1 and R'~ are each CH3 and R5 is 1H--2-pyridon-1-yl.
Compounds of the formulae I' and Ia' to Ii' which correspond to the formulae I and Ia to Ii, but in which in each case R3 additionally is OH, OCHO or OCOCH3 and R4 is addition-ally H are also prefearred.
Compounds of the formulae I " and Ia " to Ii" which correspond to the formulae I and Ia to.Ii, but in which in each case R3 and R4 i:ogether are additionally a'bond are also preferred.
Compounds of the formulae I, I', I " , Ia to Ii, Ia' to Ii' and Ia " to Ii" in which, in each case, additionally _ 9 _ 1340960 (a) Rb is other tlhan H and R7 is H;;
(b) R6 is other than H and is in the 6-position and R7 is H;;

(c) Rb is N02, CN,, CHO, ACO, HOOC, AOOC, AC00, F, Cl, 6r, I, CF3, H21VC0, H2NCS or NH2 and R7 is H;
(d) R6 is NC12, CN,, CHO, ACO, HOOC, AOOC, AC00, F, Cl, Br, L, CF3,, H2NC0, H2NCS or NH2 and is in the b-position and R7 is H;
(e) R6 is N02, CN" CHO, CH3C0, CH300C, C2HSOOC
or CE13C00 and R7 is H;
(f) Rb is N02, CN,, CHO, CH3C0, CH300C, C2HSOOC
or CH3C00 <~nd is in the b-position and R7 is H;
(g) R6 is N0~2 or (;N and R7 is H;
(h) R6 is N02 or (;N and is in the 6-position and R7 is H;
(i) R6 is CN and R7 is H;
(j) R6 is CN and its in the 6-position and R7 is H, are also preferred.
_ Incidentally, in the preceding and following text, the radicals R1 to R7, A,, "alkyl" and Ac have the meanings 134~96Q

indicated in formula I unless anything to the contrary is expressly indicated.
The invention also relates to a process for the prepara-tion of the compounds of the formula I and their salts, which is characterized in that a 3,4-epoxychroman of the formula II

~ ~ ~R2 I I
O

wherein R1, R2, R6 and R7 have the meaning indicated in formula I, is reacted with a compound of the formula III

wherein R5 has the meaning indicated in formula I, or with one of its reactive derivatives, and/or a compound of the formula I, wherein R3 is OH and R4 is H is dehydrated, and/or in a compound of the formula I one or more of the radicals R3, R5, R6 and/or R7 are converted in-to other radicals R3, R5, Rb 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.
The compounds of the formula I are, incidentally, prepared by methods whi~:h are 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., New York; and in the patent applications indicated above) and specifically under reaction conditions which are known and suitable for..t.he reactions mentioned. In this regard it is also possible to make use of variants which are known per se but are not mentioned here in detail.
If desired, the starting materials can also be formed in situ in such a way that 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 re-acting compounds of t:he formula II with compounds of the for-mula III, preferably in the presence of an inert solvent, at temperatures between about 0 and 150° .
As a rule, the starting materials II and III are known. If they are not known, they can be prepared by methods known per se. Thus the starting materials of the formula II can be ob-tained by reacting propargyl chlorides of the formula HC---C-CR1R2-Cl with phenols of the formula R6R7C6H30H to give phenol ethers of the formulas R6R7CbH30-CR1R2-C--_CH, cyclizing the pro-ducts to give chromenes corresponding to formula I wherein R3 and R4 together are a~ bond, but there is an H atom instead of the radical RS, adding on a molecule of HOBr to give the bro-mohydrin (IV) corresponding to formula I, R3 = OH, but Br in-stead of R4 and H instead of RS, and dehydrobrominating the product (for method cf., for example, EP-A1-76,075).
Suitable reactive derivatives of III are the corresponding salts, for example the Na or K salts, which can also be formed in situ.
It is preferable to carry out the reaction in the presence of a base. Examples of suitable bases are alkali metal hydrox-ides, hydrides or amides or alkaline earth metal hydroxides, hydrides or amides, such as NaOH, KOH, Ca(OH)2, NaH, KH, CaH2, NaNH2 or KNH2, and also organic bases, such as triethylamine or pyridine, which can also be used in excess and can then 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, tetrahydro-furan or dioxane; glycol ethers, such as ethylene glycol mono-methyl or monoethyl ether (methylglycol or ethylglycol) or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; nitrites, such as acetonitrile; vitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate; amides, such as dimethylformamide (DMF), di-methylacetamide or phosphoric acid hexamethyltriamide; sulfox-ides, such as dimethyl sulfoxide (DMSO); chlorinated hydrocar-bons, such as methylene dichloride, chloroform, trichloroethyl-ene, 1,2-dichloroethane or carbon tetrachloride; or hydrocar-bons, such as benzene, 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 IV.
A compound of the formula I wherein R3 is OH and R4 is H can be converted by treatment with a dehydrating agent into a compound of the formula I wherein R3 and R4 together are a bond. This is effected, for example, by the action of one of the bases indicated, for example NaH, in one of the solvents indicated, for example DMSO, at temperatures between 0 and 150° .
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, Rb and/or R7.
For example, it is possible to replace an H atom by a halo-gen atom by halogenation or to replace an H atom by a vitro group by nitration and/or to reduce a vitro group to an amino group and/or to alkylate or acylate an amino or hydroxyl group and/or to convert a cyano group into a carboxyl group (for example by means of HCl in water/methanol at 20-100°) or into a formyl ~3roup (for example by means of Raney nickel in water/acetic acid/pyridine in the presence of sodium.p,hos-phate) or into a carbamoyl group (for example by means of KOH
in tert.-butanol) or into a thiocarbamoyl group (for example by means of H2:. in pyridine/triethylamine) and/or to convert a substituted or unsubstituted 1H-2-pyridon-1-yl radical into the correspond'ng 1H--2-thiopyridon-1-yl radical (for example by means of P2~~5 or by means of t_awesson reagent in toluene).
A nitration reaction is carried out under customary conditions, for example using a rnixture of concentrated HN03 and concen-trated H2S04 at: temperatures between 0 and 30°. If at least one of the subs~tituents R6 and R7 is an electronegative group, such as CN or X102, the nitration takes place predominantly on the RS radical; otherwise mixtures in which the nitro groups can be on the f5 radical or in the chroman ring are usually obtained.
Analogous considerations apply to halogenation, which can be carried out, for exannple, using elementary chlorine or bromine in one of the custom<~ry inert solvents at temperatures between about 0 and 30c~.
A primary or secondary amino group and/or an OH group can be converted by treatment with alkylating agents into the corre-sponding secondary or tertiary amino group and/or alkoxy group. Examples of suitable alkylating agents are compounds of the formulae A-Cl,, A-Br or A-I or corresponding sulfuric acid esters or sulfonic acid esters, such as methyl chloride, bromide or iodide, dimethyl sulfate or methyl p-toluenesul-fonate. It is also possible, for example, to introduce one or two methyl groups by means of formaldehyde in the presence of formic acid. The alkylation is preferably carried out in the presence or' absence of one of the inert solvents mention-ed, for example DMF, at temperatures between about 0° and about 120°, and a cal:alyst can also be present, preferably a base, such as potassium tert.-butylate or NaH.
Suitable acylating agents for the acylation of amino or 134096p hydroxyl group:, are preferably the halides (for e.cam.ple chlorides or bromides) or anhydrides of carboxylic acids of the formula Ac-OH, for example acetic anhydride, pro-pionyl chloride, isobutyryl bromide, formic/acetic anhyd-ride or benzoyl. chloride. It is possible to add a base, such as pyridine or triethylamine, during the acylation.
It is preferable to carry out the acylation in the pres-ence or absencE~ of an inert solvent, for example a hydro-carbon, such as toluene, a nitrite, such as acetonitrile.
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°.
Formylation can also be carried out by means of formic acid in the presence of pyridine.
A base of the -formula I can be converted into the approp-riate acid addition salt by means of an acid. Acids which afford physiologically acceptable salts are particularly suitable for this reaction. Thus it is possible to use inorganic acid:>, for example sulfuric acid, nitric acid, hydrogen halidEa acids, such as hydrochloric acid or hydro-bromic acid, phosphoric acids, such as orthophosphoric acid, and sulfamic acid, and also organic acids, in par-ticular alipha~:ic, alicyclic, 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, malefic acid, lactic acrid, tartaric acid, malic acid, benzoic acid, salicylic: acid, 2-phenylpropionic or 3-phenylpro-pionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid,, isonicotinic acid, methanesulfonic or ethanesulfonic acid, ethanedisulfonic acid, 2-h,ydroxy-ethanesulfonic acid, benzenesulfonic acid, p-toluenesul-fonic acid, naFrhthal~ene monosulfonic and naphthalene di-sulfonic acids,. and laurylsulfuric acid. Salts with phy-siologically unacceptable acids, for example picrates, can be used to purify the compounds of the formula I.

The compounds of the formula I can contain one or more chiral centres. When they are prepared, therefore, they can be ob-tained in the Dorm of racemates or, if optically active start-ing materials are used, also in an optically active form. If S the compounds have two or more chiral centres, they can be pro-duced, in the synthesis, as mixtures of racemates, from which the individual racem~stes can be isolated in a pure form, for example by recrystalilization from inert solvents. Thus, for example, compounds of the formula I wherein R1 is R2, R' is OH and R4 is H have 'two chiral centres; however, when they are prepared by reacting II with III the product formed is very predominantly only one racemate having the substituents R3 - OH and R5 in the trans-position. The resulting racemates can, if desired, be separated into their enantiomers by mech-anical or chemical means, in accordance with methods known per se. Thus diastereomers can be formed from the racemate by reacting it with <~n optically active separating agent.
Examples of suitable separating agents for basic compounds of the formula I acre optically active acids, such as the D-forms and L-forms of tartaric acid, dibenzoyltartaric acid, diacetyl tartaric acid, camphorsulfonic acids, mandelic acid, malic acid or lactic acid. Carbinols (I, R3 = OH) can also be est-erified by means of c:hiral acylating reagents, for example D-a-methylbenzyl isoc:yanate or L-a-methylbenzyl isocyanate, and can then be~ separated (cf. EP-A1-120,428). The differ-ent forms of the diastereomers can be separated in a manner known per se, for ex<~mple by fractional crystallization, and the enantiomers of the formula I can be liberated from the diastereomers in a manner known per se. It is also possible to carry out separation of enantiomers by chromatography over optically actives supporting materials.
The compounds of the formula I and their physiologically acceptable salts can be used for the preparation of phar-maceutical 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, 13409fi0 in combination with one or more further active compounds.
The invention also rE~lates to agents, in particular phar-maceutical formulations, containing at least one compound S of the formula I andior one of its physiologically accep-table salts.
These formulations can be used as medicaments in human or vet-erinary medicine. Suitable excipients are organic or inorgan-is substances which are suitable for enteral (for example oral) or parenteral administration or topical application and which do not react wiith the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycer-ol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc or petroleum jelly. Tablets, coated tablets, capsules, syrups, elixirs or drops are espec-ially used for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants are used for parenteral administration, while ointments, creams or powders are used for topical application. The new com-pounds can also be lyophilized, and the resulting lyophili-sates can be used, for example, for the preparation of injec-tion preparations. The formulations described can be steril-ized and/or can contaiin auxiliaries, such as lubricants, pre-servatives, 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 their physiologically ac-ceptable salts 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 in combating diseases, particularly in the therapy and/or prophylaxis of disorders of the cardiovascular system, in particular decompensated cardiac insufficiency, -17_ 1340960 angina pectoris;, peripheral or cerebral vascular diseases and also states of diseases which are associated with high blood pressure.
In this regard the substances according to the invention are generally administered analogously to known anti-anginal agents or hypotensive agents, for example nicorandil or 9RL-34915 C2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-6-cyanochroman-3-0l; cf. EP-A1-173,8407, .preferably in dosages between about 0.1 and 50 mg, especially between 0.2 and 5 mg, per dosage unit. The daily dosage is pre-ferably between about 0.001 and 1, in particular between 0.003 and 0.1, mg/kg of body weight. The particular dose for each specific patient de-pends, however, on a very wide variety of factors, for example on the effectiveness of the particular compound employed, on the age, body weight,, general state of health, sex, on the diet, on the time and method of administration, on the rate of excretion, the combination of medicaments and the severity of the particular disease against which the therapy is used.
Oral administration its preferred.
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, the organic phase is dried over sodium sulfate, filtered and evaporated and the product is purified by chromatography and/or crystallization.
All temperatures quoted in the preceding and following text are in °C. .
Example 1 A mixture of 20.1 g o~f 2,2-dimethyl-3,4-epoxy-6-cyano-chroman ("IIa"), 9.5 g of 1H-2-pyridone ("pyridone"), 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-Dimethyl-4-(1H-2-pyridon-1-yl)-6-cyano-2H-chromene ("A"; m.p. 146-148°) is eluted with methylene dichloride, and then 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-6-cyanochroman-3-o:l ("B"; m.p. 244°) is eluted with ethyl acetate;
the ratio of "A" to "B" is about 9:7.
The following .are obtained analogously:
2,2-dimethyl-4-(iH--2-thiopyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H--2-thiopyridon-1-yl)-6-cyanochroman-3-of 2,2-dimethyl-4-(1H--3-chloro-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H--3-chloro-2-pyridon-1-yl)-6-cyanochroman-3-of 2,2-dimethyl-4-(1H--5-chloro-2-pyridon-1-yl)-6-cyano-2H-chromene, m.p. 185-188°
2,2-dimethyl-4-(1H--5-chloro-2-pyridon-1-yl)-6-cyanochroman-3-ol, m.p. 268-270°
2,2-dimethyl-4-(1H-~6-chloro-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H-~6-chloro-2-pyridon-1-yl)-6-cyanochroman-3-ol, 2,2-dimethyl-4-(1H-~3-hydroxy-2-pyridon-1-yl)-6-cyano-2H-chromene the product of reacting :?,2-dimethyl-3,4-epoxy-6-cyanochroman with 3-hydroxy-1H-2-pyri.done, m.p. 262-265°
the products of reacting 2,2-dimethyl-3,4-epoxy-6-cyanochroman with 4-hydroxy-iH-2-pyridone, product "A"; m.p. 290-295°~ product "B"; m.p. 248-250°
2,2-dimethyl-4-(1H-~5-hydroxy-2-pyridon-1-yl)-6-cyano-2H-chromene the product of reacting 2,2-dimethyl-3,4-epoxy-6-cyanochroman with 5-hydroxy-1H-2-pyri.done, m.p. 256.5-258°
2,2-dimethyl-4-(1H-3-methoxy-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H-3-~methoxy-2-pyridon-1-yl)-b-cyanochroman-3-oL, m.p. 245-248°
2,2-dimethyl-4-(1H-3--acetoxy-2-pyridon-1-yl)-b-cyano-2H-chromene 2,2-dimethyl-4-(1H-3-~acetoxy-2-pyridon-1-yl)-6-cyanochroman-3-0l, m.p. 260-263°
2,2-dimethyl-4-(1H-3--vitro-2-pyridon-1-yl)-6-cyano-2H-chromene, m.p. 148-1'..0°
2,2-dimethyl-4-(1H-3--vitro-2-pyridon-1-yl)-b-cyanochroman-3-0l, m.p. 240-242°
2,2-dimethyl-4-(1H-5-vitro-2-pyridon-1-yl)-6-cyano-2H-chro-mene, m.p. 214-216°
2,2-dimethyl-4-(1H-S-vitro-2-pyridon-1-yl)-b-cyanochroman-3-0l, m.p. 249-251°
2,2-dimethyl-4-(1H-3-amino-2-pyridon-1-yl)-b-cyano-2H-chro-mene 2,2-dimethyl-4-(1H-3-amino-2-pyridon-1-yl)-b-cyanochroman-3-0l, m.p. 213-215°
2,2-dimethyl-4-(1H-5--amino-2-pyridon-1-yl>-b-cyano-2H-chromene, m.p. 180°
2,2-dimethyl-4-~(1H-5--amino-2-pyridon-1-yl)-b-cyanochroman-3-0l, m.p. 260-264°
2,2-dimethyl-4-~(1H-3--acetamido-2-pyridon-1-yl)-b-cyano-2H-chromene 2,2-dimethyl-4-~(1H-3--acetamido-2-pyridon-1-yl>-b-cyano-chroman-3-ol, m.p. 2i'4-276°
2,2-dimethyl-4-U 1H-5--acetamido-2-pyridon-1-yl)-b-cyano-2H-chromene, m.p. 255-2-'ib°
2,2-dimethyl-4-U 1H-5--acetamido-2-pyridon-1-yl)-b-cyano-chroman-3-ol, m.p. 303-305°
2,2-dimethyl-4-~(1H-3--carboxy-2-pyridon-.1-yl)-b-cyano-2H-chromene 2,2-dimethyl-4-U 1H-3--carboxy-2-pyridon-1-yl)-b-cyanochro-man-3-ol, m.p. 250-253°
2,2-dimethyl-4-U 1H-5--carboxy-2-pyridon-1-yl)-b-cyano-2H-chromene 2,2-dimethyl-4-~(1H-5--carboxy-2-pyridon-1-yl)-b-cyanochroman-3-0l, m.p. 238-240°
2,2-dimethyl-4-(1H-3,'.~-dichloro-2-pyridon-1-yl)-b-cyano-2H-chromene, m.p. 230-232°
2,2-dimethyl-4-(1H-3,_'~-dichloro-2-pyridon-1-yl>-b-cyano-chroman-3-ol, m.p. 16i'-170°
2,2-dimethyl-4-(1H-3,'_~-dibromo-2-pyridon-1-yl)-b-cyano-2H-chromene, m.p. 268-270°
2,2-dimethyl-4-(1H-3,'_~-dibromo-2-pyridon-1-yl)-b-cyanochro-man-3-ol, m.p. 207-205°
2,2-dimethyl-4-(1H-3-c:hloro-S-vitro-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H-3-c:hloro-S-vitro-2-pyridon-1-yl)-6-cyanochroman-3-of 2,2-dimethyl-4-(1H-3-vitro-S-chloro-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H-3-vitro-5-chloro-2-pyridon-1-yl)-6-cyanochroman-3-of 2,2-dimethyl-4-(1H-3-bromo-5-vitro-2-pyridon-1-yl)-b-cyano-2H-chromene 2,2-dimethyl-4-(1H-3-k~romo-5-vitro-2-pyridon-1-yl)-b-cyano-chroman-3-of 2,2-dimethyl-4-(1H-3-vitro-5-bromo-2-pyridon-1-yl)-b-cyano-2H-chromene 2,2-dimethyl-4-(1H-3-vitro-5-bromo-2-pyridon-1-yl)-6-cyano-chroman-3-of 2,2-dimethyl-4-(1H-3,5-dinitro-2-pyridon-1-yl>-b-cyano-2H-chromene 2,2-dimethyl-4-(1H-3,.'~-dinitro-2-pyridon-1-yl)-b-cyano-chroman-3-of 2,2-dimethyl-4-(1h+-3-c:hloro-5-amino-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H-3-c:hloro-5-amino-2-pyridon-1-yl)-b-cyanochroman-3-of 2,2-dimethyl-4-(1H-3-amino-5-chloro-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H-3-amino-5-chloro-2-pyridon-1-yl)-b-cyanochroman-3-of 2,2-dimethyl-4-(1H-3-bromo-5-amino-2-pyridon-1-yl>-6-1340960 , cyano-2H-chromene - 2,2-dimethyl-4-~(1H-3--bromo-5-amino-2-pyridon-1-yl)-b-cyanochroman-3-of 2,2-dimethyl-4-O 1H-3--amino-5-bromo-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-~(1H-3--amino-5-bromo-2-pyridon-1-yl)-b-cyanochroman-3-of 2,2-dimethyl-4-(1H-3--chloro-5-acetamido-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H-3--chloro-S-acetamido-2-pyridon-1-yl)-6-cyanochroman-3-of 2,2-dimethyl-4-(1H-3--acetamido-5-chloro-2-pyridon-1-yl)-6-cyano-2H-chrcmene 2,2-dimethyl-4-(1H-3--acetamido-S-chloro-2-pyridon-1-yl)-6-cyanochroman-3-of 2,2-dimethyl-4-(1H-3--bromo-5-acetamido-2-pyridon-1-yl)-b-cyano-2H-chromene 2,2-dimethyl-4-(1H-3--bromo-5-acetamido-2-pyridon-1-yl)-6-cyanochroman-3-of 2,2-dimethyl-4-(1H-3--acetamido-S-bromo-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H-3--acetamido-5-bromo-2-pyridon-1-yl)-6-cyanochroman-3-of 2,2-dimethyl-4-(1H-2--pyridon-1-yl)-b-vitro-2H-chromene, m.p. 158°
2,2-dimethyl-4-(1H-2--pyridon-1-yl)-b-nitrochroman-3-ol, m.p. 229-231°
2,2-dimethyl-4-(1H-2--thiopyridon-1-yl)-b-vitro-2H-chromene 2,2-dimethyl-4-(1H-2--thiopyridon-1-yl)-b-nitrochroman-3-of 2,2-dimethyl-4-(1H-3--chloro-2-pyridon-1-yl>-b-vitro-2H-chromene 2,2-dimethyl-4-(1H-3--chloro-2-pyridon-1.-yl>-b-nitrochroman-3-0l 2,2-dimethyl-4-(1H-5-~chloro-2-pyridon-1-yl)-b-vitro-2H-chromene 2,2-dimethyl-4-(1H-5--chloro-2-pyridon-1-yl)-b-nitrochroman-3-0l 2,2-dimethyl-4-(1H-b-~chloro-2-pyridon-1-yl)-b-vitro-2H-chromene 2,2-dimethyl-4-(1H-6-chloro-2-pyridon-1-yl)-6-nitrochroman-3-0l 2,2-dimethyl-4-(1H-3-hydroxy-2-pyridon-1-yl)-6-vitro-2H-chromene 2,2-dimethyl-4-C1H-3-hydroxy-2-pyridon-1-yl)-6-nitrochre-man-3-of 2,2-dimethyl-4-(1H-4-hydrox-y-2-pyridon-1-yl)-6-vitro-2H-chromene 2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-nitrochro-man-3-of 2,2-dimethyl-4-;1H-5-hydroxy-2-pyridon-1-yl)-6-vitro-2H-chromene 2,2-dimethyl-4-;1H-5-hydroxy-2-pyridon-1-yl)-6-nitrochro-'IS man-3-of 2,2-dimethyl-4-~,1H-3-methoxy-2-pyridon-1-yl)-b-vitro-2H-chromene 2,2-dimethyl-4-~;1H-3-methoxy-2-pyridon-1-yl)-b-nitrochro-man-3-of 'c!0 2,2-dimethyl-4-t:1H-3-~acetoxy-2-pyridon-1-yl)-b-vitro-2H-chromene 2,2-dimethyl-4-i:1H-3-,acetoxy-2-pyridon-1-yl)-6-nitrochro-man-3-of 2,2-dimethyl-4-f1H-3-vitro-2-pyridon-1-yl)-b-vitro-2H-chro-~'. 5 m a n a 2,2-dimethyl-4-t:1H-3-vitro-2-pyridon-1-yl)-b-nitrochroman-3-0l 2,2-dimethyl-4-t:1H-5-vitro-2-pyridon-1-yl)-b-vitro-2H-chro-mene ?.0 2,2-dimethyl-4-(;1H-S-vitro-2-pyridon-1-yl)-b-nitrochroman-3-0l 2,2-dimethyl-4-(1H-3-amino-2-pyridon-1-.yl)-b-vitro-2H-chro-mene 2,2-dimethyl-4-(1H-3-<amino-2-pyridon-1-yl)-b-nitrochroman-?~5 3-0l 2,2-dimethyl-4-(1H-5-<jmino-2-pyridon-1-yl)-b-vitro-2H-chro-mene 2,2-dimethyl-4-(1H-5-amino-2-pyridon-1-yl)-b-nitrochroman-3-0l 2,2-dimethyl-4--(1H-3--acetamido-2-pyridon-1-yl)-b-nitro-2H-chromene 2,2-dimethyl-4--(1H-3--acetamido-2-pyridon-1-yl)-b-nitro-chroman-3-of 2,2-dimethyl-4--(1H-5--acetamido-2-pyridon-1-yl>-b-nitro-2H-chromene 2,2-dimethyl-4--(1H-5--acetamido-2-pyridon-1-yl)-b-nitro-chroman-3-of 2,2-dimethyl-4--(1H-3--carboxy-2-pyridon-1-yl)-6-nitro-2H-chromene 2,Z-dimethyl-4--(1H-3-carboxy-2-pyridon-1-yl)-b-nitrochro-man-3-of 2,2-dimethyl-4--(1H-5--carboxy-2-pyridon-1-yl)-b-vitro-2H-chromene 2,2-dimethyl-4--(1H-5--carboxy-2-pyridon-1-yl)-b-nitrochro-man-3-of 2,2-dimethyl-4--(1H-3,,5-dichloro-2-pyridon-1-yl)-6-nitro-2H-chromene 2,2-dimethyl-4--(1H-3,,5-dichloro-2-pyridon-1-yl)-b-nitro-chroman-3-of 2,2-dimethyl-4--(1H-3,,5-dibromo-2-pyridon-1-yl)-b-vitro-2H-chromene 2,2-dimethyl-4--(1H-3,,5-dibromo-2-pyridon-1-yl)-b-nitro-chroman-3-of 2,2-dimethyl-4--(1H-3--chloro-5-vitro-2-pyridon-1-yl)-6-nitro-2H-chromene 2,2-dimethyl-4--(1H-3-chloro-5-vitro-2-pyridon-1-yl)-6-nitrochroman-3--of 2,2-dimethyl-4--(1H-3-vitro-5-chloro-2-pyridon-1-yl)-b-nitro-2H-chromene 2,2-dimethyl-4--(1H-3-vitro-5-chloro-2-pyridon-1-yl)-6-nitrochroman-3--of 2,2-dimethyl-4--(1H-3-bromo-5-vitro-2-pyridon-1-yl>-6-vitro-2H-chromene 2,2-dimethyl-4--(1H-3-bromo-5-vitro-2-pyridon-1-yl)-6-nitrochroman-3--ol 2,2-dimethyl-4-(1H-3-vitro-5-bromo-2-pyridon-1-yl)-b-nitro-2H-chromene 2,2-dimethyl-4-(1H-3-vitro-5-bromo-2-pyridon-1-yl)-6-nitro-chroman-3-of 2,2-dimethyl-4-(1H-3,5-dinitro-2-pyridon-1-yl)-b-nitro-2H-chromene 2,2-dimethyl-4-(1H-3,5-dinitro-2-pyridon-1-yl)-b-nitro-chroman-3-of 2,2-dimethyl-4-(1H-3-chloco-5-amino-2-pyridon-1-yl)-6-nitro-2H-chrome~~e 2,2-dimethyl-4-(1H-3-chloro-5-amino-2-pyridon-1-yl)-6-nitrochroman-3-~~l 2,2-dimethyl-4-(1H-3-amino-5-chloro-2-pyridon-1-yl)-6-nitro-2H-chromene 2,2-dimethyl-4-(1H-3-amino-5-chloro-2-pyridon-1-yl)-b-nitrochroman-3-~~l 2,2-dimethyl-4-(1H-3-bromo-5-amino-2-pyridon-1-yl)-6-nitro-2H-chromene 2,2-dimethyl-4-(1H-3-bromo-5-amino-2-pyridon-1-yl)-6-nitro-chroman-3-of 2,2-dimethyl-4-(1H-3-amino-5-bromo-2-pyridon-1-yl)-6-nitro-2H-chromene 2,2-dimethyl-4-(1H-3-amino-5-bromo-2-pyridon-1-yl)-b-nitro-chroman-3-of 2,2-dimethyl-4-(1H-3-chloro-5-acetamido-2-pyridon-1-yl>-6-vitro-2H-chromene 2,2-dimethyl-4-(1H-3-chloro-5-acetamido-2-pyridon-1-yl)-6-nitrochroman-3-~~l 2,2-dimethyl-4-(1H-3-acetamido-5-chloro-2-pyridon-1-yl)-6-nitro-2H-chrome~ne :30 2,2-dimethyl-4-(1H-3-acetamido-5-chloro-2-pyridon-1-yl>-6-nitrochroman-3-~~l 2,2-dimethyl-4-(1H-3-bromo-5-acetamido-2-pyridon-1-yl)-6-nitro-2H-chrome~ne 2,2-dimethyl-4-(1H-3-bromo-5-acetamido-2-pyridon-1-yl)-6-:35 nitrochroman-3-of 2,2-dimethyl-4-(1H-3-acetamido-5-bromo-2-pyridon-1-yl)-b-nitro-2H-chrome~ne 2,2-dimethyl-4-(1H-3-acetamido-5-bromo-2-pyridon-1-yl)-b-nitrochroman-3-of 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-acetyl-2H-chromene, m.p. 148-150°
2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-acetylchroman-3-ol, m.p. 257-259°
2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-methoxycarbonyl-2H-chromene, m.p. 126-12:7°
2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-methoxycarbonylchro-man-3-ol, m.p. 267-267.5°
2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-ethoxycarbonyl-2H-chromene 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-ethoxycarbonylchroman-3-0l, m.p. 213°
2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-fluoro-2H-chromene 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-fluorochroman-3-of 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-chloro-2H-chromene 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-chlorochroman-3-of 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-trifluoromethyl-2H-chromene 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-trifluoromethylchro-man-3-of 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-acetamido-2H-chromene 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-acetamidochroman-3-of 2,2-dimethyl-4-( 1H-2-~pyridon-1-yl )-b-carbamoyl-2H-chromene,m.p.250-252°
2,2-dimethyl-4-<1H-2-~pyridon-1-yl)-b-carbamoylchroman-3-of 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-thiocarbamoyl-2H-chromene 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-thiocarbamoylchroman-3-0l 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-7-cyano-2H-chromene 2,2-dimethyl-4-(1H-2-~pyridon-1-yl>-7-cyanochroman-3-of 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-ac,etamido-7-vitro-2H-chromene 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-b-acetamido-7-nitro-chroman-3-of 2,2-dimethyl-4-(1H-3--vitro-2-pyridon-1-yl)-b-methoxy-carbonyl-2H-chromene 2,2-dimethyl-4-(1H-3--vitro-2-pyridon-1-yl>-b-methoxy-1340960 , carbonylchroman-3-of 2,2-tetramethylene-4-(1H:-2-pyridon-1-yl)-6-cyano-2H-chromene, m.p.

2,2-tetramethylene-4-(1H:-~2-pyridon-1-yl)-6-cyano-3-chromanol, m.p.

2,2-pentamethylene-4-(1H-2-pyridon-1-yl)-6-cyano-2H-chromene, m.p.
202-204°
2,2-pentamethylene-4-(1H-2-pyridon-1-yl)-6-cyano-3-chromanol, m.p.

2,2-dimethyl-4-(1H-2-pyridazinon-1-yl)-6-cyano-2H-chromene, m.p.
136-138°
2,2-dimethyl-4-(1H-2-pyridazinon-1-yl)-6-cyano-3-chromanol, m.p.

2,2-dimethyl-4-(4,5-dihydro-1H-6-pyridazinon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(4,5-dihydro--1H-6-pyridazinon-1-yl)-6-cyano-3-chromanol, m.p. 163-164.50 2,2-dimethyl-4-(1H-3-hydroxy-6-pyridazinon-1-yl)-6-cyano-2H-chromene the product of reacting 2,2-dimethyl-3,4-epoxy-6-cyanochroman with 3-hydroxy-6-pyridazinone, m.p. 254-256°
2,2-dimethyl-4-(1H-3-ethoxycarbonyl-6-pyridazinon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H-3-ethoxycarbonyl-6-pyridazinon-1-yl)-6-cyano-3-chromanol, m.p. 259-260.5°
2,2-dimethyl-4-(1H-2-pyrimidinon-1--yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H-2-pyri.midinon-1-yl)-6-cyano-3-chromanol, m.p.

1~409fi0 250-252°
2,2-dimethyl-4-(1H-4-hyd,roxy-2-pyrimidinon-1-yl)-6-cyano-2H-chromene, m.p. 278-279.50 2,2-dimethyl-4-(1H-4-hyd.roxy-2-pyrimidinon-1-yl)-6-cyano-3-chromanol, no m.p. up to~ 300°
2,2-dimethyl-4-(iH-6-pyrimidinon-1--yl)-6-Cyano-2H-chromene 2,2-dimethyl-4-(1H-6-pyrimidinon-1-yl)-6-cyano-3-chromanol, m.p.
207-208°
2,2-dimethyl-4-(1H-4-hydroxy-6-pyrimidinon-1-yl)-6-cyano-2H-chromene the product of reacting 2,2-dimethyl-3,4-epoxy-6-cyanochroman with 4-hydroxy-6-pyrimidinone, m.p. 235--237°
2,2-dimethyl-4-(1H-2-pyrazinon-1-yl)-6-cyano-2H-chromene, m.p.
136-138°
2,2-dimethyl-4-(1H-2-pyrazinon-1-yl)-6-cyano-3-chromanol, m.p.
255-257°.
Example 2 A mixture of 20.1 g of ITa, 9.5 g of pyridone and 150 ml of triethylamine is heated at 110° for 2 hours, cooled, evaporated and then worked up in the customary manner. This gives "B", together with only traces of "A".
The following are obtained analogously from the corresponding 3,4-epoxychromans:
2-methyl-4-(1H-2-pyridon-1-yl)-2H-~chromene 2-methyl-4-(1H-2-pyridon-1-yl)-6-cyano-2H-chromene 2-methyl-4-(1H-2-pyridon-1-yl)-6-nitro-2H-chromene 2-methyl-2-ethyl-4-(1H-2-pyridon-1-~yl)-6-cyano-2H-chromene 134p9fi0 ' 2,2-diethyl-4-(1H-~-pyridon-1-yl)-6-cyano-2H-chromene 2,2-trimethylene-4--(1H-2-pyridon-:1-yl)-6-cyano-2H-chromene 2,2-tetramethylene-4-(1H-2-pyridon-1-yl)-6-cyano-2H-chromene, m.p.
181-183°
2,2-pentamethylene--4-(1H-2-pyridon-1-yl)-6-cyano-2H-chromene, m.p.

2,2-hexamethylene-~~-(1H-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H--6-met:hyl-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H--3-flu~oro-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H--3,5-diiodo-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H~-5-hydroxy-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H--5-met;hoxy-2-pyridon-1-yl)-6-cyano-2H-chromene 27a . 2,2-dimethyl-4-(1H-S--methoxycarbonyl-2-pyridon-1-yl)-6-cyano-2H-chromene 2,2-dimethyl-4-(1H-2--pyridon-1-yl)-2H-chromene 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-6-methyl-2H-chromene 2,2-dimethyl-4-(1H-2--pyridon-1-yl>-6-methoxy-2H-chromene 2,2-dimethyl-4-(1H-2--pyridon-1-yl)-6-thioacetyl-2H-chromene 2,2-dimethyl-4-(1H-2--pyridon-1-yl>-b-methoxythiocarbonyl-2H-chromene 2,2-dimethyl-4-(1H-2--pyridon-1-yl)-6-thio(no)acetoxy-2H-chromene 2,2-dimethyl-4-(1H-2--pyridon-1-yl)-b-hydroxymethyl-2H-chromene 2,2-dimethyl-4-(1H-2--pyridon-1-yl)-b-dimethylamino-2H-chromene 2,2-dimethyl-4-(1H-2--pyridon-1-yl)-b-bromo-2H-chromene 2,2-dimethyl-4-(1H-2--pyridon-1-yl>-b-iodo-2H-chromene 2,2-dimethyl-4-(1H-2--pyridon-1-yl)-b-methylsulfinyl-2H-chromene 2,2-dimethyl-4-(1H-2--pyridon-1-yl)-b-methylsulfonyl-2H-chromene.
Example 3 A mixture of 2 g of l:Ia and 1 g of pyridone is heated at 110° for 2 hours and cooled, and the residue is worked up in the customary manner. This gives "8", together with only traces of "A".
Example 4 A mixture of 2 g of ):Ia, 1.17 g of pyridone Na salt and 30 ml of ethanol is boiled for 3 hours. Working up analo-gously to Example 1 dives "A" and "B" in a ratio of approx.
3:2.
Example S
A solution of 2 g of IIa and 1.17 g of pyridone Na salt in 30 ml of ethanol is allowed to stand at 20° for 1b hours. This gives "B", together w ith only traces of "A".
Example 6 A solution of 2 g of IIa and 1.17 g of pyridone Na salt in 30 ml of ethanol and 2 ml of pyridine is boiled for 1.5 hours and cooled; the "B" which has been precipitated is filtered off. Only traces of "A" are formed.
Example 7 0.4 g of a boy dispersion of NaH in oil is added with stirring to a solution of 2.82 g of trans-2,2-dimethyl-3-bromo-b-cyanochroman-4-of in 15 mil of DMSO. The mixture is stirred for 1 hour, 2,2-dimethyl-3,4-epoxy-b-cyano-chroman being formed as an intermediate. 1.43 g of 1H-2-pyridone and a further 0.5 g of the NaH dispersion are added and the mixture is stirred for 16 hours at 20°.
Working up analogously to Example 1 gives "A" (m. p. 146-148°) and "B" (m.p. 244°).
Example 8 96 mg of 809 NaH in paraffin oil are added to a solution of 1 g of "B" in 30 ml of DMSO and the mixture is allowed to stand at 20° for 16 hours. Working up in the cus-tomary manner gives "A", m.p. 146-148°.
Example 9 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 working up in the customary manner gives 2,2-dimethyl-3-formyloxy-4-(1H-2-pyridon-1-yl)-b-cyanochroman, m.p.
203.5-204°.

- 3° - 1340860 The following are obtained analogously from the corresponding 3-hydroxy-chromans:
2,2-dimethyl-3-formyloxy-4-(1H-2-pyr:idon-1-yl)-6-nitro-chroman, m.p. 188-193~~
2,2-dimethyl-3-formyloxy-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-cyano-chroman 2,2-dimethyl-3-formyloxy-4-(1H-3-hyd:roxy-6-pyridazinon-1-yl)-6-cyano-chroman.
'Example 10 A mixture of 1 ~3 of "B" and 5 ml of acetic anhydride is boiled for 1 hour. The mixture is cooled and worked up in the customary m~3nner to give 2,2-dimethyl-3-acetoxy-4-(1H-2-pyridon-1-yl)-6-cyanochroman, m.p. 228-228.5°.
Example 11 2.96 g of "B" ai~e suspended in 100 ml of water, and 3.2 g of bromine are .added dropwise, with stirring, at 10-20°.
The substance dissolves and 2,2-dime~thyl-4-(1H-3,5-dibromo-2-pyridon-1-yl)-6-cyanochroman-3-of is precipitated and is filtered off,, m.p. 207-209°.
Example 12 2.78 g of "A" are dissolved in a mixture of 10 ml of concentrated nitric acid (68%; D - '1.41) and 12 ml of concentrated sulfuric acid, the mixture is stirred for 3 hours at 20° an~~ is poured onto ice;; filtering off the product and washing it with water gives a mixture of 2,2-dimethyl-4-(1H-3-nitropyridon-1-yl)--6-cyano-2H-chromene and 2,2-dimethyl-4-(1H-5-nitropyridon-1-yl)-6-cyano-2H-chromene in the ratio of approx. 1:a, which can be separ-ated by chromatography.

134096p Example 13 A solution of 1 g of 2,2-dimethyl-4--(1H-3-vitro-2-pyridon-1-yl)-6-methoxycarbonylchroman-3-of in 25 ml of methanol is hydrogenated at 20° and 1 bar over 0.5 g of S% Pd-on-C until absorption ceases.' The mixture is filtered and the filtrate is evaporated to give 2,2-dimethyl-4-(1H-3-amino-2-pyridon-1-yl)-b-methoxycarbonylchroman-3-ol.
Example 14 A solution of 1 g of 2,2-dimethyl-4~-(1H-3-amino-2-pyridon-1-yl)-b-cyano-2H-chromene in 15 ml of HCOOH and 1 ml of pyridine is boiled for 19 hours and evaporated. Working up in the customary manner gives 2,2-dimethyl-4-(1H-3-formamido-2-pyridon-1-yl)-6-cyano-21~-chromene_ Example 15 A mixture of 1 g of 2,2-dimethyl-4-(1H-5-amino-2-pyridon-1-yl)-b-cyano-2H-chromene, 10 ml of acetic anhydride and 10 m1 of pyridine is allowed to stand at 20° for 16 hours.
The mixture is evaporated and the product is purified by chromatography to give 2,2-dimethyl-4-(1H-5-acetamido-2-pyridon-1-yl)-6-cyano-2H-chromene.
Example 16 HCl is passed, with stirring, into a boiling solution of 1 g of "A" in SO ml of methanol and 2 ml of water for 14 hours. The mixture is allowed to cool and to stand overnight. The precipitated 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-2H-chromene-b-carboxylic acid is filtered off, m.p.
281-284°.

Example 17 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 (moist with water) is starred for 3 hours at 20°. The mixture is filtered and worked up in the customary manner to give 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-6-formyl-2H-chr~amene, m.p. 160-162°.
The following are obtained analogously:
2,2-dimethyl-4-(1H-2-pyridon-1-yl)-E>-formylchroman-3-ol~
m.p. 210-214°
2,2-dimethyl-4-(1H-2-pyridon-1-yl)-7-formyl-2H-chromene 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-7-formyl-chror,~an-3-0l 2,2-dimethyl-4-(.1H-4-hydroxy-2-pyridon-1-yl)-6-formyl-2H-chromene 2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-formyl-chroman-3-of 2,2-dimethyl-4-(1H-3-hydroxy-6-pyrid<3zinon-1-yl)-6-formyl-2H-chromene 2,2-dimethyl-4-(1H-3-hydroxy-6-pyrid<3zinon-1-yl)-6-formyl-2H-chroman-3-ol.
Example 18 2.78 g of "A" are dissolved in 40 mt. of tert.-butanol and 5.6 g of powdered KOH are added with stirring. Boiling for 1 hour and working up in the customary manner gives 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-ti-carbamoyl-2H-chromene, m.p. 250-252°

The following are obtained analogously:
2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-~5-carbamoylchroman-3-of 2,2-dimethyl-4-(1H-2-~pyridon-1-yl)-7-carbamoyl-2H-chromene 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-7-carbamoyl-chroman-3_0l 2,2-dimeioyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-carbamoyl-2H-chromene 2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-carbamoyl-chroman-3-of 1'= 2,2-dimethyl-4-(1H-3-hydroxy-6-pyridazinon-1-yl)-p-carbamoyl-2H-chromene 2,2-dimethyl-4-(1H-3-hydroxy-6-pyridazinon-1-yl)-6-carbamoyl-chroman-3-ol.
Example 19 H2S is passed at 20° for S hours into a solution of 2.78 g of "A" in a mixture of 20 ml of pyridine and 10 ml of triethylamine; the mixture is evaporated and worked up in the customary manner to give 2,2-~dimethyl-4-(1H-2-pyridon-1-yl)-6-thiocarbamoyl-2H-chromene, m.p. 254-257°.
Z4 The following are obtained analogously:
2,2-dimethyl-4-(1H-2-pyridon-1-yl)-ti-thiocarbamoylchroman-3-0l, m.p. 228°.
2,2-dimethyl-4-(1H-2-pyridon-1-yl)-i'-thiocarbamoyl-2H-chromene :?5 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-7-thiocarbamoyl-chroman-3-of 2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-thio-carbamoyl-2-H-chromene 2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-thio-carbamoyl-chroman-3-of 2,2-dimethyl-4-(1H-3-hydroxy-6-pyridazinon-1-yl)-6-thio-carbamoyl-2H-chromene 2,2-dimethyl-4-(1H-3-hydro.xy-6-pyridazinon-1-yl)-6-thio-carbamoyl-chroman-3-ol.
Example 20 A mixture of 2.96 mg of "B", 808 mg of Lawesson reagent and 50 ml of toluene is boiled for 1 hour under N2.
Working up in the customary manner gives 2,2-dimethyl-4-(1H-2-thiopyridon-1-yl)-6-cyanochroman-3-ol.
2,2-Dimethyl-~t-(1H-2-thiopyridon-"I-yl)-6-cyano-ZH-chromene is obtained ana.ogously from "A".

Example 21 Analogously to Example 1, there is obtained:
2,2-dimethyl-4-(1H-4-methoxy-2-pyridon-1-yl)-6-cyan-2H-chromene, m.p. 92-95°
2,2-dimethyl-4-(1H-4-methoxy-2-pyridon-1-yl)-5-cyan-chroman-3-ol, m.p. 228-230°
2,2-dimethyl-4-(1H-4-ethoxy-2-pyri<ion-1-yl)-6-cyan-2H-chromene, m.p. 102-1.04°
2,2-dimethyl-4-(1H-4-ethoxy-2-pyri<ion-1-yl)-6-cyan-chroman-3-ol, m.p. 210-212°
2,2-dimethyl-4-(1H-4-acetoxy-2-pyridon-1-yl)-6-cyan-2H-chromene, m.p. 170-1.72°
2,2-dimethyl-4-(1H-4-acetoxy-2-pyridon-1-yl)-6-cyan-chroman-3-of 2,2-dimethyl-4-(1H-2-pyridon-1-yl)~-6-cyan-8-vitro-2H-chromene, m.p. 149-1.51°
2,2-dimethyl-4-(1H-2-pyridon-1-yl)~-6-cyan-8-nitro-chroman-3-of 2,2-dimethyl-4~-(1H-2-pyridon-1-yl)-6-hydroxymethyl-2H-chromene 2,2-dimethyl-4~-(1H-2-pyridon-1-yl)~-6-hydroxymethyl-chroman-3-ol, m.p. 170-172°
2,2-tetramethylene-4-(1H-2-pyridon~-1-yl)-6-vitro-2H-chromene, m.p. 229-230°
2,2-tetramethylene-4-(1H-2-pyridon-1-yl)-6-nitro-chroman-3-ol, m.p. 2 49°
2,2-pentameth~~lene-4-(1H-2-pyridon-1-yl)-5-vitro-2H-chromene, m.p. 210-212°
2,2-pentameth~~lene-4-(1H-2-pyridon-1-yl)-6-nitro-chroman-3-ol, m.p. 247°
2,2-dimethyl-~E-(1H-3-methoxy-6-pyridazinon-1-yl)-6-cyan-2H-chromene 2,2-dimethyl-~~-(1H-3-methoxy-6-pyridazinon-1-yl)-6-cyan-chroman-3-ol, m.p. 165-167°
2,2-dimethyl-~~-(1H-4-hydroxy-2-pyridon-1-yl)-6-acetyl-2H-chromene PAT LOG 16 21:L087/0001Ø0 _.. . 13409fi0 2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-acetyl-chroman-3-of 2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-methoxy-carbonyl-2H-chromene 2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-methoxy-carbonyl-chroman-3-of 2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-ethoxy-carbonyl-2H-chromene 2,2-dimethyl-4-(1H-4-hydroxy-2-pyridon-1-yl)-6-ethoxy-carbonyl-chroman-3-al 2,2-dimethyl-4-(1H-3-hydroxy-6-pyridazinon-1-yl)-6-acetyl-2H-chromene 2,2-dimethyl-4-(1H-3~-hydroxy-6-pyridazinon-1-yl)-6-acetyl-chroman.-3-of 2,2-dimethyl-4-(1H-3-hydroxy-6-pyr:idazinon-1-yl)-6-methoxycarbonyl-2H-chromene 2,2-dimethyl-4-(1H-8-hydroxy-5-pyr:idazinon-1-yl)-6-methoxycarbonyl-chroman-3-of 2,2-dimethyl-4-(1H-3-hydroxy-6-pyr:idazinon-1-yl)-6-ethoxycarbonyl-2H-chromene 2,2-dimethyl-4~-(1H-3-hydroxy-6-pyr:idazinon-1-yl)-6-ethoxycarbonyl-chroman-3-of 2,2-dimethyl-9~-(1H-3-hydroxy-6-pyr:idazinon-1-yl)-6-nitro-2H-chromene 2,2-dimethyl-9~-(1H-8-hydroxy-6-pyr:idazinon-1-yl)-6-nitro-chroman-3-ol.
PAT LOG 15 21:L087/0002Ø0 The examples below relate to pharmaceutical formulations containing compounds of the formula I or their physio-logically acceptable salts:
Example A Tablets A mixture of 1 kg of 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-6-cyano-2H-chromene, 4 kg of lactose, 1.2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearate is compressed in i:he customary manner to give tablets in suci;
a way that each tablet contains 10 mg of active compound.
Example a (:oated tablets Tablets are compressed analogously to Example A and are then coated in the customary manner with a coating composed of sucrose, potato starch, talc, tragacanth gum and colorant.
Example C (:apsules 1 kg of 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-6-cyanochroman-3-0l is filled into hard gelatine capsules in the custom-ary manner in :;uch a way that each capsule contains 20 mg of active compound.
Example D Ampoules A solution of 'I kg of 2,2-dimethyl-4-(1H-2-pyridon-1-yl)-6-vitro-2H-chromene in a mixture of 20 l of 1,2-propane-diol and 10 l of twice-distilled water is filtered under sterile conditiions and filled into ampoules, which are lyophilized and sealed under steril~= conditions. Each am-poule contains S mg of active compound.
Tablets, coated tablets, capsules or ampoules containing one or more of the remaining active compounds of the formula I and/or their physialogically acceptable salts can also be obtained analogously.

SUPPLEMENTARY DISCLOSURE
The invention relates to novel chroman deriv-atives of the :Formula I

R6 RS_Z. 9 ~ R2 Q Rt R~
in which R1 is A, R2 and R° are each H or A, R1 and RZ together are also alkylene having 3-6 C atoms, R' is H, OH, OA or OAc, R' is H, R' and R' together are also a bond, R5 is a pyridyl, pyridazinyl, pyrimidinyl, pyraz 1.'i inyl,oxodihydropyridyl,oxodihydropyridazinyl, oxodihydropyrimidinyl or oxodihydropyrazinyl radical which is unsubstituted, monosubstituted or disubstituted by A, F, C1, Br, I, OH, OA, OAc, SH, N02, NH2, AcNH, HO(JC and/or AOOC, 2~0 R° 8nd R' ate each H, A, HO, A0, CHO, ACO, ACS, HOOC, AOOC, AO-CS, ACOO, A-CS-O, hydroxyalkyl having 1-6 C atoms, mercaptoalkyl having 1-6 C atoms, N02, NHZ, NHA, NA2, CN, F, C1, Br, I, CF" ASO, AS02, AO-S0, AO-SO2, AcNH, AO-CO-NH, HZNSO, 25 HANSO, A2NS0, H=NSOz, HANSOZ, AZNSOZ, HZNCO, HANCO, .AZNCO, HZNCS, HANCS, AZNCS, ASOLTH, ASOZNH, AOSO~NH, AOSOZNH, 2-oxopropyl, 2-oxobutyl, 3-oxobutyl., 3-oxopentyl, nitro-(C1-C2)-alkyl, cyano-(C1-C2)-alkyl, A-C(=NOH) or A-C(=NNH2), Z is 0~, S, or NH, ' A ~ is alkyl having 1-6 C atoms, and Ac is a.lkanoyl having 1-8 C atoms or aroyl having 7-11. C atoms .
and their salts .
The invention was based on the object of finding novel compounds having useful properties, in particular those which can be usfd for the preparation of 7.0 medicaments .
It has been found that the compounds of the formula I and their physiologically acceptable salts possess, combined with good tolerability, useful pharma-cological properties. Thus, they show effects on the L5 cardiovascula~~ system, it usually being possible to observe a selective effect on the coronary system at lower doses and a hypotensive effect at higher doses. In the coronary system, for example, decreases in resistance and increases ih flow occur, the influence on the heart a0 rate remaining low. Furthermore, the compounds show a relaxant effect on various smooth muscle organs (gastrointest.inal tract, respiratory system and uterus).
The effects of the compounds can be detezmined with the aid of methoda which are known per se, as are given, for 25 example, in EF~-A1-76,075, EP-A1-173,848 or AU-A-45,547/85 ( Dez,~rent Farm.doc No. 86081769 ) and by K. S . Meesmann et al., Arzneimattelforschung 2~ (:L1), 1975, 1770-1776.
Suitable exps:rimental animals are, for example, mice, rats, guineapigs, dogs, cats, apes or pigs.
30 The compounds can therefore be used as active medicament compounds in human and veterinary medicine. In addition, they can be used as intermediates for the preparation of further active medicament compounds.
In the formulae given, A is a preferably un 35 branched alkyl group having 1-(a, preferably 1-4, in particular 1, 2 or 3 C atoms, in detail preferably methyl, in addition preferably ethyl, propyl, isopropyl, butyl, isobut~~l, and furthermore preferably sec.-butyl, tert.-butyl, p~entyl, isop~entyl (3-methylbutyl), hexyl or isohexyl (4-me~thylpentyl).
If R1 and RZ together are alkylene, the alkylene group is prel'erably unbranched, in detail preferably -(CH=)n-, where n is 3, 4, 5 or 6.
Ac is preferably alkanoyl having 1-6, in par-1.0 ticular l, 2, 3 or 4 C atoms, in detail preferably formyl or acetyl, furthermore preferably propionyl, butyryl, isobutyryl, pentanoyl or hexanoyl, and in addition preferably benzoyl, o-, m- or p-t:oluyl, 1- or 2-naph-thoyl.
7.5 R1 and R2 are preferably each alkyl, in particular each methyl o:r ethyl, preferably each methyl; R' and RZ
together are l:urthermore preferably -(CH=),- or -(CH=)s-.
If R' is H, R' is preferably OH, and in addition preferably 0-<:HO or 0-COCH,.
:!0 ' R5 is preferably 6-hydroxy-3-pyridazinyl (= 1,6-dihydro-6-oxo--3-pyridazinyl) or 2-hydroxy-4-pyridyl (_ 1,2-dihydro-2--oxo-4-pyridyl), and .in addition preferably unsubstituted 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidin-yl, 3-, 4- or S-pyridazinyl or pyrazinyl, :!5 hydroxypyridyl such as 3-, 4-, 5- or 6-hydroxy-2-pyridyl, 2-, 4- or 5-hydroxy-4-pyridyl, 3-hydroxy-5-pyridyl, 2-hyciroxy-5-pyridyl; hydroxypyridazinyl such as 4- or 5-hydroxy-3-pyridazinyl, 3-~, 5- or 6-hydroxy-4-pyridazinyl; hydroxypyrimidinyl such as 4- or 5-hydroxy-:30 2-pyrimidinyl,, 2-, 5- or 6-hydroxy-4-pyrimidinyl, 2- or 4-hydroxy-5-p~,rrimidinyl; hydroxypyrazinyl such as 3-, 5-or 6-hydroxy-:~-pyrazinyl; dihydroalkyloxopyridyl such as 1, 2-dihydro-1--methyl-2-oxo-3-, -4--, -5- or -6--pyridyl, 1,2-dihydro-1~-et.hyl-2-oxo-3-, -4-, -5- or -6-pyridyl;
:35 dihydroalkylo:KOpyridazinyl such as 1,6-dihydro-1-methyl-6-oxo-3-, -4- or -S-pyridazinyl, 1,6-dihydro-1-ethyl-6-oxo-3-, -4- o:r -5-pyridazinyl;

alkoxypyridyl such as 3-, 4-, 5- or 6-methoxy-2-pyridyl, 2-, 4- or 5-methoxy-3-pyridyl, 2- or 3-methoxy-4-pyridyl, 2-methoxy-5-pyridyl, 2- or 3-ethoxy-4-pyridyl; alkoxy-pyridazinyl e~uch as 4-, 5- or 6-methoxy-3-pyridazinyl, 4-, 5- or 6-ethoxypyridazinyl, 3-, 5- or 6-methoxy-4-pyridazinyl, 3-, 5- or 6-ethoxy-~-pyridazinyl; alkoxy-pyrimidinyl such as 4- or 5-methoxy-2-pyrimidinyl, 2-, 5-or 6-methoxy-4-pyrimidinyl, 2- or 4-methoxy-5-pyrimid-inyl; alkoxypyrazinyl ouch as 3-, 5- or 6-methoxy-2-pyrazinyl; aminopyridyl such as 3-, 4-, 5- or 6-amino-pyridyl, 2-, 4- or 5-amino-3-pyridyl, 2- or 3-amino-4-pyridyl, 2-amino-5-pyridyl; aminopyridazinyl such as 4-, 5- or 6-amino-3-pyridazinyl, 3-, 5- or 6-amino-4-pyridaz-inyl; aminopyrimidinyl such as 4- or 5-amino-2-pyrimid-inyl, 2-, 5- or 6-amino-4-pyrimidinyl, 2- or 4-amino-5-pyrimidinyl; aminopyrazinyl such as 3-, 5- or 6-amino-2-pyrazinyl; m~ercaptopyridyl such as 3-, 4-, 5- or 6-mercapto-2-pyridyl, 2-, 4- or 5-mercapto-3-pyridyl, 2- (_ 1,2-dihydro-2-thioxo-4-pyridyl) o=' 3-mercapto-4-pyridyl, 2-mercapto-5-~pyridyl; mercaptopyridazinyl such as 4-, 5-or 6-mercapto-3-pyridazinyl (= 1,6-dihydro=6-thioxo-3-pyridazinyl), 3-, 5- or 6-mercapto-4-pyridazinyl; mercap-topyrimidinyl. such as 4- or 5-mercapto-2-pyrimidinyl, 2-, 5- or 6-mez~capto-4-pyrimidinyl, 2- or 4-mercapto-5-pyrimidinyl; mercaptopyrazinyl such as 3-, 5- or 6-mercapto-2-pyrazinyl.
Radicals of the type Rs which contain a hydroxyl or mercapto group adjacent to a ring N atom may also exist in the tautomeric lactam or thiolactam form, as indicated above in individual cases.
In Ra and R', the following are preferably:
A: methyl, and in addition ethyl;
AO: methoxy, and in addition ethoxy;
ACO: acetyl, and in addition propionyl;
ACS: thioacetyl, and in addition thiopropionyl;
AOOC: mothoxycarbonyl, and in addition ethoxy carbonyl;
PAT LOG 16 0 i~ 10 8 8 AO-CSs methoxy-thiocarbonyl, and in addition ethoxythiocarbonyl;

AC00: acetoxy, and in addition propionoxy;

ACSO: thio(no)acetoxy, and in addition thio(no)-propionoxy;

hydroxyalkyl: hydroxymethyl or 1- or 2-hydroxyethyl;

mercaptoalkyl: mercaptomethyl or 1- or 2-mercaptoethyl;

NHA: methylamino, and in addition ethylamino;

NAZ: dimethylamino, and in addition diethyl-amino;

ASOs methylsulfinyl, and in addition ethyl-sulfinyl;

ASOZ: methylsulfonyl, and in addition ethyl-sulfonyl;

7.5 AO-S0: methoxy-sulfinyl, and in addition ethoxy-sulfinyl;

AO-SO=: methoxy-sulfonyl, and in addition ethoxy-sulfonyl;

Ac-NH: acetamido, and in addition formamido, :!0 propionamido or benzamido;

AO-CO-NH: methoxycarbonylamino, and in addition ethoxycarbonylamino;

HANSOs methylaminosulfinyl, and in addition ethylaminosulfinyl;

25 AzNSO: dimethylaminosulfinyl, and in addition diethylaminosulfinyl;

HANSOZ: methylaminosulfonyl, and in addition ethylaminosulfonyl;

A2NS0=: dimethylaminosulfonyl, and in addition 30 diethylaminosulfonyl;

HANCO: N-methylcarbamoyl, and in addition N-ethylcarbamoyl;

AZNOC: N,N-dimethylcarbamoyl, and in- addition N,N-diethylcarbamoyl;

35 HANCS: N-methylthiocarbamoyl, and in addition N
ethylthiocarbamoyl;

A2NCS: N,N-dimethylthiocarbamoyl, and in addition N,N-diethylthiocarbamoyl;

ASONH: methylsulfinylamino, and in addition ethylsulfinylamino;

AS02NH: methylsulfonylamino, and in addition ethylsulfonylamino;

AOSONHs methoxysulfinylamino, and in addition ethoxysulfinylamino;

AOS02NH: methoxysulfonylamino, and in addition :LO ethoxysulfonylamino;

Nitroalkyl: nitromethyl, 1- or 2-nitroethyl;
Cyanoalkyl: cyanomethyl, 1- or 2-cyanoethyl;
A-C(s NOH): 1-oximinoethyl, and in addition 1-oximino-propyl;
A-C(= NNHZ): 1-hydrazinoethyl, and in addition 1-hydrazinopropyl.
The radicals R° and R' are preferably in the 6-:20 and 7-position of the chroman system. However, they may also be in th~a 5- and 6-, 5- and 7-., 5- and 8-, 6- and B-and 7- and 8-position.
One o~f the radicals R° and R' is preferably H, whereas the otther is different from H. This other radical is preferably in the 6-position, but also in the 5-, 7 or 8-position, and is preferably CN or NOZ, in addition preferably C~~O, ACO (in particular acetyl), AOOC (in particular me~thoxycarbonyl or ethoxycarbonyl), ACOO (in particular ac:etoxy) , and furthetraore preferably F, C1, Br, I, CFA, H;~NCO, H2NCS or NHz.
The radical R° is preferably H, and furthermore preferably methyl ar ethyl.
Accordingly, the invention in particular relates to those compounds of the formula 'I in which at least one of the radicals mentioned has one of the previously mentioned prE:ferred meanings. Some preferred groups of compounds can. be expressed by the formulae Ia to Ii below, which correspond to the formula I
and in which the radica ls ot <iesignated in more detail have the meaning n indica tedin t:he formula I, in which however in In R1 and R= are each A;

in Ib Rl and R~ are each CHs;

in Ic R1 and. R= together are alkylene having 3-6 C atoms ;

in Id R' is a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl radical which is unsub-:l0 stituted or substituted by an OH group or an oxodihydropyridyl or oxodihydro-pyridaz,inyl radical which is sub-stituted by A;

in Ie Rs is 2-hydroxy-4-pyridyl or 6-hydroxy-:LS 3-pyridazinyl;

in If Rs is 6-hydroxy-3-pyridazinyl;

in Ig R1 and, R~ are each CHs or together are -(CH=),-or -(CH=)s-:

Rs is a pyridyl, pyridazinyl, a0 pyrimidinyl or pyrazinyl radical which is unsubstituted or substituted by an OH group or an oxodihydropyridyl or oxodihydropyrida-zinyl radical which is substituted by :2 5 A;

R is H Or CHs and Z is O, S or NH;

in Ih Rl and R= are each CHI;

Rs is 2-hydroxy-4-pyridyl, 6-hydroxy-3-30 pyrida zinyl or 1,6-dihydro-1-methyl-6-oxo-3-pyrida~zinyl and is O;

in Ii R1 and R2 are each CHI;

R' is 6-hydroxy-3-pyridazinyl and 35 Z is O.

Compounds of the formulae I' and Ia' to Ii' are furthermore preferred which correspond to the formulae I

and Ia to Ii, but in which in each case additionally R' is H, OH, OCHO or OCOCH~ and R' is H, in particular those compounds of the formulae I' and Ia' to Ii' in which in each case additionally R' is OH
and R' is H.

Compounds of the formulae I" and Ia" to Ii" are furthermore preferred which correspond to the formulae I, and Iato Ii, but in which in each case R' and R' together are additionally a bond.

Compounds of the formulae I, I', I", Ia to Ii , Ia' toIi' and Ia" to Ii" are in addition preferred, in whic h in each case additionally (a) R is .different from H and R'is :H;

(b) R is different from H and is in the 6-position and R'is IEI;

(c) R6is lN0=, CN, CHO, ACO, HOOC, AOOC, ACOO, F, C1, Br, I, CFa, H2NC0, HiNCS or NH= and R'is H;

(d) R is INOz, CN, CHO, ACO, HOOC, AOOC, AC00, F, C1, Br, I, CF3, H=NCO, H2NCS or NH2 and is in the posation and R'is Ia;

( a R is N02, CN, CHO, CH~CO, CN~OOC, C=HsOOC or CH~COO
) :25 and R'is 13;

( f R is NO=, CN, CHO, CH~CO, CH~OOC, C=HSOOC or CH~COO
) and is in the 6-position and R'is I~;

(g) R is I!10Z or CN and R'is 13;

( h Rdis IHOi or CN and is in the 6-pos ition and ) R'is I~;

( i Rdis I~N and ) .35 R'is I~;

(j) Rais f~N and is in the 6-position and R'is l~.

PAT LOG 16 07:1088 Compounds of the formulae I, I', I", Ia to Ii, Ia' to Ii', l~a' to Ii" and the remaining groups of com-pounds previously indicated as preferred are particularly preferred, in which R° is. additionally CH3.
Otherwise, th,e radicals R1 to R°, A, 'alkyl" and Ac above and below have the meanings given in fonaula I, if not expressly stated otherwise.
The ~:nvention in addition relates to a process for the preparation of chroman derivatives of the formula I, characterized in that a chroman of the formula II
~6 Z ~Y
II
R

-, 8~
in which X-Y is -CH-CR - or -C~-CR'R°- and E is C1, H;r, I or a reactively esterified OH group and Rl, Rt, R', R°, R' and R° have the meanings given in formula I
is reacted with a compound of the formula III
R'-ZH III
in which. R' and Z have the meanings indicated in formula I, or with one of its reactive derivatives and/or in that a compound of the formula I, in which R' is OH and R' is H, is dehydrated and/or in that one or more of the radiciils R', R', R° and/or R' are converted into other radicals R', R', R° and/or R' in a compound of the formula I and/or in that a basic compound of the formula I is converted into one of its acid addition salts by treating with an acid.
The <:ompounds of the fox~nula I are othenrise prepared by methods which are known per se, as are A

described in t:he literature (for example in the standard works such as Houben-Weyl, Methoden der organiechen Chemie (Methods of Organic Chemistzy), Georg-Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, S Inc., New York:; and in the abovementioned patent applica-tions ) , in particular under reaction conditions which ere known and suitable for the reactions mentioned. In this case, use can alsa be made of variants which are known per se but wh:Lch are not mentioned in more detail here.
:10 The starting materials may also be formed, if desired, in s9.tu in such a way that they are not isolated from the reaction mixture, but immediately reacted further to gi~re the compounds of the formula I.
Preferably, the compounds of the formula I are 15 prepared by reacting compounds of the formula II with compounds of the formula III, preferably in the presence of an inert solvent at temperatures between about 0 and 150°.
Start:Lng materials of the formula II with X-Y
:20 0 ~ 8 -CH-CR - (3,4-epoxychromans) are preferred.
The starting materials II and III are usually known (compare, for example, DE-OS 3,726,261). If they are not known,, they can be prepared by methods which nre 25 known per se. Thus, the starting materials of the formula II (-X-Y- s -~-CR8- ) are obtainable by reacting 2-hydroxyacetopihenones of the formula 2-Ii0-RaR'CsH=-COCH~
with ketonee of the formula Rl-CO-Rx to give corresponding 4-chromanones of the formula IVa IVa -:~-Y- - -CO-CH2-IVb -~~s-Y- _ -Cp-C(-CH-R9)-v _ !Vc -~-Y- -CHOH-CHRB-IVd -X-i- _ -CH-CR8-R' p7 :tle -X-Y- - -CF:Br-CR80H-30 if desired condensing with aldehydea of the formula Ro-CHO
R' = alkyl having 1-5 C atoms) to give 3-alkylidene-4-yf chromanones of the formula IVb, reducing, for example with NaBH" to give chromanols of the formula IVc, dehy-drating, for e~cample with p-toluenesulfonic acid, to give chromenes of the formula IVd and oxidizing, for example with 3-chloroperbenzoic acid. The last-mentioned oxidation can also be carried out in a number of steps.
Thus, for example, the bromohydrins of the formula IVe can initially be prepared using N-bromosuccinimide in aqueous solution and HHr can subsequently be eliminated 1~0 from these using a base, for example sodium hydroxide solution.
The chromenes of the formula Ivd can also be obtained by condensation of salicylaldehydes of the formula 2-HO-R''R'C°H=-CHO with ketones of the fonaula 1'S R1-CO-CH2-R° to give hydroxyketones of the formula 2-HO-R°R'C°H~-CH=CR°-CO-Rl, reaction with organolithium com-pounds of the formula R2-Li and subsquent hydrolysis to give diols of the formula 2-HO-R°R'C6Hi-CH=CR°-CR'R~-OH, and cyclization with elimination of water.
21) In compounds of the formula II (-X-Y--CHE-CR'R°-), possible ~reactively esterified OH groups~
are in particular esters with alkylsulfonic acids (in which the alkyl group contains 1-6 C atoms) or with arylsulfonic acids (in which the aryl group contains 6-2!i 10 C atoms). These compounds are obtainable from the 4-chromanols of the formula IVc by reacting with an inorganic acid halide such as PCl" PBr~, SOC1= or SOBr= or with a sulfonyl chloride such as methanesulfonyl or p-toluenesulfony:L chloride.
30 Reacti~re derivatives of III which are suitable are the corresponding salts, for example the Na or R
salts, which c~~n also be formed in situ.
It is expedient to work in the presepce of a base. Suitable bases are, for example, hydroxides, 3.'S carbonates, alkoxides, hydrides and also amides of alkali metals or alkaline earth metals, such as NaOH, ROH, Ca ( OH ) Z, Na~CO~, RZCOa, Na methoxide ' or R methoxide, Na 1~4o9so .
ethoxide or B: ethoxide or Na tert.-butoxide or R tert.
butoxide, Na7i, Rtt, CaH:, NaNH=, KNH=, and in eddition organic basef~ such as triethylamine or pyridine, which can also be used in excess and then at the same time serve as solvent.
Suitable inert solvents are, in particular, alcohols such as methanol, ethanol, isopropanol, n-butanol or teat.-butanol; ethers such as diethyl ether, diisopropyl .ether, tetrahydrofuran or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), etriylene glycol dimethyl ether (diglyme);
ketones such as acetone or butanone; nitriles such ae acetonitrile; vitro compounds such as nitromethane or nitrobenzene; eaters such as ethyl acetate; amides such as dimethylfonaamide (DMF), dimethylacetamide or hexa-methylphosphoramide; sulfoxides such as dimethyl sul-foxide (DMSO); chlorinated hydrocarbons such as dichloro-methane, chlorofona, trichloroethylene, 1,2-dichloro-ethane or carbon tetrachloride; hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are furthermore suitable.
O\ 3 The epoxide II (X-Y ~ -CH-CR - ) can also be prepared in situ, for example by the action of a base on the corresponding bromohydrin IVe.
A pa~:ticularly preferred procedure consists in using an alcohol (for example ethanol) as a solvent and adding an o:cganic base (for example pyridine), the reaction mixture expediently being boiled for about 0.5 to 20 hours.
A compound of the formula I in which R' = OH and R' = H can be converted into a compound of the formula I
in which R' a.nd R' together are a bond by treating with a dehydrating agent. This is carried out, for example by the action of one of the bases mentioned, for example NaH, in one of the solvents mentioned, for example DMSO, at temperatures between 0 and 150°. In particular, com-pounds in which Z ~ S can be dehydrated in this manner.
Furthermore, one or more of the radicals R', Rs, R° and/or R' scan be converted into other radicals R', R', R6 and/or R' .in a compound of the formula I.
Por Example, it ie possible to replace en H atom by a halogen. atom by means of a halogenation or by a vitro group :by means of a nitration and/or to reduce a vitro group to an amino group and/or to alkylate or acylate an a~nrino or hydroxyl group and/or to convert a cyano group (for example with HC1 in water/methanol at 20-100°) into a carboxyl group or (for example with Raney nickel in wa~ter/acetic acid/pyridine in the presence of sodium phosp:hatej into a formyl~ group or (for example with ROH in tert.-butanol) into a carbamoyl group or ( for example with H=S in pyridine/triethylaminej into a thio-carbamoyl group and/or to convert a -CO-NH- group ( for example with PZSs or with Lawesson reagent in toluene]
into a -CS-NFi- or -C(SHj=N- group.
Nitration is carried out under customary condi-tions, for example using a mixture of concentrated HNO~
and concentrated HZSO, at temperatures between 0 and 30°.
If at least one of the substituents Rs and R' is an electronegat:Lve group such as CN or NOZ, the nitration predominantly takes place at the radical R'; otherwise mixtures are usually obtained in which the vitro groups are on the radical Rs or on the chroman ring.
This applies analogously to the halogenation which can be carried out, for example, using elemental chlorine or bromine in one of the customary inert sol vents at temperatures between about 0 and 30°.
A primary or secondary amino group and/or an OH
group can be converted into the c:orresponding_secondary or tertiary ;amino group and/or alkoxy group by treating with alkylatang agents. Suitable alkylating agents are, for example, compounds of the formulae A-C1, A-Br or A-I
or corresponding sulfuric acid or sulfonic acid esters, PAT LOG 16 0'.11088 SO
A

134pg6p ouch as methyl chloride, bromide or iodide, dimethyl sulfate or methyl p-toluenesulfonate. In addition, for example, one or two methyl groups can be introduced with formaldehyde in the presence of forzaic acid. The alkyln-tion is preferably carried out in the presence or absence of one of the inert solvents mentioned, for example D1~, at temperatures between about 0° and about 120°, in which case a catalyst can also be present, preferably a base such as potassium tert.-butoxide or NaH.
Suitable acylating agents for the acylation of amino or hydroxyl groups are preferably the halides (for example chlorides or bromides) ar anhydrides of car-boxylic acidf~ of the formula Ac-OH, for example acetic anhydride, propionyl chloride, isobutyryl bromide, formic acid/acetic anhydride and benzoyl chloride. The addition of a base such as pyridine or triethylamine during the acylation is possible. The 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 acetonitrile, an amide such as DMF or an excess of a tertiary base such as pyridine or triethyl amine, at temperatures between about 0° and about 160°, preferably between 20° and 120°. Fonaylation is also carried out using formic acid in the presence of pyridine.
A base of the formula I can be converted into the respective acid addition salt using an acid. Acids which give physiologically acceptable salts are particularly suitable for this reaction. Thus, inorganic acids can be used, for exaunple sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric ac: ids such as orthophosphoric acid, sulfamic acid, and in addition organic acids, in particular aliphatic, a.licyclic, araliphatic, aromatic or hetero-cyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic PAT LOG 16 0 i~ 10 8 8 134p9fi0 acid, euccinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethane-sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphtha:Lenemonosulfonic and -disulfonic acids, and laurylsulfuric acid. Salts with physiologically unaccept-:10 able acids, for example picrates, can be used for purify-ing the compounds of the formula I.
The compounds of the fonuula I may possess one or more chiral centres. They can therefore be obtained during their preparation as racemates or also, if opti-:15 cally active starting materials are used, in optically active form. If the compounds have two or more chiral centres, they may be obtained during synthesis as mix-tures of racemates from which the individual racemates can be isolated in pure form, for example by recryatal-20 lizing from inert solvents. Thus, for example, compounds of the formula I in which R1 ~ R~, R' = OH and R' = H have two chiral centres; during preparation by reaction of II
with III, however, very predominantly only one racemate having the trans-position of the substituents R' = OH and :25 R'-Z is formed,. Racemates obtained can, if desired, be separated mechanically, chemically or biochemically into their enantiomers by methods known per se. Thus, diastereomers can be formed from the racemate by reaction with an opt:Lcally active resolving agent. Suitable 30 resolving agents for basic compounds of the formula I
are, for example, optically active acids, such as the D-and L-fozins of tartaric acid, di.benzoyltartaric acid, diacetyltarta:ric acid, camphanic acid, camphorsulfonic acids, mandelic acid, malic acid or lactic acid.
35 Carbinols (I, R' = OH) can in addition be esterified and then resolved with the aid of chiral acylating reagents, for example t:he cited acids, particularly (+)- or (-)-camphanic acid or (+)- or (-)-camphor-10-sulfonic acid or with D-or C,-rt-methylbenzyl isocyanate (cf.

EP-A1-120,428J~. 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 fonaula I can be liberated in a manner known per se from the diastereomers. Resolution of enantiomers is in addition carried out by chromatography on optically active support: materials.
The compounds of the formula I and their physio logically accE~ptable salts can be used for the production :l0 of pharmaceutical preparations, in particular in non chemical ways. In this connection, they can be brought into a suitab7Le form for administration together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, if desired, in combination with one or :l5 more further active compound(s).
The invention in addition relates to agents, in particular pharmaceutical preparations, containing at least one compound of the formula I and/or one of its physiologically acceptable salts.
a0 These preparations can be used as medicaments in human or vetE~rinary medicine: Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical ad-ministration and which do not react with the novel a5 compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, mag-nesium stearate, talc, lanolin or petroleum jelly.
Tablets, coated tablets, capsules, syrups, elixirs or :30 drops are usE~d in particular for oral administration, suppositories are used in particular for rectal adminis-tration, solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implants are used in part:Lcular for parenteral administration, and 35 ointments, cr~aams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example solutions in alcohols such as eth~snol or isopropanol, acetonitrile, DMF, a ~3~o9so dimethylacetamide, 1,2-propanediol or their mixtures with each other and/or with water) or powders are used in particular for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. Liposomal preparations are in particular also suitable for topical application. The preparations mentioned 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, colourants and flavourings and/or aromatizers. 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 their physio-logically acceptable salts can be administered to humans or animals, in particular mammals such as apes, dogs, cats, rats o:r mice and can be used in the therapeutic treatment of the human or animal body and also in the control of diseases, in particular in the therapy and/or prophylaxis of disturbances of the cardiovascular system, in particular decompensated cardiac insufficiency, angina pectoris, arrhythmia, peripheral. or cerebral vessel disorders, and disease conditions which are connected with high blood pressure, and in addition disorders which are connected with changes in the non-vascular muscul-ature, for example asthma or urinary incontinence.
In this connection, the substances according to the invention are usually administered analogously to known antiang~inals or hypotensivea, for example nicoran dil or cromakalim, preferably in doses between about 0.01 and 5 mg, in particular between 0.02 and 0.5 mg per dose 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 specific dose for each particular patient depends, however, on a variety of factors, for example on the efficacy of the specific compound w..

134096p employed, on the age, body weight, the general state of health, sex, on the food, on the time and route of administration, on the excretion rate, medicament combin-ation and severity of the particular disease to which the therapy applies. Oral administration is preferred.
The compounds of the formula I and their salts are in adiii~tion suitable, in particular on topical application, for the treatment of alopecia areata. For this purpose, in particular, pharmaceutical preparations are used which are suitable for the 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 for:aula I and/or at least one of its salts. Otherwise, these compounds can be used against alopecia in analogy to the statements in WO
88/00822.
In the following examples ~customary working up~
means:
water is addE:d, if necessary; then mixture is extracted using an organic solvent such as ethyl acetate, the organic phase is separated off, dried over sodium sul fate, filtered and evaporated, and the residue is purifi ed by chromatography and/or crystallization.
All t~amperatures indicated above and below are in °C. ~"'c~;f = ~'~,~DO in methanol, c = 1.
Example 1 A mixture of 20.1 g of 2,2-dimethyl-3,4-epoxy-6-cyanochroman (~IIa~), 14 g of 2-hydroxypyridine (1H-2-pyridone), 7 ml of pyridine and 70 ml of ethanol is boiled for 2 hours. The mixture is cooled, the precipi tate is filtered off, the filtrate is concentrated and the residue is chromatographed on silica gel. Using diethyl ether/ethyl acetate (1:1), 2,2-dimethyl-4-(2 pyridyloxy)-6-cyano-3-chromanol is obtained, m.p. 102 103°.

r_ .~"~, The following are obtained analogously (boiling times up to 15 hours):
2,2,3-Trimethyl-4-(2-pyridyloxy)-6-cyano-3-chromanol,m.p.105-107°
2,2-Tetramethylene-4-(2-pyridyloxy)-6-cyano-3-chromanol m.p. 126-127°
2,2-Pentamethy:lene-4-(2-pyridyloxy)-6-cyano-3-chromanol, m.p. 108-110°
2,2-Dimethyl-4-(2-pyridyloxy)-6-nitro-3-chromanol 2,2-Dimethyl-4-(2-pyridyloxy)-6-bromo-3-chromanol 2,2-Dimethyl~-4-(2-pyridyloxy)-6-methoxycarbonyl-3-chromanol 2,2-Dimethyl-4-(3-pyridyloxy)-6-cyano-3-chromanol, m.p. 202-204°
2,2,3-Trimethyl-4-(3-pyridyloxy)-6-cyano-3-chromanol 2,2-Dimethyl-4-(4-pyridyloxy)-6-cyano-3-chromanol, m.p. 193-196°
2,2,3-Trimethyl-4-(4-pyridyloxy)-6-cyano-3-chromanol 2,2-Dimethyl-4-(3-pyridazinyloxy)-6-cyano-3-chromanol 2,2,3-Trimethyl-4-(3-pyridazinyloxy)-6~cyano-3-chromanol f0 2,2-Dimethyl-4.-(4-pyrimidinyloxy)-6-cyano-3-chromanol, m.p. 93-105°
2,2,3-Trimethyl-4-(4-pyrimidinyloxy)-6-cyano-3-chromanol 2,2,Dimethyl-4~-(2-pyrazinyloxy)-6-cyano-3-chromanol, m.p. 103-105°
2,2,3-Trimethyl-4-(2-pyrazinyloxy)-6-cyano-3-chromanol.
Example 2 A mixture of 20.1 g of IIa, 11.1 g of 2,4-di-hydroxypyridine~8 ml of pyridine and 400 ml of ethanol is boiled for 15 hours. The mixture is :30 evaporated, the residue is extracted with ethyl acetate, the organic phase is washed with dilute hydrochloric acid and then witlh water, dried and evaporated, and 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-cyano-3-chromanol ("A") is obtained, m.p. 249-249.5° (from ethanol).
PAT LOG 16 07:1088 13409fi4 The following are obtained analogously using 2,4-dihydroxypyridine:
2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-cyano-3-chromanol, m.p. 198-200°
2,2-Tetramethylene-4-(2-hydroxy-4-pyridyloxy)-6-cyano-3-chromanol 2,2-Pentamethylene-4-(2-hydroxy-4-pyridyloxy)-6-cyano-3-chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-vitro-3-:10 chromanol, m.p. 224-226°
2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-vitro-3-chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-bromo-3-:15 chromanol 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-bromo-3-chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-methoxy-carbonyl-3-ch;comanol, m.p. 251-252°
.20 2,2,3-Trimeth,yl-4-(2-hydroxy-4-pyridyloxy)-6-methoxy-carbonyl-3-ch:romanol;
using 2,3-dih;Ydroxypyridine:
2,2-Dimethyl,-4-(2-hydroxy-3-pyridyloxy)-6-cyano-3-chromanol, m.~p. 262-265°;
25 2,2,3-Trimeth,yl-4-(2-hydroxy-3-pyridyloxy)-6-cyano-3-chromanol;
using 2,5-dih;ydroxypyridina:
2,2-Dimethyl,-4-(2-hydroxy-5-pyridyloxy)-6-cyano-3-chromanol, m.;p. 256-258°;
30 2,2,3-Trimeth,yl-4-(2-hydroxy-5-py~idyloxy)-6-cyano-3-chromanol;

~3~o9so us ing 4 , 6 dihydroxypyritaidine 2,2-Dimethyl-4-(6-hydroxy-4-pyrimidinyloxy)-6-cyano-3-chromanol, m.p. 235-237°
2,2,3-Trimethyl-4-(6-hydroxy-4-pyrimidinyloxy)-6-cyano-3-chromanol;
using 3,6-dihydroxypyridazines 2,2-Dimethyl-~4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-3-chromanol ("8"), m.p. 255-256°
2,2,3-Trimeth;yl-4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-:LO 3-chromanol, m.p. 236-239°
2,2-Tetramethylene-4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-3-chromanol 2,2-Pentamethylene-4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-3-chromanol, no m.p. up to 275°
2,2-Dimethyl-~4-(6-hydroxy-3-pyridazinyloxy)-6-nitro-3-chromanol, no m.p. up to 260°
2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-nitro-3-chromanol, m.p. 223-225°
2,2-Dimethyl-~4-(6-hydroxy-3-pyridazinyloxy)-6-bromo-3-:!0 chromanol, m.p. 257-259°
2,2,3-Trimeth;yl-4-(6-hydroxy-3-pyridazinyloxy)-6-bromo-3-chromanol 2,2-Dimethyl-~4-(6-hydroxy-3-pyridazinyloxy)-6-methoxy-carbonyl-3-chromanol, m.p. 242°
2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-methoxy-carbonyl-3-chromanol.
Example 3 A mixture of 20.1 g of IIa, 11.1 g of 2-mercapto-pyridine, 6.6 ml of pyridine and 265 ml of ethanol is .'10 boiled for 3 hours. The mixture is concentrated and the 2,2-dimethyl-4-(2-pyridylthio)-.6-cyano-3-chromanol obtained is crystallized from diisopropyl ether, m.p.
101-103°.
PAT LOG 16 0 7 ~. 0 8 8 l.t.

The following are obtained analogously:
2,2,3-Trimethyl-4-(2-pyridylthio)-6-cyano-3-chromanol 2,2-Dimethyl-4-(3-pyridylthio)-6-cyano-3-chromanol 2,2,3-Trisnethyl-4-(3-pyridylthio)-6-cyano-3-chxomanol S 2,2-Di.methyl-4-(4-pyridylthio)-6-cyano-3-chromanol 2,2,3-Trimethyl-4-(4-pyridylthio)-6-cyano-3-chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyridylthio)-6-cyano-3-chromanol 2,2,3-Tri.methyl-4-(2-hydroxy-4-pyridylthio)-6-cyano-3-chromanol 2,2-Dimethyl-4~-(6-hydroxy-3-pyridaxinylthio)-6-cyano-3-chromanol 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinylthio)-6-cyano-3-chromanol 2,2-Dimethyl-4--(6-mercapto-3-pyridaxinylthio)-6-cyano-3-chromanol 2,2,3-Trimethy:l-4-(6-mercapto-3-pyridazinylthio)-6-cyano-3-chromanol.
Example 4 21) A mixture of 2 g of IIa, 1.11 g of 2-mercapto-pyridine, 60 m:L of DMSO and 0.3 g of NaH (80 ~ strength) is stirred for 6 hours at 20° and worked up as customary.
2,2-Dimethyl-4--(2-pyridylthio)-6-cyano-3-chromene, m.p.
110-112° is obtained.
2!i The following are obtained analogously:
2,2,3-Trimethy:l-4-(3-pyridylthio)-6-cyano-3-chromene 2,2-Dimethyl-4--(3-pyridylthio)-6-cyano-3-chromene 2,2,3-Trimethy:l-4-(3-pyridylthio)-6~-cyano-3-chromene 2,2-Dimethyl-4--(4-pyridylthio)-6-cyano-3-chromene 30 2,2,3-Trimethy:L-4-(4-pyridylthio)-6-cyano-3-chromene 2,2-Dimethyl-<<-(2-hydroxy-4-pyridylthio)-6-cyano-3-chromene 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridylthio)-6-cyano-3-PAT LOG 16 071088 "

chromene 2,2-Dimethyl-~4-(6-hydroxy-3-pyridazinylthio)-6-cyano-3-chromene 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinylthio)-6-cyano-3-chromene 2,2-Dimethyl-4-(6-mercapto-3-pyridazinylthio)-6-cyano-3-chromene 2,2,3-Trimethyl-4-(6-mercapto-3-pyridazinylthio)-6-cyano-3-chromene.
7l0 Example 5 2,2-Dimethyl-4-(3-hydroxy-2-pyridylamino)-6-cyano-3-chromanol, m.p. 207-208.5°, is obtained from IIa and 2-amino-3--hydroxypyridine analogously to Example 1.
The following are obtained analogously:
:l5 2,2,3-Trimethyl-4-(3-hydroxy-2-pyridylamino)-6-cyano-3-chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyrimidinylamino)-6-cyano-3-chromanol, no m.p. up to 280°
2,2,3-Trimethyl-4-(2-hydroxy-4-pyrimidinylamino)-6-cyano-:20 3-chromanol 2,2-Dimethyl.-4-(2-hydroxy-4-pyridylamino)-6-cyano-3-chromanol 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridylamino)-6-cyano-3-chromanol 25 2,2-Dfmethyl~-4-(2-hydroxy-4-pyri.dylamino)-6-nitro-3-chromanol 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridylamino)-6-nitro-3-chromanol 2,2-Dimethyl~-4-(2-hydroxy-4-pyridylamino)-6-bromo-3-30 chromanol 2,2,3-Trimeth.yl-4-(2-hydroxy-4-pyridylamino)-6-bromo-3-chromanol 2,2-Dimethyl-44-(6-hydroxy-3-pyridazinylamino)-6-cyano-3-chromanol 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinylamino)-6-cyano-3-chromanol 2,2-Dimethyl-4~-(6-hydroxy-3-pyridaz.inylamino)-6-vitro-3-chromanol 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinylamino)-6-nitro-3-chromanol' 2,2-Dimethyl-4-(6-hydroxy-3-pyridazinylamino)-6-bromo-3-chromanol 1.0 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinylamino~-6-bromo-3-chromanol.
The following are obtained analogously from 1,6-dihydro-3-amino-1-methyl-6-pyridazinone:
2,2-Dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinylamino)-6-1.5 cyano-3-chroma~nol 2,2,3-Triaiethl~l-4-(1,6-dihydro-6-oxo-3-pyridazinylamino)-6-cyano-3-chromanol 2,2-Dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinylamino)-6-nitro-3-chromamol :!0 2,2,3-Trimethyl-4-(l,b-dihydro-6-oxo-3-pyridazinylamino)-6-vitro-3-chromanol 2,2-Dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinylamino)-6-bromo-3-chromanol 2,2,3-Trimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinylamino)-:!5 6-bromo-3-chramanol.
Example 6 1.2 g of 80 % NaH are added to a solution of 2.66 g of 2,2-dimEathyl-4-bromo-6-cyanochroman (m.p. 89-92°;
obtainable by:reduction of 2,2-dimethyl-6-cyano-4-chroma-:30 none with NaftH, in CH~OH to give oily 2, 2-dimethyl-6-cyano-4-chromanol and reaction with PBr~ in toluene at 20°) and 2.5 g of pyridazine-3,6-dial in 70 ml of DMSO and the mixture is. stirred at 20° for 3 days. After customary working up, 2,2-dimethyl-4-(6-hydraxy-3-pyridazinyloxy)-PAT LOG 16 07:1088 13409fip 6-cyanochroman, m.p. 221-224°, is obtained.
The following are obtained analogously:
2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-chroman 2,2-Dimethyl-~4-(6-hydroxy-3-pyridazinyloxy)-6-bromo-chroman 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-bromo-chroman 2,2-Dimethyl-.4-(6-hydroxy-3-pyridazinyloxy)-6-nitro-7.0 chroman 2,2,3-Trimeth;Yl-4-(6-hydroxy-3-pyridazinyloxy)-6-nitro-chroman 2,2-Dimethyl-4:-(2-hydroxy-4-pyridyloxy)-6-cyanochroman 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-cyanochroman 7.5 2,2-Dimethyl-4.-(2-hydroxy-4-pyridyloxy)-6-bromochroman 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-bromochroman 2,2-Dimethyl-4:-(2-hydroxy-4-pyridyloxy)-6-nitrochroman 2,2,3-Trimeth.yl-4-(2-hydroxy-4-pyridyloxy)-6-nitro-chroman.
f, 0 Example 7 A mixture of 10 g of 2,2-dimethyl-4-(2-pyridyl-thio)-6-cyano-3-chromanol, 3 g of sodium hydroxide and 350 ml of dioxane is boiled for 20 minutes. The mixture is cooled and filtered, the filtrate is evaporated and 25 2,2-dimethyl-4-(2-pyridylthio)-6-cyano-3-chromene, m.p.
110-112°, is obtained.
Example 8 A mixture of 2 g of "e", 11.7 ml of formic acid and 3.3 ml of acetic anhydride is allowed to stand at 20°
3.0 for 16 hours and then warmed to 40-42° for 2 hours. After evaporating and customary working~up, 2,2-dimethyl-3-a~

~3~ogso fonayloxy-4-(6-hydroxy-3-pyridazinyloxy)-6-cyanochroman is obtained.
The following are obtained analogously from the cor-responding 3-hydroxychromans:
2,2,3-Trimet.hyl-3-formyloxy-4-(6-hydroxy-3-pyrid-azinyloxy)-6-c:yanochroman 2,2-Dimethyl-3-fonayloxy-4-(2-hydroxy-4-pyridyloxy)-6-cyanochroman 2,2,3-Trimethyl-3-formyloxy-4-(2-hydroxy-4-pyridyloxy)-:LO 6-cyanochroman.
Example 9 A mixture of 1 g of "B" and 5 ml of acetic anhydride is boiled for 1 hour. The mixture is cooled, worked up as customary and 2,2-dimethyl-3-acetoxy-4-(6-:15 hydroxy-3-pyr:i.dazinyloxy)-6-cyanochroman is obtained,m.p.210-212'.
The following are obtained analogously:
2,2,3-Trimeth~,rl-3-acetoxy-4-(6-hydroxy-3-pyridazinyloxy)-6-cyanochroman 2,2-Dimethyl~-3-acetoxy-4-(2-hydroxy-4-pyridyloxy)-6-20 cyanochroman 2,2,3-Trimethyl-3-acetoxy-4-(2-hydroxy-4-pyridyloxy)-6-cyanochroman.
Example 10 A solution of 1 g of 2,2-dimethyl-9-(2-hydroxy :25 4-pyridyloxy )-6-nitro-3-chromanol in 25 ml of methanol is hydrogenated at 20° and 1 bar on 0.5 g of 5 ~ Pd-C to completion. The mixture is filtered, evaporated and 2,2 dimethyl-4-(2-hydraxy-4-pyridyloxy)-6-amino-3-chromanol is obtained.
.30 The following are obtained analogously:
PAT LOG 16 0?1088 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3-chromanol 2,2-Dimethyl-4~-(6-hydroxy-3-pyridnzinyloxy)-6-amino-3-chromanol !i 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-amfno-3-chromanol.
Example 11 A solution of 1 g of 2,2-dimethyl-4-(2-hydroxy 4-pyridyloxy)-E~-amino-3-chromanol in 15 ml of IiCOOH and 1 ml of pyridine is boiled for 19 hours and evaporated.
After customary working up, 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-t:ormamido-3-chromanol is obtained.
Example 12 A mixture of 1 g of 2,2-dimethyl-4-(2-hydroxy-4 1-'i pyridyloxy)-6-amino-3-chromano1~10 ml of acetic anhydride and 10 ml of p:~rridine is allowed to stand at 20° for 16 hours. The mixture is evaporated, purified chromatograph ically and 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6 acetamido-3-ch~:omanol is obtained.
Example 13 HC1 is introduced with stirring for 14 hours into a boiling solution of 1 g of "B" in ~0 ml of methanol and 2 ml of water. The mixture is allowed to cool and stand overnight. The 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-3-chromanol-6-carboxylic acid deposited is filtered off.
Example 14 A mixture of 3.13 g of "B", 31 g of Na,P0,.12 HBO, 28 ml of pyrid:i.ne, 28 ml of water, 67 ml of acetic acid and 25 g of Raney Ni (water-moist) is stirred at 20° for '3 hours. After filtering, the mixture is worked up as customary and 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyl-oxy)-6-formyl-~1-chromanol, m.p. 256-257°, is obtained.

~3~o9so The following are obtained analogously:
2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-formyl-3-chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-formyl-3-chromanol 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-formyl-3-chromanol.
Example 15 3.13 c~ of "B" are dissolved in 40 ml of tert.- , 1.0 butanol and 5..6 g of powdered ROH are added with stirr-ing. After boiling for 1 hour and customary working up, 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-carbamoyl-3-chromanol is. obtained.
The following are obtained analogouslys 7.5 2,2,3-Trimet.hyl-4-(6-hydroxy-3-pyridazinyloxy)-6-carbamoyl-3-chromanol .
2,2-Dimethyl-~4-(2-hydroxy-4-pyridyloxy)-6-carbamoyl-3-chromanol 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-carbamoyl-:LO 3-chromanol.
Example 16 HZS i;s introduced at 20° for 5 hours into a solution of :3.12 g of "A" in a mixture of 20 ml of pyridine and 10 m1 of triethylamine, the mixture is 25 evaporated and worked up as customary, and 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-thiocarbamoyl-3-chromanol, m.p. 242°, is obtained.
The following are obtained analogously:
2,2,3-Trimethyl-4-(2-hydroxy-4-py:;idyloxy)-6-thiocarb-:30 amoylchroman-:3-ol.

a 2,2-Dimethyl-~4-(6-hydroxy-3-pyridazinyloxy)-6-thio-carbamoyl-3-ch:romanol, m.p. 142-144°
2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-thio-carbamoyl-3-chromanol.
Example 17 A mixture of 310 mq of ~8~, 808 mg of Laweeaon reagent and 5G ml of toluene is boiled under N= for 1 hour. Customary working up gives 2,2-dimethyl-4-(6-mercapto-3-pyr.idazinyloxy)-6-cyano-3-chromanol (2,2-dimethyl-4-(1,6-dihydro-6-thioxo-3-pyridazinyloxy)-6-cyano-3-chromanol].
2,2-Di~aethyl-4-(2-mercapto-4-pyridyloxy)-6-cyano-3-chromanol is obtained analogously from ~A~.
The followinq are obtained analogously:
2,2,3-Trimethy7,-4-(6-mercapto-3-pyridazinyloxy)-6-cyano-3-chromanol 2,2-Dimethyl-4-(6-mercapto-3-pyridazinyloxy)-6-vitro-3-chromanol 2,2,3-Trimethyl-4-(6-mercapto-3-pyridazinyloxy)-6-nitro-3-chromanol 2,2-Dimethyl-9~-(6-mercapto-3-pyridazinyloxy)-6-bromo-3-chromanol 2,2,3-Trimethy7l-4-(6-mercapto-3-pyridazinyloxy)-6-bromo-3-chromanol 2,2,3-Trimethyl-4-(2-mercapto-4-pyridyloxy)-6-cyano-3-chromanol 2,2-Dimethyl-4-(2-mercapto-4-pyridyloxy)-6-vitro-3-chromanol 2,2,3-Trimethyl-4-(2-mercapto-4-pyridyloxy)-6-vitro-3-chromanol 2,2-Dimethyl-4-(2-mercapto-4-pyridyloxy)-6-vitro-3-chromanol 2,2,3-Trimethyl-4-(2-mercapto-4-pyridyloxy)-6-vitro-3-~...., ~r:~

134p960 chromanol.
Example 18 A mixture of 312 mg of 'A' , 20 ml of ecetone, 400 mg of RZCO~ and 0.2 ml of dimethyl sulfate is boiled for 2 hours. The mixture is filtered, evaporated and chromatographed on silica gel. Using ethyl acetate/metha-nol (9:1), 2,2-~dimethyl-4-(1,2-dihydro-1-methyl-2-oxo-4-pyridyloxy)-6-cyano-3-chromanol, m.p. 202-203°, is obtained.
1~0 The following are obtained analogouelys 2,2,3-Trimethyl.-4-(1,2-dihydro-i-methyl-2-oxo-4-pyridyl-oxy)-6-cyano-3~-chromanol 2,2-Dimethyl-4~-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-cyano-3~-chromanol, m.p. 206-208°
1!i 2,2,3-Trimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyri-dazinyloxy)-6-<:yano-3-chromanol, m.p. 197-199°
2,2-Dimethyl-4~-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-vitro-3--chromanol 2,2,3-Trimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyri-20 dazinyloxy)-6-vitro-3-chromanol 2,2-Dimethyl-4~-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-oxy)-6-bromo-3--chromanol 2,2,3-Triethy:L-4-(1,6-dihydro-1-methyl-6-oxo-3-pyri-dazinyloxy)-6-bromo-3-chromanol 25 2,2-Dimethyl-4-~(1,2-dihydro-1-ethyl-2-oxo-4-pyridyloxy)-6-cyano-3-chronnanol 2,2,3-Trimethyl-4-(1,2-dihydro-1-ethyl-2-oxo-4-pyridyl-oxy)-6-cyano-3--chromanol 2,2-Dimethyl-4-(1,2-dihydro-1-ethyl-6-oxo-3-pyridazinyl-30 oxy)-6-cyano-3--chromanol, m.p. 164-167°
2,2,3-Trimethyl-4-(1,2-dihydro-1-ethyl-6-oxo-3-pyri-dazinyloxy)-6-c:yano-3-chromanol.m.p. 166-168'.

,_ ,>

Example 19 A mixture of 313 mg of "H", 1 g of K=CO" 0.65 ml of dimethyl sulfate and 16 ml of DID is boiled for 3 hours and worked up ae customary. 2,2-Dimethyl-4-(6-methoxy-3-pyridazinyloxy)-6-cyano-3-chromanol, m.p. 224-227°, is obtained.
The following are obtained analogously:
2,2,3-Trimethyl-4-(b-methoxy-3-pyridazinyloxy)-6-cyano-3-chromanol 2,2-Dimethyl~-4-(2-methoxy-4-pyridyloxy)-6-cyano-3-chromanol 2,2,3-Trimethyl-4-(2-methoxy-4-pyridyloxy)-6-cyaao-3-chromanol.
Example 20 In analogy to Example 18, 2,2-dimethyl-4-(1,6-dihydro-1-isopropyl-6-oxo-3-pyridazinyloxy)-6-cyan-3-chromanol is obtained from "B" and 2-bromopropane; m.p. 201-203°.
Example 21 a) A mixture of 5 g of "H", 5 g of (+)-camphor-10-sulfonic acid chloride and 50 ml of pyridine is warmed to~ 70° for 5 hours. After working up with dilute hydrochloric acid and ethyl acetate as usual and chromatographic separation on silica gel with mixtures of dichloromethane and ethyl acetate, there area obtained two epimers of "B"-(+)-campher-10-sulfonic acid ester, m.p. 223-224° and m.p.
127-150°, respectively.

b) A mixture: of 2 g of the "unpolar" epimer (m. p.
223-224°), 16 g of "sodium hydroxide on carrier"
("Natriumhydroxid auf Trager", E. Merck, catalogue "Reagenz;ien, Diagnostica, Chemikalien", 1987/88, page 587, No. 1567) and 80 ml of methanol is stirred for 20 hours at 20°. The mixture is concen-trated to dryness and dissolved in water. HC1 is added until pH 8 and the 2,2-dimethyl-4-(1,6-di-hydro-6-oxo-3-pyridazinyloxy)-6-cyan-3-chromene thus obtained (m. p. 226-228°) is filtered off.
Working up of the filtrate with hydrochloric acid/
ethyl aceaate at pH 4 and chromatography on silica gel with dichloromethane/ethy;l acetate/methanol yields (-~)-2,2-dimethyl-4-(1,6-dihydro-6-oxo-pyridazinyl-oxy)-6-cyan-3-chromanol, m.p. 229°; [a]
-168.5°.
c) Analogously, (+)-2,2-dimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinyl-oxy)-6-cyan-3-chromanol (m.p. 232-233°;
[a) +170.0°) is obtained from the "polar" epimer 20 (m,p, 127-150°).
Analogously, 2,2-dimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-cyan-3-chromer.~e (m.p. 263-264°) as well as (-)- and (+)-2,2-dimethyl-4-(2-hydroxy-4-pyridyl-oxy)-6-cyan-3-chromanol are obtained from "A" via the corresponding 25 (+)-campher-sulfonic acid esters.

Claims (38)

1. Chroman derivatives of the formula I
wherein R1 is A, R2 is 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 is a 1H-2-pyridon-1-yl, 1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl, 1H-2-pyrazinon-1-yl or 1H-2-thipyridon-1-yl radical which is unsubstituted or monosubstituted or disubstituted by A, F, Cl, Hr, I, OA, OAc, NO2, NH2, AcNH, HOOC or AOOC, it being also possible for these radicals to be partially hydrogenated, R6 and R7 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, NO2, NH2, NHA, NA2, CN, F, Cl, Br, I, CF3, ASO, ASO2, AO-SO, AO-SO2, AcNH, AO-CO-NH, H2NSO, HANSO, A2NSO, H2NSO2, HANSO2, A2NSO2, H2NCO, HANCO, A2NCO, H2NCS, HANGS, A2NCS, ASONH, ASO2NH, AOSONH, AOSO2NH, 2-oxopropyl,
2-oxobutyl, 3-oxobutyl, 3-oxopentyl, nitro-(C1-C2)-alkyl, cyano-(C1-C2)-alkyl, A-C(=NOH) or A-C(=NNH2), A is alkyl having 1-6 C atoms, and Ac is alkanoyl having 1-8 C atoms or aroyl having 7-11 C atoms, or a salt thereof.
2. A chroman compound which is active on the cardiovascular system and which is obtainable by reacting a
3,4-epoxy-chroman of the formula II
wherein R1, R2, R6 and R7 are as defined in claim 1, with a compound of formula III
R5-H ~III

or with a reactive derivative thereof, wherein R5 is a 1H-2-pyridon-1-yl, 1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl, 1H-2-pyrazinon-1-yl or 1H-2-thio-pyridon-1-yl radical, which radical is substituted by OH and is optionally further substituted by A, F, Cl, Br, I, OH, OA, OAc, NO2, NH2, AcNH, HOOC or AOOC, wherein A and Ac are as defined in claim 1, it being possible also for these radicals to be partially hydrogenated, followed, if required by conversion of the obtained compound into a pharmaceutically acceptable salt thereof,.
3. A compound according to claim 1 or 2 wherein each of R1 and R2 is alkyl. having 1-6 C atoms.
4. A compound according to claim 1 or 2 wherein each of R1 and R2 is alkyl having 1-2 C atoms.
5. A compound according to claim 1 or 2 wherein each of R1 and R2 is methyl.
6. A compound according to claim 1 or 2 wherein R3 and R4 together form a bond.
7. A compound according to claim 1 or 2 wherein R3 is OH.
8. A compound according to claim 1 wherein R5 is 1H-2-pyridon-1-yl or 1H-2-pyrazinon-1-yl.
9. A compound according to claim 2 wherein R5 is 1H-4-hydroxy-2-pyridon-1-yl.
10. A compound according to claim 1 or 2 wherein R6 and R7 are each H, cyano or nitro.
11. 2,2-Dimethyl-4-(1H-2-pyridon-1-yl)-6-cyano-2H-chromene.
12. 2,2-Dimethyl-4-(1H-2-pyridon-1-yl)-6-cyanochroman-3-ol.
13. 2,2-Dimethyl-4-(1H-2-pyridon-1-yl)-6-nitro-2H-chromene.
14. 2,2-Dimethyl-4-(1H-2-pyridon-1-yl)-6-nitrochroman-3-ol.
15. A compound according to claim 2 obtained as a reaction product of 2,2-dimethyl-3,4-epoxy-6-cyanochroman with 4-hydroxy-1H-2-pyridone, said compound being selected from product A
having a melting point of 290-295°C and product B having a melting point of 248-250°C.
16. 2,2-Dimethyl-4-(1H-2-pyrazinon-1-yl)-6-cyano-2H-chromene.
17. 2,2-Dimethyl-4-(1H-2-pyrazinon-1-yl)-6-cyanochroman-3-ol.
18. Process for the preparation of a chroman derivative of the formula I as defined in claim 1, characterized in that a 3,4-epoxy-chroman of the formula II
wherein R1, R2, R6 and R7 have the meaning indicated in formula I, 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, or a compound of the formula I
wherein R3 is OH and R4 is H is dehydrated, or one or more of the radicals R3, R5, R6 or R7 in a compound of the formula I
are converted into other radicals R3, R5, R6 or R7 or a basic compound of the formula I is converted into one of its acid addition salts by treatment with an acid.
19. Process for the preparation of a pharmaceutical formulation, characterized in that a compound as defined in any one of claims 1 to 17 or one of its physiologically acceptable salts 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.
20. Pharmaceutical formulation characterized in that it contains at least one compound as defined in any one of claims 1 to 17 or one of its physiologically acceptable salts.
21. Compound as defined in any one of claims 1 to 17 for combating a disease which relates to the cardiovascular system.
22. Use of a compound as defined in any one of claims 1 to 17 for the preparation of a medicament for treatment of a disease which relates to the cardiovascular system.
23. Use of a compound as defined in any one of claims 1 to 17 in combating a disease which relates to the cardiovascular system.
24. A process which comprises reacting a 3,4-epoxychroman of tree formula II

wherein R1, R2, R6 and R7 are as defined in claim 1, with a compound of formula III
R5-H ~III
or with a reactive derivative thereof, wherein R5 is a 1H-2-pyridon-1-yl, 1H-6-pyridazinon-1-yl, 1H-2-pyrimidinon-1-yl, 1H-6-pyrimidinon-1-yl, 1H-2-pyrazinon-1-yl or 1H-2-thiopyridon-1-yl radical, which radical is substituted by OH
and is optionally further substituted by A, F, Cl, Br, I, OH, OA, OAc, NO2, NH2, AcNH, HOOC or AOOC, wherein A and Ac are as defined in claim 1, it being possible also for these radicals to be partially hydrogenated, followed, if required by conversion of the obtained compound into a pharmaceutically acceptable salt thereof.
25. Chroman derivatives of the formula I
in which R1 and R8 are each A; R2 is H or A; R1 and R2 together are also alkylene having 3-6 C atoms; R3 is H, OH, OA
or OAc; R4 is H; R3 and R4 together are also a bond; R5 is a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxodihydro-pyridyl, oxo-dihydropyridazinyl, oxodihydropyrimidinyl or oxodihydropyrazinyl radical which is unsubstituted or substituted by A, F, Cl, Br, I, OH, OA, OAc, SH, NO2, NH2, AcNH, HOOC or AOOC; R6 and R7 are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AOOC, AO-CS, ACOO, A-CS-O, hydroxyalkyl having 1-6 C atoms, mercapto-alkyl having 1-6 C atoms, NO2, NH2, NHA, NA2, CN, F, Cl, Br, I, CF3, ASO, ASO2, AO-SO, AO-SO2, AcNH, AO-CO-NH, H2NSO, HANSO, A2NSO, H2NSO2, HANSO2, A2NSO2, H2NCO, HANCO, A2NCO, H2NCS, HANCS, A2NCS, ASONH, ASO2NH, AOSONH, AOSO2NH, 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl, nitro-(C1-C2)-alkyl, cyano(C1-C2)-alkyl, A-C(=NOH) or A-C(=NNH2); Z is O, S or NH; A is alkyl having 1-6 C atoms;
and Ac is alkanoyl having 1-8 C atoms or aroyl having 7-11 C
atoms; with the proviso that if Z is O then R3 is not OH or OAc; or a salt thereof.
26. A compound according to claim 25 wherein each of R1 and R2 is alkyl having 1-6 C atoms.
27. A compound according to claim 25 wherein each of R1 and R2 is alkyl having 1-2 C atoms.
28. A compound according to claim 25 wherein each of R1 and R2 is methyl.
29. A compound according to claim 25 wherein R3 and R4 together form a bond.
30. A compound according to claim 25 wherein R3 is OH.
31. A compound according to claim 25 wherein R5 is substituted by OH.
32. A compound according to claim 25 wherein R6 and R7 are each H, cyano, nitro, bromo, methoxy or amino.
33. Process for the preparation of a chroman derivative of the formula I according to claim 25, characterized in that a chroman of the formula II

in which X-Y is or -CHE-CR3R8- and E is Cl, Br, I or a reactively esterified OH group and R1, R2, R3, R6, R7 and R8 have the meanings given in formula I is reacted with a compound of the formula III
R5-ZH ~~III
in which R5 and Z have the meanings indicated in formula I, or with one of its reactive derivatives or in that a compound of the formula I in which R3 is OH and R4 is H, is dehydrated or in that one or more of the radicals R3, R5, R6 or R7 are converted into other radicals R3, R5, R6 or R7 in a compound of the formula I or in that a basic compound of the formula I
is converted into one of its acid addition salts by treating with an acid.
34. Process for the production of a pharmaceutical preparation, characterized in that a compound of the formula I
as defined in any one of claims 25 to 32 or one of its physiologically acceptable salts is brought into a suitable form for administration together with at least one solid, liquid or semi-liquid excipient or auxiliary and, if desired, in combination with one or more further active compound(s).
35. Pharmaceutical preparation which contains at least one compound of the formula I as defined in any one of claims 25 to 32 or one of its physiologically acceptable salts.
36. Compounds of the formula I as defined in any one of claims 25 to 32 for the control of a disease which relates to the cardiovascular system.
37. Use of a compound of the formula I as defined in any one of claims 25 to 32 for the production of a medicament for treatment of a disease which relates to the cardiovascular system.
38. Use of a compound of the formula I as defined in any one of claims 25 to 32 in the control of a disease which relates to the cardiovascular system.
CA000554945A 1986-12-23 1987-12-21 Chroman derivatives Expired - Fee Related CA1340960C (en)

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JPS63170376A (en) 1988-07-14
HU207728B (en) 1993-05-28
KR880007507A (en) 1988-08-27
DE3726261A1 (en) 1988-07-07
EP0273262A2 (en) 1988-07-06
AU8268987A (en) 1988-06-23
HUT48621A (en) 1989-06-28
EP0273262A3 (en) 1989-12-06
JP2523343B2 (en) 1996-08-07
AU604809B2 (en) 1991-01-03

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