AU628395B2 - Chroman derivatives - Google Patents

Description

derive(s) title from actual Inventor(s) assignee of the invention from the actual inventor(s).

Attestation or rrom the actual inventors.

r 0 4. The basic application(s) referred to in paragraph 2 of this Declaration was/were the first application(s) made in a Convention country in respect of the invention the subject of the application.

legalization M notquid. Declared at DARMSTAD-T this 25th day of August 1989 ME K PATENT GMB To: a.

The Commissioner of Patents Heumann Dr. Schittler ARTHUR S. CAVE &c principal authorized agenigatre of Declarant(s) PATENT AND TRADE MARK ATTORNEYS officer

SYDNEY

i Our Ref: 291073 I- -i ;i-ra~anar~

AUSTRALIA

Patents Act FORM COMPLETE SPECIFICATION

(ORIGINAL)

Application Number: Lodged: 2~3~r Complete Specification Lodged: Accepted: Published: S I.

Priority: Related Artt

C

SApplicant(s) Applicant(s): Merck Patent Geselilchaft Mit Beschrankter Haftung

S

4 Address for Service: D-6100 Darmstadt FEDERAL REPUBLIC OF GERMANY ARTHUR S. CAVE CO.

Patent Trade Mark Attornerys Level 10, 10 Barrack Street SYDNEY NSW 2000 1 Complete specification for the invention entitled

I

r "Chroman derivatives".

The following statement is a full description of this invention, including the best method of performing it known to me:- 1 5020 m UI f Merck Patent Gesellschaft mit beschrankter Haftung 6100 D a r m s t a d t Chroman derivatives The invention relates to novel chroman derivatives of the f ormula I 6 -z 4 R R 8

RR

R 7, I I 4 4*4 4 *4 4 1 C II 4 C C '4

CC

CC4 4 CC I 44 C C C CCC

IC

C C 4

CC'''

in which R' and R'

R

1 and R' R' and R 4

R

5

R

6 and R' is A, are each H or A, togethei: are also alkylene hav~ing 3-6 C atoms, is H, OH, OA or OAc.

is H, together are also a bond, is a py-ridyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxodihydropyridyl, oxodihydropyridazinyl, oxodihydropyrimidinyl or oxodihydxopyraziny'l radical which is unsubstituted, monosibstituted or disubstituted by A, F, Cl, Br, I, OH, OA, QAc, SH, NO 2 NH2 AcNH, HOOC and/or AOOC, are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AQOC, AO-CS, ACQO, A-CS-O, hydroxy-B- -having 1-6 C atoms, mercapto-B- having 1-6 C atoms,

NO

2

NH

2 1 NHA, NA 2 CN, F, Cl, Br, CF 3

ASO'

AS0 2 AO-SO, AO-S0 2 AcNII, AO-CO-Nfl, H 2

NSO,

HANSO, A 2 NSO, H 2

NSO

2

H'ANSO

2

A

2

NSO

2 71 2

NCO,

HANCO, A 2 NCO, H 2 14CS, HANCS, A 2 NCS, ASONHI ASO 2

NHI

AOSONH, AQSO 2 NH, ACO-B-, nitro-B, r cyano- .A-C(=NOH) or A-C(=NNH 2 PAT LOG 16 071088 ,1.

S0372p:mmb 2 Z is O, S, or NH, A is alkyl having 1-6 C atoms, B is alkylene having 1-6 atoms and AC is alkanoyl having 1-8 atoms or aroyl having 7-11 C atoms with the proviso that, when Z Is oxygen, R 5 is one of the radicals specified but must be monosubstituted or disubstituted by SH and their salts.

The invention was based on the object of finding novel compounds having useful properties, in particular those which can be used for the preparation of medicaments.

It has been found that the compounds of the formula I and their physiologically acceptable salts possess, combined with good tolerability, useful pharmacological properties.

Thus, they show effects on the cardiovascular 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 in flow occur, the influence on the heart rate remaining low. Furthermore, the compounds show a relaxant effect on various smooth muscle organs (gastrointestinal tract, respiratory system and uterus). The effects of the compounds can be determined Swith the aid of methods which are known per se, as are given, for example, in EP-Al-76,075, EP-A1-173,848 or AU-A-45,547/85 (Derwent Farmdoc No. 86081769) and by K.S.

Meesmann et al., Arzneimittelforschung 25 1975, 1770-1776. Suitable experimental animals are, for example, mice, rats, guineapigs, dogs, cats, apes or pigs.

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 l preparation of further active medicament compounds.

In the formulae given, A is a preferably unbranched alkyl group having 1-6, preferably 1-4, in particular 1, 2 or 3 C atoms, in detail preferably methyl, in addition preferably ethyl, propyl, isopropyl, -3butyl, isobutyl, and furthermore preferably sec. -butyl, tert. -butyl, pentyl, isopentyl (3-methylbutyl), hexyl or isohexyl (4-methylpentyl).

I f R 1 and R 2 together are alkylene, the alkylene group is pref-erably unbranched, in detail preferably where n is 3, 4. 5 or 6.

The group B preferably stands for or -CHzCH 2 Ac is preferably alkanoyl having 1-6, in particu'-,r 1, 2, 3 or- 4 C atoms, in detail preferably formyl or acetyl, fur-t-hermore preferably propionyl, butyryl, isobutyryl, pentanoyl or hexanoyl, and in addition preferably benzoyl, m- or p-toluyl, 1- or 2-naphthoyl.

R' and R 2 are preferably each alkyl, in particular each methyl or 4ethyl, preferably each methyl; R1 and R 2 together are furthermore preferably (CH 2 or (CH 2 If R* is H, R 3 is preferably OH, and in addition preferably 0-CHO or O-COCK- 3 20 R5 is preferably 6-hydroxy-3-pyridazinyl 1,6dihydro-6-oxo-3-pyridazinyl) or 2-hyd-roxy-4-pyridy'l l,2-dihydro-2-oxo-4-pyridyl), and in addition preferably unsubstituted 3- or 4-pyridyl, 4- or 4- or 5-pyridazinyl or pyrazinyl, hydroxypyrzidyl such as 5- or 6-hydroxy- 2-pyridyl, 4- or 5-hydroxy-4-pyridyl, pyridyl, 2-hydroxy-5-pyridyl; hydroxypyridazinyl such as 4- or 5-hydiroxy-3-pyridazinyl, 5- or 6-hydroxy-4- 04 ~,*pyridazinyl; hyd-roxypyrimidinyl such as 4- or 2-pyrimidinyl, 5- or 6-hydroxy-4-pyriniidinyl, 2- or 4-hydroxy-5-pyrimidinyl; hydroxypyrazinyl such as or 6-hydroxy-2-pyirazinyl; dihydroalkyloxopyridyl such as 1, 2-dihydro-l-mxethyl-2-oxo-3-, or -6--pyridyl, 1,2-dihydro-l-ethyl-2-oxo-3--, or -6-pyridyl; dihydroalkyloxopyridazinyl such as 1, 6-dihydro- 1-methyl- 6-oxo-3-, or -5--pyridazinyl, 1,6-dihyciro-l.-ethyl-6oxo-3-, or PAT L0G"16 071088

I

I

I

-4 E I I

III

I

#111

II

I

444~ 4 alkoxypyridyl such as 5- or 6-methoxy-2-pyridyl, 4- or 5-methoxy-3-pyridyl, 2- or 3-methoxy-4-pyridyl, 2- or 3-ethoxy-4-pyridyl; alkoxypyridazinyl such as 5- or 6-methoxy-3-pyridazinyl, or 6-ethoxypyridazinyl, 5- or 6-methoxy-4pyridazinyl, 5- or 6-ethoxy-4-pyridazinyl; alkoxypyrimidinyrf such as 4- or 5-methoxy-2-pyrimidiny1, or 6-methoxy-4-pyrimidinyl, 2- or inyl; alkrxypyrazinyl such as 5- or 6-methoxy-,2pyrazinyl; aminopyridyl such as 5- or 6-am3.nopyridyl, 4- or 5 -amino- 3-pyridyl, 2- or 3-amino-4pyridyl, 2-amino-5-pyridyl; aminopyridazinyl such as or 6 -amino- 3-pyrida zinyl, 5- or 6 -amino- 4-pyridaz inyl; aminopyrimidinyl such as 4- or 5 -amino- 2-pyrimidinyl, 5- or 6-amino-4-pyrimidinyl, 2- or pyrimidinyl; aminopyrazinyl such as 5- or 6-amino-2pyrazinyl; mercaptopyridyl such as 5- or 6mercapto-2-pyridyl, 4- or 5-mercapto-3-pyridy1, 2- 1, 2-dihydro-2-thioxo-4-py-ridyl) or 3-rnmrcapto-4-pyridyl, 2-mercapto-5-pyridyl; mercaptopyridazinyl such as or 6-mercapto-3-pyridazinyl 1, 6-dihydro-6-thioxo-3pyridazinyl), 5- or 6-mercapto-4-pyridazinyl; mercaptopyrimidinyl such as 4- or 5-mercapto-2--pyrimidinyl, 2-, or 6-mercapto-4-pyrimidinyl, 2- or pyrimidinyl; mercaptopyrazinylI such as 5- or 6mercapto-2-pyrazinyl.

Radicals of the type R 5 which contain a hydroxyl or mercapto group adjacent to a ring N atom may also exist in the tautomer~.c lactam or thiolactam form, as 430 indicated above in individual cases.

In R 6 and R7, 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: methoxycarbonyl, and in addition ethoxycarbonyl; 44 4 e 4~1 4 14 4 4 4 44 .1 PAT LOG 16 071088

AG-CS:

ACOO:

ACSO:

hydroxyalicyl: mercaptoalkyl:

NHA:

NA

2

ASO:

ASO

2

AG-SO:

AG-SO

2 Ac-NH:

AG-CO-NH:

HANSO:

A

2

NSO:

HANSO

2 A2NS0 2

HANCO:

A

2

NOC:

methoxy-thiocarbonyl, and in adc~ition ethoxythiocarbonyl; acetoxy, and in addition propionoxy; thio(no)acetoxy, and in addition thio(no)propionoxy; hydxoxymethyl or 1- or 2-hydroxyethyl; mercaptomethyl or 1- or 2-mercaptoethyl; methylanuino, and in addition ethylamino; dimethylaiino, and in addition diethylamino; methylsulfinyl, and in addition ethylsulfinyl; methylsulfonyl, and in 'addition ethylsulfonyl; methoxy-sulfinyl, and in addition ethoxy- SUMAfiiy; mnethoxy-sulfonyl, and in addition ethoxysulfonyl; acetamido, and in addition formamido, ft t I I t

'I

A

4,

A

o A A A A

'A

a A *AA A A A propionamido or benzamido; methoxycarbonylamnino, and ethoxycarbonylamino; methylaminosulfinyl, and ethylaminosulfinyl; dimethylaminosulfinyl, and diethylaminosulfinyl; methylaminosul fonyl, and ethylaminosulfonyl; dimethylaminosulfonyl, and diethylaminosulfonyl; N-methylcarbamoyl, and in ethylcarbamoyl; NN-dimethylcarbamoyl, and F~,N-diethylcarbaoyl; in in in in in addition add.ition addition addition addition addition Nin addition HANCS: N-methylthiocarbamoyl, and ethylthiocarbanioyl; in addition N- PAT LOG 16 071088 6

A

2 NCS: N,N-dimethyithiocarbamoyl, and in addition N,N-diethylthiocarbamoyl; ASONH: methylsulfinylamino, and in addition ethylsulfinylamino;

ASO

2 NH: methylsulfonylamino, and in addition ethylsulfonylamino; AOSONH: methoxysulfinylamino, and in addition ethoxysulfinylamino;

AOSO

2 NH: methoxysulfonylamino, and in addition ethoxysulfonylamino; ACO-B-: 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-.

oxopentyl; Nitro-B-: nitrorethyl, 1- or 2-nitroethyl; Cyano,-B-: cyanoLethyl, 1- or 2-cyanoethyl; NOH): 1-oximinoethyl, and in addition 1-oximinopropyl;

NNH

2 1-hydrazinoethyl, and in addition 1hydrazinopropyl.

The radicals R 6 and R 7 are preferably in the 6and 7-position of the chroman system. However, they may also be in the 5- and 5- and 5- and 6- and 8and 7- and 8-position.

One of the radicals R 6 and R 7 is preferably H, whereas the other is different from H. This other radical 4444 is preferably in the 6-position, but also in the 7or 8-po'sition, and is preferably CN or NO 2 in addition preferably CHO, ACO (in particular acetyl), AOOC (in I particular methoxycarbonyl or ethoxycarbonyl), ACOO (in particular acetoxy), and furthermore preferably F, C1, Br, I, CF 3

H

2 NCO, H 2 NCS or NH 2 ij The radical R 8 is preferably H, and furthermore preferably methyl or ethyl.

Accordingly, the invention in particular relates to those compounds of the fric-mula I in which at least one of the radicals mentioned has one of the previously mentioned preferred meanings. Some preferred groups of compounds can be expressed by the formulae la to Ii PAT LOG'-16 071088

I

7 below, which correspond to the f ormula I and in which the radicals not designated in more detail have the meaning indicated in the formula I, in which however in Ia R' and R 2 are each A; in lb R 1 and R 2 are each CH 3 in Ic R1 and R 2 together are alkylene having 3-6 C atoms; .in Id R 5 is a pyridvi. pyridazinvi. pyrimidinyi in Ie R 5 in If in Ig R 5

R

1 and R 2 t QI 251 or pyrazinyl radical which is unsubstituted or substituted by an OH group or an oxodihydropyridyl or oxodihydxopyridazinyl radical which is substituted by A; is 2-hydroxy--4-pyridyl or 6-hydroxy- 3-pyridazinyl; is 6-hydroxy-23-pyridaziny1; are each CH 3 or together are -(CH 2 4

I-

or is a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl radical which is unsubstituted or substituted by an OH group or an oxodihyd-ropyridyl or oxodihydropyridazinyl radical which is substituted by

A;

is H or CH 3 and is 0, S or NHl; are each CH 3 is 2-hydroxy-4-pyridyl, 6-hydroxy-3pyrida zinyl or 1,6-dihydro-l-methyl- 6-oxo-3-pyrida,-inyl and z in Ih R1 and R 2 R 5 4040 4 44 44 I 4 44 4 4. ''30 444.

I 4 4444 4 4 *4444 4 4 z is 0; in Ii R' and R 2 are each Cl! 3 R 5 is 6-hydroxy-3-pyridazinyl and z is 0., Compounds of the formulae IV and Ia' to Ii' are furthermore preferred which correspond to the formulae I PAT LOG 16 071088 :I 8 and Ia to Ii, but in which in each case additionally R 3 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 3 is OH and R 4 is H.

Compounds of the formulae I" and la" to Ii" are furthermore preferred which correspond to the formulae I, and Ia to Ii, but in which in each case R 3 and R* together are additionally a bond.

Compounds of the formulae I, Ia to Ii, Ia' to Ii' and Ia" to Ii" are in addition preferred, in which in each case additionally

R

6 is different from H and

R

7 is H;

R

6 is different from H and is in the 6-position and

R

7 is H;

R

6 is NO 2 CN, CHO, ACO, HOOC, AOOC, ACOO, F, Cl, Br, I, CF 3

H

2 NCO, H 2 NCS or NH 2 and

R

7 is H; 20 R 6 is NO z CN, CHO, ACO, HOOC, AOOC, ACOO, F, Cl, Br, I, CF 3 HzNCO, H 2 NCS or NH 2 and is in the 6position and t R 7 is H;

R

6 is NO 2 z CN, CHO, CH 3 CO, CH 3 00C, CH 5 00C or CH 3

COO

and

R

7 is H;

R

6 is NO 2 CN, CH CH CH CH CH 3 OOC, C 2

H

5 OOC or CH 3

COO

and is in the 6-position and R is H;

R

6 is NO 2 or CN and

R

7 is H;

R

6 is NO 2 or CN and is in the 6-position and S' R 7 is H;

R

6 is CN and

R

7 is H;

R

6 is CN and is in the 6-position and

R

7 is H.

PAT LOG 16 071088 I- I P7iTi ii..il.;i.;i-li9~ ~-II 9 Compounds of the formulae I, Ia to Ii, Ia' to Ii', Ia" to Ii" and the remaining groups of compounds previously indicated as preferred are particularly preferred, in which Re is. additionally CH 3 Otherwise, the radicals R 1 to A, B and Ac above and below have the meanings given in formula I, if not expressly stated otherwise.

The invention 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 R6

X

Y II 7 R1 in which

O

8 X-Y is -CH-CR or -CHE-CR3R and E is Cl, Br, I or a reactively esterified OH group and S 1 R 2

R

3

R

6

R

7 and R e have the meanings given in formula

I

is reacted with a compound of the formula III 20 I, t r t or with one of its reactive derivatives I and/or in that a compound of the formula I, in which R 3 is OH and R' is H, is dehydrated and/or in that one or more of the radicals R 3

R

5

R

6 and/or R 7 are converted into other radicals R 3

R

5

R

6 and/or R' in a compound of the formula I and/or in that a bas.c compound of the formula I is converted into one of its acid addition salts by treating with an acid.

The compounds of the formula I are otherwise T- prepared by methods which are known per se, as are PAT LOG 16 071088 10 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 abovementioned patent applications), in particular under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se but which are not mentioned in more detail here.

The starting materials may also be formed, if desired, in situ in such a way that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.

Preferably, the compounds of the formula I are prepared by reacting compounds of the formula II with compounds of the formula IIl, preferably in the presence of an inert solvent at temperatures between about 0 and 150°.

t( Starting materials of the formula II with X-Y 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 are known per se. Thus, the starting materials of the formula 0 8 II -CH-R- are obtainable by reacting 2hydroxyacetophenones of the formula 2-HO-R 6

RC

6

H

2

-COCH

3 with ketones of the formula R 1

-CO-R

2 to give corresponding 0 4-chromanones of the formula IVa 6 IVa -CO-CH 2 ma rX IVb -CO-C(=CH-R9)- 2 iVc -CHOH-CHR O/1 IVd -CH=CR- SIVe -CHBr-CR OHif desired condensing with aldehydes of the formula R 9

-CHO

(R

9 alkyl having 1-5 C atoms) to give 3-alkylidene-4- PAT LOG 16 071088 ~'~ClsPp-. -CIR~I~_*Y;P~~I~IU~I 11 chromanones of the formula IVb, reducing, for example with NaBH 4 to give chromanols of the formula IVc, dehydrating, for example 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 HBr can subsequently be eliminated 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-RRC 6

H

2 -CHO with ketones of the formula

R'-CO-CH

2

-R

8 to give hydroxyketones of the formula 2-HO-R 6

R

7

C

6

H

2

-CH=CR

8

-CO-R

1 reaction with organolithium compounds of the formula R 2 -Li and subsquent hydrolysis to give diols of the formula 2-HO-R 6

R

7

C

6

H

2

-CH=CR

8

-CR

1

R

2

-OH,

and cyclization with elimination of water.

In compounds of the formula II

-CHE-CR

3

R

8 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- 10 C atoms). These compounds are obtainable ftr£ V-he 4- I chromanols of the formula IVc by reacting with an inorganic acid halide such as PCl 3 PBr 3 SOCIz or SOBr 2 or with a sulfonyl chloride such as methanesulfonyl or ptoluenesulfonyl chloride.

^'SO Reactive derivatives of III which are suitable are the corresponding salts, for example the Na or K salts, which can also be formed in situ.

It is expedient to work in the presence of a base. Suitable bases are, for example, hydroxides, carbonates, alkoxides, hydrides and also amides of alkali metals or alkaline earth metals, such as NaOH, KOH, Ca(OH) 2 Na 2

CO

3

K

2 CO, Na methoxide or K methoxide, Na PAT LOG 16 071088

(I

i: 12 a U U

U(

Ut i o o ethoxide or K ethoxide or Na tert.-butoxide or K text.butoxide, NaH, KH, CaH 2 NaNH 2

KNH

2 and in addition organic bases 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, nbutanol or tert.-butanol; ethers such as diethyl ether, d&isopropyl ether, tetrahydrofuran or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; nitriles such as acetonitrile; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; amides such as dimethylformamide (DMF), dimethylacetamide or hexamethylphosphoramide; sulfoxides such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons such as dichlorot' methane, chloroform, trichloroethylene, 1,2-dichloro- 20 ethane or carbon tetrachloride; hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are furthermore suitable.

0 3 The epoxide II (X-Y -CH-CR can also be prepared in situ, tor example by the action of a base on 25 the corresponding bromohydrin IVe.

A particularly preferred procedure consists in using an alcohol (for example ethanol) as a solvant and adding an organic base (for example pyridine), the reaction mixture expediently being boiled for about -o0 to 20 hours.

A compound of the formula I in which R 3 OH and

R

4 H can be converted into a compound of the formula I in which R 3 and 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, I~ rO O 0* Cao.

LOU

4 r O0000 PAT LOG 16 071088 amh i-I i; i C C I Cr I C .44 0 13 at temperatures between 0 and 1500. In particular, compounds in which Z S can be dehydrated in this manner.

Furthermore, one or more of the radicals R 3

R

5

R

6 and/or R 7 can be converted into other radicals R 3

R

5

R

6 and/or R' in a compound of the formula I.

For example, it is possible to replace an H atom by a halogen atom by means of a halogenation or by a nitro group by means of a nitration and/or to reduce a nitro group to an amino group and/or to alkylate or acylate an amino or hyd.-oxyl 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 water/acetic acid/pyridine in the presence of sodium phosphate) into a formyl group or (for example with KOH in tert.-butanol) into a carbamoyl group or (for example with H 2 S in pyridine/triethylamine) into a thiocarbamoyl group and/or to convert a -CO-NH- group (for example with P 2 zS or with .Lawesson reagent in toluene) into a -CS-NK.- or group.

20 Nitration is carried out under customary conditions, for example using a mixture -f concentrated HNO 3 and concentrated H 2 SO, at temperatures between 0 and If at least one of the substituents R 6 and R 7 is an electronegative group such as CN or NO2, the nitration predominantly takes place at the radical R 5 otherwise mixtures are usually obtained in which the nitro groups are on the radical R 5 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 solvents at temperatures between about 0 and 300 A primary or secondary amino group and/or an OH S group can be converted into the corresponding secondary or tertiary amino group and/or alkoxy group by treating with alkylating 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, g.4 4 4 0 PAT LOG 16 071088 -1 5020 6-

'MOO

14 such 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 formic acid. The alkylation is preferably carried out in the presence or absence of one of the inert solvents mentioned, for examr le DMF, at temperatures between about 0C 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) or anhydrides of carboxylic acids 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 tolue. a nitrile such as acetonitrile, an amide such as DMF or an excess of a tertiary base such as pyridine or triethylamine, at temperatures between about 00 and about 160", preferably between 200 and 120°. Formylation is also carried out using formic acid in the presence of pyridine.

f o" 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 example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, p phosphoric acids such as orthophosphoric acid, sulfamic acid, and in addition organic acids, in particular aliphatic, 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 PAT LOG 16 071088 HANSO,

A

2 NSO, H 2 NS02, HANSO 2

A

2 NS02, IHNCO, HANCO, A 2 NCO, H2NCS, HANCS, AzNCS, ASONH, ASO2NH, AOSONH, AOSO 2 NH, ACO-B-, nitro-B, cyano- A-C(=NOH) or A-C(=NNH SPAT LOG 16 071088 acid, succinic 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 ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemonosulfonic and -disulfonic acids, and laurvlsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for purifying the compounds of the formula I.

The compounds of the formula I may possess one or more chiral centres. They can therefore be obtained during their preparation as racemates or also, if optically 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 mixtures of racemates from which the individual racemates o can be isolated in pure form, for example by recrystal- .o20 lizing from inert solvents. Thus, for example, compounds 0, of the formula I in which R' R 2

R

3 OH and R* H have 0 0 S 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 3 OH and RS-Z is formed. Racemates obtained can, if desired, Sbe separated mechanically, chemically or biochemically into their enantiomers by methods known per se. Thus, diastereomers can be formed from the racemate by reaction 0 oo with an optically active resolving agent. Suitable resolving agents for basic compounds of the formula I are, for example, optically active acids, such as the D- 'and L-forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, camphanic acid, camphorsulfonic .acids, mandelic acid, malic acid or lactic acid.

Carbinols R 3 OH) can in addition be esterified and then resolved with the aid of chiral acylating reagents, for example the cited acids, particularly or camphanic acid or or (-)-camphor-l0-sulfonic acid or with D-or L-4-methylbenzyl isocyanate (cf.

or 3 C atoms, in detail preferably methyl, in addition preferably ethyl, propyl, isopropyl, k 16 EP-Al-120,428). The different forms of the diastereomers I can be separated in a manner known per se, for example by fractional crystallization, and the enantiomers of the formula 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 physiologically acceptable salts can be used for the production of pharmaceutical preparations, in particular in nonchemical ways. In this connection, they can be brought into a suitable 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 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.

These preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, mag- Snesium stearate, talc, lanolin or petroleum jelly.

Tablets, coated tablets, capsules, syrups, elixirs or drops are used in particular for oral administration, suppositories are used in particular for rectal administration, solutions, preferably oily or aqueous solutions, and in addition suspensions, emulsions or implants are used in particular for parenteral administration, and ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example solutions in alcohols such as ethanol or isopropanol, acetonitrile, DMF, PAT LOG 16 071088 1,2-dihydro-1-ethyl-2-oxo-3-, or -6-pyridyl; dihydroalkyloxopyridazinyl such as 1,6-dihydro-1-methyl- 6-oxo-3-, or -5-pyridazinyl, 1,6-dihydro-3.-ethyl-6oxo-3-, or PAT LOG 16 071088 17 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 physiologically acceptable salts can be administered to humanor animals, in particular mammals such as apes, dogs, cats, rats or mice and can be used in the therapeutic S treatment of the human or animal body and also in the control of diseases, in particular in the therapy and/or

S

prophylaxis of disturbances of the cardiovascular system, in particular decompensated cardiac insufficiency, angina pectoris, arrhythmia, peripheral or cerebral vessel 1 disorders, and disease conditions which are connected with high blood pressure, and in addition disorders which 1 are connected with changes in the non-vascular musculature, for example asthma or urinary incontinence.

C" E In this connection, the substances according to the invention are usually administered analogously to known antianginals or hypotensives, for example nicoran- S"t 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 mand 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 PAT LOG 16 071088 -A cyj, A. IL L1 aUU.LL.LIJAL kLR.Jk.L.%L- ,I ACS: thioacetyl, and in addition thiopropionyl; AOOC: methoxycarbonyl, and in addition ethoxycarbonyl; PAT LOG 16 071088 18 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 combination 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 adaition 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 formula 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 added, if necessary; the mixture is extracted using an organic solvent such as ethyl acetate, the organic phase is separated off, dried over sodium sul- .t fate, filtered and evaporated, and the residue is purified by chromatography and/or crystallization.

L L All temperatures indicated above and below are in Jd' eCJ20 in methanol, c 1.

ti. Example 1 A mixture of 20.1 g of 2,2-dimethyl-3,4-epoxy-6cyanochroman 14 g of 2-hydroxypyridine (1H-2pyridone), 7 ml of pyridine and 70 ml of ethanol is boiled for 2 hours. The mixture is cooled, the precipi-

S

L tate is filtered off, the filtrate is concentrated and the residue is chromatographed on silica gel. Using diethyl ether/ethyl acetate 2,2-dimethyl-4-(2pyridyloxy)-6-cyano-3-chromanol is obtained, m.p. 102- 1030.

PAT LOG 16 071088 U,N-diethylcarbamoy8; HANCS: I4-methylthiocarbamoyl, and in addition Nethylthiocarbamoyl; PAT LOG 16 071088 -19 The following are obtained analogously (bailing times up to 15 hours): 2,2,3-Trimethyl-4-(2-pyr.Ldyloxy)-6-cyano-3-chromanol 105-107' 2, 2-Tetramethylene-4- (2-pyridyloxy) -6-cyano-3-chromanol m.p. 126-1270 2, 2-Pentamethylene-4- (2-pyridyloxy) -6-cyano-3-chromanol, m.p. 108-1100 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 -methoxycarbo nyl -3 chromanol 2, 2-Dimethyl-4- (3-pyridyloxy) -6-cyano-3-chromanol, m.p. 202-204* 2, 2, 3-Trimethyl-4- (3 3-pyridyloxy) -6-cyano-3-chromanol 2,2-Dimethyl-4-(4-pyridyloxy)-6-cyano-3-chromanol, m.p. 193-1960 2,2, 3-Trimethyl-4 (4 4-pyridyloxy) -6 -cyano-3 -chromanol 2,-iehy--3pyiaiylx)6cyn--h1oao 2,22,2-imethyl-4-(3-pyridaziyloxy)-6-cyano-3-cromano 2,2, 3-Trimethyl-4- -pyrimdinyloxy) -6-cyano-3-chromanol 2, 2-Dimethyl-4-( 4-pyrimiinyloxy) -6-cyano-3-chromanol, m.p. 103-1050 252,2,3-Trimethyl-4-(4-pyrmiinyloxy) -6-cyano-3-chromanol j 2,2,Dimethyd-4-(8-mlrofipyridine -ano400cmoaol 2,2, 3-Tr (2ehy-4-( -yraziyloxy) -6-cyano-3-chronanol sotand66424-4.*(ro tao) PAT LOG 16 071088 To0 rnose compounds ot the furinula. I in which at least one of the radicals mentioned has one of the previously mentioned preferred meanings. Some preferred groups of compounds can be expressed by the formulae Ia to Ii d PAT LOG--16 071088 The following are obtained analogously using 2, 4-dihydroxypyridine: 2,2,3-Trimethyl-4-(2-hydroxy--4-pyridyloxy)-6-cyano-3chromanol, map. 198-2000 2, 2-Tetramethylene-4- (2-hydroxy-4-pyridyloxy) -6-cyano-3chromanol 2, 2-Pentamethylene-4-( 2-hydroxy-4 -pyridyloxy) -6-cyano-3chromanol 2, 2-Dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-nitro-3chromanol, (J m.p. 224-2260 2,2, 3-Triznethyl-4- (2-hydroxy-4-pyridyloxy) -6-nitro-3chromanol 2, 2-Dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-bromo-3chromanol 2,2, 3-Trimethyl-4- (2-hydroxy-4-pyridyloxy) -6-bromo-3chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-methoxycarbonyl-3-chromanol, m.p. 251'-2520 ?0 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-methoxycarbonyl-3-chromanol; using 2, 3-dihydroxypyridine: 2, 2-Dimethyl-4- (2-hydroxy-3-pyridyloxy) -6-cyano-3chromanol, m.p. 262-2650; 0,60425 2,2, 3-Trimethyl-4-(2-hydroxy-3-pyridyloxy) -6-cyano-3- *ova chromanol; using 2,2-Dimethyl-4-(2-hydroxy-5-pyridyloxy)-6-cyano-3chromanol, m.p. 256-258'; 2,2,3-Trimethyl-4-(2-hydroxy-5-pyridyloxy) -6-cyano-3chromanol; PAT LOG 16 071088 o~I -fyuraxy-3-pyJ.uazL~y.L cdHu is 0.

Compounds of the formulae I' and Ia' to Ii' are furthermore preferred which correspond to the formulae I PAT LOG 16 071088 -21 using 4,6 dihydzoxypyrimidine 2,2-Dimethyl-4-(6-hydroxy-4-pyrimidinyloxy) -6-cyano-3chromanol, m.p. 235-237* 2,2 ,3-Trimethyl-4-(6-hydroxy-4-pyrimidinyloxy)-6-cyano- 3-chromanol; using 3,6-dfihydroxypyridazine: 2,2-Dimethyi-4-( 6-hydroxy-3-pyridazinyloxy) -6-cyano-3chromanol m.p. 255-2560 2,2, 3-Trimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-cyano- 3-chromanol, m.p. 236-2390 2,2-Tetramethylene-4-(6-hydroxy-3 -pyridazinyloxy)-6cyano-3 -chromanol 2,2-Pentamethylene-4-(6-hydroxy-3-pyridazinyloxy) -6cyano-3-chromanol, no m.p. up to 2750 2,2-Dimethyl-4-(6-hydroxy-3-pyridazinyloxy) -6-nitro-3chromanol, no m.p. up to 2600 2, 2, 3-Trimethyl- 4 -hydroxy-3 -pyridaz inyloxy) -6 -nitro- 3-chromanal, m.p. 223-2250 2,2-Dimethy1-4-(6-hydroxy-3-pyridazinyoxy)-6bromo-3-.

210 chromanol, m.p. 257-2590 4. 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-bromo- 9,9: 3-chromanol 2 ,2-Dimethyl-4- 6-hydroxy-3-pyridazinyloxy) -6-methoxycarbonyl-3-chromanol, m.p. 2420 2,2, 3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy) -6-methoxycarbonyl-3-chromanol.

Example 3 A mixture of 20. 1 g of Iha, 11. 1 g of 2-mercapto-.

6 0 4pyridine, 6.6 ml of pyridine and 265 ml -of ethanol is boiled for 3 hours. The mixture is concentrated and the 11 XT2, 2-dimethyl-4- (2-pyridylthio) -6-cyano-3-chromaniol obtained is crystallized from diisopropyi ether, in.p.

101-1030.

PAT LOG 16 071088 -22- 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-cluomanol 2,2, 3-Trimethyl-4- (3-pyridylth 1 o) -6-cvano-3-chromanol 2 ,2-Diethy-4-(4-pyridylthio)-6-c-yano-3-chromanol 2,2, 3-Trimethyl-4-( 4-pyridylthio) -6-cyano-3-chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyridylthio)-6-cyano-3chromanol 2,2,3-Trimethyl-4-(2-hydroxy-4--pyridylthio)-6-cyano-3chromanol 2, 2-Dimethyl-4- 6-hydroxy-3-pyridazinylthio) -6-cyano-3chromano 1 2,2, 3-Trimethyl-4- (6-hydroxy-3-pyridazinylthio) -6-cyano- 3-chromanol 2,2-Dimethyl-4- (6-mercapto-3-pyridazinylthio) -6-cyano-3chomno 2, 2, 3-Trimethyl-4- 6-mercapto-3-pyridazinylthio) -6-cyano- 3-chromanol.

Example 4 mixture of 2 g of Iha, 1.11 g of 2-mercaptopyridine, 60 ml of DMSO and 0.3 g of NaH (80 strength) h is stirred for 6 hours at 200 and worked up as customary.

2 ,2-Dimethyl-4-(2-pyridylthio) -6-cyano-3-chromene, M.P.

110-1120 is obtained.

45 The following are obtained analogously:' ehl4-3prdyti 6-yn--crmn 4 2,2, 32-imethyl-4- (3-pyridylthio) -6-cyano-3-chromene 2,,-rmtyH-3prdyti)6cao3crmn LIII2,2-Dimethyl-4-(3-pyridylthio)-6-cyano-3-ch-romene 2,2,3-Trimethyl-4-(3-pyridylthio)-6-cyano-3-chromene 2,2-Dimethyl-4-(2-hydroxy-4-pyridylthio)-6-cyano-3c hromene 2,2,3-Trimethyi-4-(2-hydroxy-4-pyridylthio)-6-cyano-3- PAT LOG 16 071088 -LIA d L-ol-ajas-c compound ot the formula 3: is converted into one of its acid addition salts by treating with an acid.

The compounds of the formula I are otherwise prepared by methods which are known per se, as are PAT LOG 16 071088 r77' 23 chromene 2, 2-Dimethyl-4- (6-hydroxy-3-pyridazinylthio) -6-cyano-3chromene 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinylthio)-6-cyano- 3-chromene 2 ,2-Dimethyl-4-( 6-mercapto-3-pyridazinylthio) -6-cyano-3chromene 2,2, 3-Trimethyl-4-( 6-mercapto-3-pyridazinylthio) -6-cyano- 3-chromene.

Example 2, 2-Dimethyl-4- 3-hydroxy- 2-pyridyl amino) -6cyano-3-chromanol, m.p. ?07-2O8.5*, is obtained from Iha and 2 -amino- 3-hydroxypyridlne analogously to Example1 The following are obtained analogously: 2,2,3-Trimethyl-4-(3-hydroxy-2-pyr-idylamino)-6-cyano-3chciomanol 2,2-Dimethyl-4-(2-hydroxy-4-pyrimidinylamino)-6-cyano-3chromanol, no m.p. up to 2800 2, 2, 3-Trimethyl-4 -hydroxy-4 -pyrimidiny"Lamino) -6 -cyano- 3-chromanol 2,2-Dimethyl-4-(2-hydroxy-4-pyridylamino)-6-cyano-3chromanol 2,2, 3-Triinethyl-4-( 2-hydrox-y-4-pyridylanino)-6-cyano-3ch.romanol 2,2,-imethyl-4-(2-hydroxy-4-pyridylamino)-6-nitro-3chromanol, 2,2, -Timethyl-4- (2-hydroxy-4-pyridylamino) -6-niro-3chromanol 2,2,-imethyl-4-(2-hydroxy-4-pyridylamino)-6-bromo-3- 2, 2-Dirnethyl-4- 6-hydroxv-3-pyridazinylamino) -6-cyano-3- PAT LOG 16 071088 o~~~kK R 1 Vd x- -C HiCR' R IVe -CHBr-CROif desired condensing with aldehydes of the foriaula R 9

-CIIO

(R

9 alkyl having 1-5 C atoms) to give 3-alkylidefle- 4 PAT LOG 16 071088 -24 chromanol 2,2, 3-Trimethyl-4-( 6-hydroxy-3-pyridazinylamino) -6-cyano- 3 -chromanol 2, 2-Dimethyl-4 (6 -hydroxy-3-pyridaz inylamino) 6 -nitro-3 chromanol 2,2, 3-Trimethyl-4- (6-hydroxy-3-pyridazinylamino) -6-nitro- 3-chromanol; 2 ,2-Dimethyl-4- (6-hydroxy-3-pyr'idazinylamino) -6-bromo-3chromanol 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 -pyridaz inyl amino) -6cyano-3-chromanol 2, 2, 3-Trimethyl-4 6-dihydro-6 -oxo-3-pyridaz inyl amino) o I 6-cyano- 3-chromanol 2, 2-Dimethyl-4 6-dihydro-6 -oxo- 3-pyridaz inyl amino) -6 nitro- 3-chromanol 120 2,2,3-Trimethyl-4-(1,6-dihydro-6-oxo-3-pyridazinylamino) -nitro- 3-chromanol .0.:2,2-Dimethyl-4- (1,6-dihydro-6-oxo-3-pyridazinylamino) -6bromo-3-chromanol K 2,2,3-Trimethyl-4-(1,6-dihyctro-6-oxo-3-pyridazinylamino) 6-bromo-3-chromanol.

Example 6 1.2 g of 80 Nail are added to a solution of 2.66 g of 2,2-dimethyl-4-bromo-6-cyanochroman 89-920; obtainable by reduction of 2,2-dimethyl-6-cyano-4-chromanone with NaBH, in CH 3 0H to give oily 2,2-dimethyl-6cyano-4-chroman-,l and reaction with PBr 3 in toluene at and 2.5 g of Ipyridazine-3,6-diol in 70 ml of DMSQ, and the mixture is stirred at 200 for 3 days. After customary working up, 2,2-dimrethyl-4-(6-hydroxy-,3-pyridazinyloxy)- PAT LOG 16 071088 base. Suitable bases are, for example, nyuzUA±LLAI= carbonates, alkoxides, hydrides and also amides of alkali metals or alkaline earth metals, such as NaOH, KOH, Ca (OH) 2 Na 2

CO

3

K

2

CO

3 Na methoxide or K methoxide, Na PAT LOG 16 071088 6-cyanoch-roman, m.p. 221-2240, is obtained.

The following are obtained analogously: 2,2 ,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy) -6-cyanochroman 2 ,2-Dimethkl-4-(6-hydroxy-3-pyridazinyloxy) -6-bromochroman 2,2, 3-TriMethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-bromochroman 2 ,2-Dimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-nitrochroman 2, 2, 3 -Trimethyl -4 6 -hydroxy- 3-pyridaz inyloxy) -6 -nitrochroman 2, 2-Dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-cyanochroman it2,2, 3-Triznethyl-4- (2-hydroxy-4-pyridyloxy) -6-cyanochroman 2 ,2-Dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-bromochroman (fir 2,,-rmtyt-2hdoy4-yiyoy--rm~ho 2,2, -imethyl-4- (2-hydroxy-4-pyridyloxy) -6-iromchroman d 2-hydroxy-4-pyridyloxy) 6-ntroc ro 2 ,,-rmtyl4(-yrxy4prdlxy6.nto.

chroman.

Example 7 A mixture of 10 g of 2,2-dimethyl-4-(2-pyridylthio)-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 2 2 -dimethyl-4-(2-pyidylthio.6cyano-3.chromene, m.p.

110-1120, is obtained.

Example 8 A mixture of 2 g of 11.7 ml of formic acid and 3.3 ml of acetic anhydride is allowed to stand at 200 for 16 hours and then warmed to 40-42* for 2 hours. After evaporating and customary workina 2,2-dimethyl-3- PAT LOG 16 071088 the action of one of the bases mentioned, for example NaH, in one of the solvents mentioned, for example DMSO, PAT LOG 16 071088 §1 26 formyloxy-4-(6-hydroxy-3-pyridazinyloxy)-6-cyanochroman is obtained.

Thet following are obtained analogously from the corresponding 3-hydroxychromans: 2,2,3-Trilethyl-3-formyloxy-4-(6-hydroxy-3-pyridazinyloxy) -6-cyanochroman 2,2-Dimethyl-3-formyloxy-4-(2-hydroxy-4-pyridyloxy)-6cyanochroman 2,2,3-Trimethyl-3-formyloxy-4-(2-hydroxy-4-pyridyloxy)- 6-cyanochroman.

Example 9 A mixture of 1 g of and 5 ml of acetic anhydride is boiled for 1 hour. The mixture is cooled, worke- up as customary and 2,2-dimethl-3-acetoxy-4-(6hydroxty-3-pyridazinyloxy) -6-cyanochroman is obtained,m.p. 210212.

The following are obtained analogously: 2,2,3-Trimethyl-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-hyiroxy-4-pyridyloxy)-6cyanochroman.

0 44 4~ 4 0 1

I

Example A solution of 1 g of 2,2-dimethyl-4-(2-hydroxy- 25 4-pyridyloxy )-6-nitro-3-chromanol in 25 ml of methanol is hydrogenated at 200 and 1 bar on 0.5 g of 5 Pd-C to completion. The mixture is filtered, evaporated and 2,2dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3-chromanol is obtained.

The following are obtained analogously: PAT LOG 16 07,088 for example, compounds of the formulae A-Cl, A-3r or A-I or corresponding sulfuric acid or sulfonic acid esters, PAT LOG 16 071088 Mlsl3ersaea*~111 rcll- 04 0 o** 4..

Ii 27 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3chromanol 2,2-Dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-amino-3chromanol 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-amino- 3-chromanol.

Example 11 A solution of 1 g of 2,2-dimethyl-4-(2-.hydroxy- 4-pyridyloxy)-6-amino-3-chromanol in 15 ml of HCOOH and 1 ml of pyridine is boiled for 19 hours and evaporated.

After customary ing up, 2,2-dimethyl-4-(2-hydroxy-4- S pyridyloxy)-6-formamido-3-chromanoI is obtained.

S Example 12 A mixture of 1 g of 2,2-dimethyl-4-(2-hydroxy-4pyridyloxy)-6-amino-3-chromanol/10 ml of acetic anhydride and 10 ml of pyridine is allowed to stand at 200 for 16 hours. The mixture is evaporated, purified chromatographically and 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6acetamido-3-chromoanol is obtained.

4 S Example 13 ICl is introduced with stirring for 14 hours into a boiling solution of 1 g of in 50 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-pyridazinyloxy)-3-chromanol-6-carboxylic acid deposited is filtered off.

Example 14 30 A mixture of 3.13 g of "BI, 31 g of Na 3

PO

4 .12 H 2 0, 28 ml of pyridini, 28 ml of water, 67 ml of acetic acid and 25 g of Raney Ni (water-moist) is stirred at 200 for 3 hours. After filtering, the mixture is worked up as customary and 2,2-dimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6-formyl-3-chromanol, m.p. 256-257a, is obtained.

PAT LOG 16 071088 -28- The following are obtained analogously: 2,2, 3-Trimethy'L-4 6-hydroxy-3-pyridazinyloxy) -6-f ormyL- 3-chromanol 2, 2-Dimethyl-4- (2-hydroxy-4-pyridyloxy) -6-formyl-3chromanol 2,2,3-Trimethyl-4-(2-hydroxy-4-pyridyloxy)-6-formyl-3chromanol.

10 0 00 0 6064 0 o o 0*0 0 00 0 0 0 0 0 00 0*04 0 0 0 4* Example 3.13 g of are dissolved in 40 ml of tert.butanol and 5.6 g of powdered KOH are added with stirring. 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 analogously: 2,2,3-Trimethyl-4-(6-hydroxy-3-pyridazinyloxy)-6carbamoyl-3 -chromanol 2, 2 -Dimethyl -4 (2 -hydroxy-4 -pyridyl oxy) 6-carbamoyl -3 chromanol 00 0 2,2, 3-Trimethyl-4- 2-hydroxy-4-pyridyloxy) -6-carbamoyl 3-chromanol.

Example 16

H

2 S is introduced at 200 for 5 hours into a solution of 3.12 g of in a mixture of 20 ml of pyridine and 10 ml of triethylamine, the mixture is evaporated and worked up as customary, and 2, 2-dimethyl- 4- (2-hydroxy-4 -pyridyloxy) -6-thiocarbamoyl -3 -chromanol, m.p. 2420, is obtained.

The following are obtained analogously: 2,2,3-Trimethyl-4-(2-hydroz7---4-pyridyloxy)-6-thiocarbamoylchroman-3-ol.

PAT LOG 16 071088 then resolved with the aid of chiral acylating reagents, for example the cited acids, particularly or camphanic acid or or (-)-camphor-lO-sulfonic acid or with D-or L--methylbenzyl isocyanate (cf.

-29 2, 2-Dimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-thiocarbamoyl-3-chromanol, m.p. 142-144o 2,2, 3-Trimethyl-4- (6-hydroxy-3-pyridazinyloxy) -6-thiocarbamoyl-3-chromanol.

Example 17 A mixture of 310 mg of 808 mg of Lawesson reagent and 50 ml of toluene is boiled under N 2 for 1 hour. Customary working up gives 2,2-dimethyl-4-(6mercapto-3-pyridazinyloxy) -6-cyano-3-chromanol [2,2dimethyl-4-(l,6-dihydro-6-thiaxo-3-pyridazinyloxy)-6cyano-3-chromanol].

4' 2, 2-Dimethyl-4- (2-mercapto-4-pyridyloxy) -6-:zyano- 3-chromanol is obtained analogously from The following are obtained analogouisly: 15 ~1 ft ft ft ft ftj ft ft 4* 4 ,4 ft 2,2, 3-Trimethyl-4- -mercapto-3-pyridazinyloxy) -6-cyano- 3 -chromanol 2, 2 -Dimethyl-4 (6 -mercapto- 3-pyridaz inyloxy) 6-nitro- 3chromano 1 2, 2, 3-Trimethyl-4 (6 -mercapto- 3-pyridaz inyloxy) -6 -nitro- 3-chromanol 2, 2-Dimethyl-4- (6-mercapto-3-pyridazinyloxy) -6-bromo-3chromanol 2,2, 3-Trimethyl-4- (6-mercapto-3-pyridazinyloxy) -6-bromo- 3-chromanol 2,2,3-Trimethyl-4-(2-mercapto-4-pyridyloxy)-6-cyano-3- I oao2, 2 -Dimethyl 4- 2 -merc apto -A-pyr idylo xy) 6 -nitro -3 chromanol 2,2, 3-Trimethyl-4- (2-mercapto3-4-pyridyloxy) -6-nitro-3chromanol 2, 2 -Dimethyl-4- (2 -mercapto- 4-pyridy..oxy) 76 -nitro-3 chromanol 2, 2,3-Trimethyl-4- (2-mercapto-4-pyridyloxy) -6-nitro-3- PAT LOG 16 071088 aersol, solutions (for example solutions in alcohols such as ethanol or isopropanol, acetonitrile, DMF, PAT LOG 16 071088 30 chromanol.

Example 18 A mixture of 312 mg of 20 ml of acetone, 400 mg of K 2 C0 3 and 0.2 ml of dimethyl sulfate is boiled for 2 hours. The mixture is filtered, evaporated and chromatogra'phed on silica gel. Using ethyl acetate/methanol 2,2-dimethyl-4-(1,2-dihydro-1-methyl-2-oxo-4py-ridyloxy) -6-cyano-3-chromanol, M. p. 202-2030i is obtained.

The following are ebtained analogously: t it 2,2, 3-Trimethyl-4- 2-dihydro-l-methyl-2-oxo-4-pyridyloxy) -6-cyano-3-chromanol 2, 2-Dimethyl-4- 6-dihydro-l-methyl-6-oxo-3-pyridazinyloxy) -6-cyano-3-chromanol, m.p. 206-208' 2,2, 3-Trimethyl-4-( 1,6-dihydro-l-methyl-6-oxo-3-pyridazinyloxy)-6-cyano-3-chromanol, m.p. 197-199* 2, 2-Dimethyl-4- 6-dihydro-l-methyl-6-oxo-3-pyridazinyloxy) -6-nitro-3-chromanol 2,2 ,3-Trimethyl-4-( l,6-dihydro-l-methyl-6-oxo-3-pyridaz inyloxy) -6 -nitro- 3-chromanol 2, 2-Dimethyl-4- 6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy) 6 -bromo- 3-chromano 1 2 2 3 -Tr iethyl 4- 1, 6 -d ihydro -l1-methyl1- 6 -oxo 3-pyr ida zinyloxy) 6-bromo- 3-c hromanol1 2, 2 -Dimethyl- 4- 2 -dihydro- I-ethyl- 2-oxo- 4-pyridyloxy) 6 -cyano-3-chromanol 2 3-Trimethyl-4- 2-dihydro-l-ethyl-2-oxo-4-pyridyloxy) -6-cyano-3-chromanol 2, 2-Dimethyl-4- 2 -dihycro- 1-ethyl- 6-oxo- 3-pyridaz inyloxy)-6-cyano-3-chromanol, m.p. 164-167* 2 ,2 ,3-Trimethyl-4- 2-dihydro-l-ethyl-6-oxo-3-pyri.dazinyloxy)-6-cyano-3-chromanol~m.P. 166-168*.

.4 .4 ti 4 25 out

I

*8*6 4 PAT LOG 16 071088 j F LAJQ L %J L L jJQXL LLU±.L patient depends,, however, on a variety of factors, for example on the efficacy of the specific compound PAT LOG 16 071088 -31- Example 19 P. mixture of 313 mg of 1 g Of KZC0 3 1 0.65 ml of dimethyl sulfate and 16 ml of DMF is boiled for 3 hours and worked up as customary. 2,2-Dimethyl-4-(6methoxy-3-pyridazinyloxy)-6-cyano-3-chomalol, m.p. 224- 2270, is obtained.

V The following are obtained analogously: 2,2, 3-Trimethyl-4- (6-methoxy-3-pyridazinyloxy) -6-cyano- 3-chromanol 2,2-Dimethyl-4-(2-methoxy-4-pyridyloxy)-6-cyano-3chromanol 2,2,3-Trimethyl-4-(2-methoxy-4-pyridyloxy)-6-cyano-3chromanol.

It Example In analogy to Example 18, 2,2-dimethyl-4-(l,6-dihydrol-isopropyl-6-oxo-3-pyridazinyloxy) -6-cyan-3-chrornanol is obtained from and 2-bromopropane,- m.p. 201-2030.

Example 21.

a) A mixture of 5 g of 5 g of (+)-campher-l0sulfonic acid chloride and 50 ml of pyridine is ~.warmed to 70' for 5 hours. After working up with j' dilute hydrochloric acid and ethyl acetate as usual mitue ofdclrmtaean ty ct"e I and chromatographic separation on silica gel with there are obtained t,-wo epimers of "B"-(+)-camnpherlO-sulfonic acid ester, m.p. 223-2240 and m.p.

127-1500, respectively.

~J~Y---~Y-u--yz~u3-cromfl 1-is obtained, m-p. 102- 1030.

PAT LOG 16 071088 32 b) A mixture of 2 g of the "unpolar" epimer (m.p.

223-2240), 16 g of "sodium hydroxide on carrier" ("Natriumhydroxid auf Trager", E. Merck, catalogue "Reagenzien, Diagnostica, Chemikalien", 1987/88, page 587, No. 1567) and 80 ml of methanol is stirred for 20 hours at 200. The mixture is concentrated to dryness and dissolved in water. HCl is added until pH 8 and the 2,2-dimethyl-4-(l,6-dihydro-6-oxo-3-pyridazinyloxy) -6-cyan-3-chromene thus obtained 226-2280) is filtered off.

Working up of the filtrate with hydrochloric acid/ ethyl acetate at pH 4 and chromatography on silica gel with dichioromethane/ethyl acetate/Methanol yields 2-dimethyl-4- 6-dihydro-6-oxopyridazinyl-oxy)-6-cyan-3-chromanol, m.p. 2290; [u] -168.50.

c) Analogously, (+)-2,2-dimethyl-4-(l, 6-dihydro-6-oxo- 3-pyridazinyl-oxy)-6-cyafl-3-chromanol (xn.p. 232-233'; +170.00) is obtained from the "polar" epimer Analogously, 2, 2-direthyl-4-(2-hydroxy-4-pyridyl-oxy)-6cyan-3-chromene 263-2640) as well as and chromanol are obtained from "A"l via the corresponding (+)-campher-sulfonic acid esters.

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Claims (2)

1. 33- The Claims defining the invention are as follows: 1. Chroman derivatives of the formula I R 4 W R3 00 4 00* 4 00 0 o 0 0 0 00 0 0 04 0 04 0.404 a a 0 o a $04, a a a 44 00 i n which RZ and Re R 3 and R 4 R 5 R 6 and R 7 is A, are each H or A, together are also alkylene having 3-6 C atoms, is H, OH, OA or OAc, is H, together are also a bond, is a pyridyl, pyridazinyl, pyrimidinyl, pyraz- inyl, oxodihydxopyridyl, o,--odihycropyridazinyl, oxodihydropyrimidinyl or oxodihydropyrazinyl radical which is unsubstituted, monosubstituted or disubstituted by A, F, Cl, Br, I, OH, OA, OAc, SH, NO 2 NH. 2 AcNH, HOOC and/or AOOC, are each H, A, HO, AO, CHO, ACO, ACS, HOOC, AQOC, AO-CS, ACQO, A-CS-O, hydroxy-B- having 1-6 C atoms, mercapto.-B- having 1-6 C atoms, NO 2 NH21 NHA, IAk, CN, F, Cl, Br, I, CF 3 ASO, ASO 2 AO-SO, AO-S0 2 AcNI, AO-CO-NH, H 2 NSO, HANSO, A 2 NSO, H 2 NSO 2 HANSO 2 A 2 NSOz, H 2 NCO, HANCO, A 2 NCO, H 2 NCS, HANCS, A 2 NCS, ASONI ASO 2 NI AOSONH, AOSO 2 NH, ACO-B-., nitro.-B-. -cyano- A-C(=NOH) or A-C(=NNH 2 is 0, S, or NiH, ~p 00 0 a. a -9444., LOG 16 071088 obtained is crystallized from diisopropyl ether, m.p.
2. 101-1030. PAT LOG 16 071088 0372p:mmb 34 Z is O, S, or NH, A is alkyl having 1-6 C atoms, B is alkylene having 1-6 atoms and AC is alkanoyl having 1-8 atoms or aroyl having 7-11 C atoms with the proviso that, when Z is oxygen, R 5 is one of the radicals specified but must be monosubstituted or disubstituted by SH and their salts. 2. 2, 2-Dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-cyano-3- chromanol. 3. 2, 2-Dimethyl-4-(1, 6-dihydro-1-methyl-6-oxo-3- pyridaz i nyl oyy) 6 cyano-3-chromanol. 4. 2-Dimethyl-4R-(1, 6-dihydro- -methyl-6-oxo- 3-pyridaziny-loxy)-6-cyano-3S-chromanol. A pharmaceutical containing as an active ingredient at least one compound as defined in claims 1 to 4 and/or a physiologically acceptable salt thereof together with a pharmaceutically acceptable carrier, diluent or adjunct. 6. A process for the manufacture of a pharmaceutical composition containing as an active ingredient at least one I of the compounds as defined in claims 1 to 4 and/or Sphysiologically acceptable salts thereof wherein this active ingredient is processed with at least one pharmaceutically o acceptable carrier material. DATED this 15th day of July, 1992. a I" MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG By Its Patent Attorneys DAVIES COLLISON CAVE S* a IL