DE2436944A1 - 3- (HYDROXYMETHYL) DERIVATIVES OF POLYCYCLIC GAMMA PYRONS, THE PROCESS FOR THEIR MANUFACTURING AND THE MEDICINAL PRODUCTS CONTAINING THESE - Google Patents

Description

HANDLE

DR. PHIL.

PATENTANWÄLTE KERN - FEILER - HÄNZEL

MÜLLER

DIPL.-ING.

DR. RER. NAT. DIPL.-ING.

TELEX: 05 2β 802 HNKL D TELEPHONE: (08 II) 66 31 97, 66 30 91-92 TELEGRAMS: ELLIPSOID MUNICH

EDUARD-SCHMID-STRASSE D-8000 MUNICH DIPL.-ING.

BAVARIAN MORTGAGE AND EXCHANGE BANK MUNICH NO. 318-83 111 POST CHECK: MCHN 162147 - 809

Warner-Lambert Company Morris Plains, NJ, V.St.A. at Jeu m

^ - (Hydroxymethyl ) derivatives of polycyclic gamma-pyrones. Process for their preparation and containing them

Medicinal products.

The invention relates to new 3- (hydroxymethyl) derivatives polycyclic gamma pyrone of the formula:

CH ₂ OH

wherein the ring system indicated by Z by the following formulas

Ca)

-2-

509811/1175

is reproduced, and a new process for their preparation using the corresponding o-hydroxy- <O- (methylsulfinyl) acetonaphthone as starting material. The new compounds according to the invention and these compounds pharmaceutical preparations or medicaments containing them are suitable for the treatment of allergic conditions and to combat hyperacidity.

When administered orally or in injected form, for example, they are able to prevent allergic and asthmatic reactions in mammals such as cats, dogs, guinea pigs and the like. If the compounds according to the invention are given to test animals in the context of the tests described in "Life Sciences", Volume 7, page 465 (1963) and "Proc. Soc. Exptl. Biol. Med.", Volume 81, page 584 (1952) ζ »B. Rats and guinea pigs, administered in a dose of about 5 to 100 mg / kg (body weight), are able to alleviate allergic and asthmatic conditions (in these test animals).

The compounds according to the invention are useful for the symptomatic relief of allergic conditions such as asthma, hay fever and the like. Generally speaking, these compounds will be administered orally, by injection or by inhalation at a dose of about 5 to 100 mg / kg 4

The compounds of the formula I also show antisecretory effects and are therefore suitable for alleviation over-acidity or hyperacidity of the stomach.

When administered intraperitoneally at a dose of The compounds according to the invention are capable of 20 mg / kg

-3-

509811/1175

in the test described by H. Shay in "Gastroenterology", Volume 5, page 43 (1945), to reduce gastric acidification in rats with a tied gastric outlet.

For parenteral administration, the pharmaceutical preparations or drugs containing the compounds of the formula I can be administered as aqueous suspensions for intramuscular injection. These aqueous suspensions are prepared, for example, by suspending the active ingredient in sterile water.

The compounds of formula I may also with known pharmaceutical diluents such as water, lactose versetinitten ρ powder sugar _v mannitol, and the like ^ and in suitable Verabreichungsformenj such as tablets, capsules and the like ,, ^ transferred w © rd®n _o

Certain derivatives of the 3 = (hydroxymethyl) polycyclic pyrons of the formula I also develop antiallergenic and acid-inhibiting properties. "pyrones to treat allergic conditions and Hyperaziditäto This 3 = formyl ~ gamma = pyrones are in US patent application Ser _o No _o 352 ^, described 135

The -new compounds of formula I according to the invention is obtained according to the invention by reacting a starting material of the formula

50981 1/1175

III

wherein Z has the meaning given, with two moles Formaldehyde under basic conditions, using an intermediate of the formula:

CH ₂ OH

II

In the Z has the meaning given, receives and a LSstang ies intermediate of the formula II in a solvent heated, with elimination of the methyl (CEU50H) the desired connections of the

esialtten are, The compounds of formula I invention device made from o-hydroxy-CJ - (methylsul-

f £ 3äjl) n ©© t © © 2iaphth n @ n silt or without isolation of the intermediate liCMiaüf © ^j @ äi3lste of the formula II,

M © iiMügaagsveAlnfengeii äer Fonael III is obtained through

oiic acid - 5it and

S 0 S 8] 1/1 1 7 5

5,6,7,8-tetrahydro-1-hydroxy-2-naphthoate) with a through Sodium hydride exposure to dimethyl sulfoxide generated Sodium methyl sulfynylcarbanion.

The following examples are intended to illustrate the invention in more detail.

example 1

Preparation of 6, 7, 8,9-tetrahydro-3- (hydroxymethyl) -4H-naphtho / 2,3-b7pyran-4-one of the formula:

CfyOH

A solution of 40 g of KpCO ^ in water was admixed with 15 g of 5 ', 6 ·, 7' ^ '- tetrahydro- 3'-hydroxy-2- (methylsulfinyl) -2'-acetonaphthone with stirring. After addition of 15 ml of methanol a clear solution was obtained ,, The solution obtained was added with 34 ml of formalin, and after 15 minutes an oil eliminated _β Then the reaction mixture was extracted three times each with 100 ml CHCl. The combined extracts were dried over NapSO »and concentrated under reduced pressure to an oil. The oil obtained in this way was dissolved in 125 ml of toluene, whereupon the solution obtained was heated to boiling temperature for 30 minutes. Crystals separated out on cooling. These were filtered off, recrystallized from absolute ethanol md ₉ wherein di desired © © © ¥ rblndung -from in a yield 6 g (4390 wyrd obtained © - _o D®r melting point ■ d @ r compound concerned was 12% 5 ° is 131.5 & ⁰ C..

9811/1175

An elemental analysis of the compound C ^ .KL -O gave the following Values:

Calculated: C 73.02 H 6.13 Found: C 73.25 H 6.23.

Example 2 .

Preparation of 7,8,9,1O-tetrahydro-3- (hydroxymethyl) -4H-naphtho / T _f 2-b7pyran-4-one of the formula:

CH ₂ OH

A solution of 32 g Κ "00, * ⁿ 320 ml of water was ^f under stirring with 12 g of 5, 6 ', 7', 8'-tetrahydro-1'-hydroxy-2- (methylsulfinyl) -2 ^r -acetonaphthon offset . After adding 40 ml of methanol, 27 ml of formalin were added to the resulting solution. After stirring for 15 minutes, an oil separated out. The reaction mixture was quenched and extracted several times with 50 ml CH Cl. The combined extracts were dried over NagSO- and concentrated under reduced pressure to an oil. The oil thus obtained was dissolved in 125 ml of toluene, and the resulting solution was heated to boiling temperature for 30 minutes and then cooled. The product which separated out was filtered off and recrystallized from absolute ethanol. In this case, 5 g of the desired compound having a melting point of 136 ° to 138.5 ⁰ C obtained.

An elemental analysis of the compound C ₁ ^ H ₁ ^ Q gave the following values:

- ·; Calculated! C 73.02 H 6.13 Found: C 73.25 H 6.15.

509 81 17 1 175. * _ ₇ _.

Claims (1)

Godparents tan sayings / Ί ·) 3- (Hydroxymethyl) derivative © of polycyclic gamma- ^ - fyrones of the forme ice where the ring system represented by Z is replaced by the following 2o connection after they from 6 ₀ 7p8j9- = T @ trahydro = 3 = (hydrosspiethyl) -4E-> naphtho / 2s, 3 = b7pyran = 4 = -on or 7 _D 8 ₉ 9i, 1IO-T © trahydrQ-3- consists. 3 ο procedure for hearing ΐ @ η by g v @ n 3- goali lasprlchen SO9811 / 1175 1 and / or 2, characterized in that one Compound of the formula: • Ό 0 - 'Il Il .CCH ₂ SCH ₃ Oh Ill in which Z has the meaning given, with formaldehyde to form an intermediate compound of the formula: CH ₂ OH II where Z has the meaning given, converts and then from the intermediate compound obtained from the Forsei Il methylsulfenic acid is thermally split off. Medicinal product, characterized in that it is a 3- (EydsOxymethyl) derivative of polycyclic gamma-pyrone formula ■ 9- 50981 1/1175 CH ₂ OH in which the ring system indicated by Z by the following formulas? Cb) or can be played _s contains. 5. 3- (hydroxymethyl) »3- (methylsulfinyl) derivatives of polycyclic gamma-pyron of the molded ice wherein the ring system represented by Z by the following formulas -10- 50981 1/1175 or can be reproduced. Verbindlang according to claim 5, characterized in that it consists of 2,3,6 _f 7,8,9-hexahydro-3- (hydroxymethyl) - 2,3-b7pyran-4-one 3- (methylsulfinyl) -4H-naphtho / or 213 1 7 ₉ 8,9110-hexahydro-3- (hydroxymethyl) -3- (methylsulfynyl) -4H-naphtho / 7,2-b7pyran-4-one. 509811/1175