CH634320A5 - Naphthyridines - Google Patents

Description

The invention relates to new naphthyridines with a 3-amino-2-OR-propoxy substituent. The compounds have beta-adrenergic blocking and immediate antihypertensive activity.

N-heteromonocyclic 3-amino-2-hydroxypropoxy-substituted compounds with β-adrenergic blocking activity are known (U.S. Patent 4,000,282; South African Patent 74/01070). Mono-N-heterobicyclic 3-amino-2-hydroxy-propoxy-substituted compounds which show a β-adrenergic blocking activity are known [Crowther et al, J. Med. Chem. 15, 260-266 (1972)].

New di-N-heterobicyclic compounds, namely 3-amino-2-OR-propoxynaphthyridines, have now been found. These compounds show β-adrenergic blocking activity and antihypertensive activity with immediate onset.

The invention relates to naphthyridine compounds with 3-substituted amino-2-OR-propoxy substituents and medicaments containing these compounds.

The new naphthyridine compounds have the following formulas

(I)

(IV)

N Nm

N "

OZ

II

V

or

III

VI

wherein

Z denotes -CH2-CHOR-CH2-NHR1, in which R is hydrogen or C2-Ci2-acyl and Ri Ci-Ci2-alkyl and

R2 is hydrogen, chlorine, bromine, fluorine, cyano, amino, nitro, trifluoromethyl or -COOR4, where R4 is hydrogen, C1-C6-alkyl or C6-Ci2-aryl, or R2 is CONRsRé, wherein

5

634320

Rs and Re individually denote hydrogen or Ci-Cs-alkyl or together for -CH2- (CH2) 3-CH2-, -CH2-CH2-O-CH2-CH: -, -CH2-CH2-NH-CH2-CH2- or -CH2-CH2-N (CH3) -CH2-CH2-, Ci-Có-alkylthio, Ci-Có-alkylsulfinyl or Ci-Ce-alkylsulfonyl.

The compounds according to the invention can also be present as salts.

Pharmaceutical preparations suitable for the production of a beta-adrenergic block or for the treatment of hypertension contain an effective amount of a compound of the formulas I-VI or pharmaceutically acceptable salts thereof.

The pharmaceutically acceptable salts are the acid addition salts of the free naphthyridine base. Suitable acids include organic as well as inorganic acids. Examples of useful organic acids are carboxylic acids such as acetic acid, pamoic acid, maleic acid, succinic acid, citric acid, tartaric acid, oxalic acid, malic acid, pivalic acid, heptanoic acid, lauric acid, propanoic acid, pelargonic acid, oleic acid and the like, and the non-carboxylic acids such as isethion -acid. Examples of useful inorganic acids are the hydrohalic acids, e.g. HCl, HBr, HJ, phosphoric acid, sulfuric acid and the like The hydrohalide salts, especially the hydrochlorides, and maleic acid salts, especially hydrogen maleate, are preferred.

R is hydrogen or C2-i2 acyl. The C2-i2 acyl groups include alkanoyl groups such as acetyl, pivaloyl, dodeconoyl, hexanoyl, succinoyl and the like, and carbocyclic aroyl groups such as benzoyl, 1- or 2-naphthoyl, p-methylben-5 zoyl, p -Phenylbenzoyl and the like The C2-C6 alkanoyl and benzoyl groups are preferred acyl groups. Hydrogen is the most preferred R group.

The Ri substituent includes Ci-Ci2-alkyl groups and preferably the Ci-Cö alkyl groups. Examples of alkyl groups are methyl, C12H25, hexyl, 2-ethylhexyl, isopropyl, sec-butyl, heptyl and the like. C3-4 branched alkyl groups are more preferred than Ri groups, with the t-butyl group being the most preferred group.

15 The R2 substituent includes hydrogen, Cl, Br, CF3, NO2, F, -CN, -NH2, the carboxy group defined above and its ester and amide derivatives, the Ci-Cö-alkyl-thio-, -sul-finyl and sulfonyl groups and their derivatives. The ester groups are Ci-Có alkyl esters, e.g. -COOCH3, -COOCòHb, 20 -COOCH (CH3) 2, -COOC2H5 and the like, and C6-Ci2-aryl esters, e.g. CeHs-OOC-, P-CH3-C6H5-OOC-, CôHs-CsHs-OOC-, CioHs-OOC- etc. The amide groups include -CONH2, Ci-Có-substituted amide groups such as -CON (CH3) 2, -CON (C6Hi3) 2, -CONHC: H5, -CON (sec-butyl) 2 and the like, and heterocyclic 2s carbonyl groups, such as

0

II / \

-c-0

0 •

h f -C-N

a „r ~ \

NH (or-CH3) and -C-N "0

The Ci-Ca-alkylthio, sulfinyl and sulfonyl groups are, for example, CHs-S, CeHn-S, (CH3> C-S-, (CH3) 2CH-SO-,

CH3-SO2-, C2H5-SO2-, C6H13-SO-, CsHu-SO-, sec-butyl-SO2- etc. CN is preferred among the R2 groups.

The naphthyridine compounds according to the invention have a chiral center which gives them optical activity. The optical isomers are designated in the usual way with L and D, 1 and d, + and -, S and R or by a combination of these symbols. If the formula or the more preferred naphthyridines have the formulas name of the compounds listed in the present application has no specific name,

the formula or name includes the individual isomers, their mixtures and racemates.

Preferred naphthyridines are those which contain an —OZ group in a position ortho to a ring nitrogen. In even more preferred naphthyridines, the R2 substituent is also ortho to the -OZ group.

Particularly preferred naphthyridines are those of the formulas I, II and III. Particularly preferred are those naphthy so ridins in which the -OZ group is ortho to the N atom, and in particular those in which the R2 group is ortho to the -OZ group.

The formulas have particularly preferred naphthyridines

55

or

60

or

In the most preferred naphthyridines, R2 is cyano and Z is -CH2-CHOH-CH2-NR1, where Ri is Ci-Có-alkyl, with C3-C4 branched alkyl being a preferred group and t-butyl being the most preferred group .

The naphthyridines include all optical isomers and their mixtures, but the S isomer is preferred.

The naphthyridines of the invention can be prepared by any suitable method.

In such a process e.g. the halonaphthy-65 ridine is coupled with a suitable substituted oxazolidine and the reaction product obtained can be hydrolyzed. The process is represented by the following scheme from reaction equations:

634320

mo-ch,

Halo

X «!

Mr'

vii viii

0-ch2-ch-ch2nhr1

Oh

IX

¥

Halo can be Cl, Br and J, with Cl being preferred. M HO-H2C-

means an alkali metal, preferably potassium or sodium. R 'represents hydrogen or the alkyl or aryl residue of any suitable aldehyde

R'-C

/

\

H

e.g. a Cg-C 12 aryl aldehyde, such as benzaldehyde, naphthalene dehyde, m-NO 2 benzaldehyde, p-phenylbenzaldehyde, tolual dehyde and the like, furfural or ò-Cn-alkanyl, such as acetaldehyde, butyraldehyde,

/

C11H23C

^ H

2-ethylhexanol and the like

The process for the preparation of oxazolidines wherein M is hydrogen (and the related coupling reaction) is described in U.S. Patents 3,718,447 and 3,657,237, and these references are expressly referenced. The alkali metal salt of oxazolidine can be prepared by a process known per se by reacting the corresponding hydroxymethyloxazolidine with a suitable amount of alkaline basic reactant. However, this reaction becomes more useful with in-situ formation of the alkali metal oxazo-lidin salt (Formula VIII) by reaction of the oxazolidine eo

65

O N-Ri

X

MR'

40

45

50

55

with the naphthyridine of formula VII in the presence of a suitable base such as K2CO3, an alkali metal alkylate [e.g. K-0-C (-CH3) 3], sodium hydride, an organolithium, e.g. Phenyllithium, n-butyllithium, lithium diisopropylamide and others.

The coupling reaction can be carried out at temperatures in the range of about 0 to about 100 ° C. A temperature range of about 10 to about 50 ° C is preferred. The reaction is suitably carried out in a solvent. Any suitable solvent can be used. Examples of suitable solvents are dioxane, toluene, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, tert-butanol, acetone, alkanols and the like. The hydrolysis is typically carried out using a conventional acidic hydrolysis reagent and procedures, e.g. Treatment with a solution of any suitable acid, such as CH3COOH, HCl or H2SO4. The hydrolysis product can be obtained directly as the salt of the acid used in the hydrolysis. The product is normally obtained as a free base after the neutralization of the salt, which is known per se.

The coupling reaction is usually carried out at atmospheric pressure. Higher pressures can optionally be used.

When a racemic oxazolidine (Formula VII or X) is used as the reactant, the product obtained is a racemate. The racemate can be separated into the individual enantiomers by cleavage methods known per se.

634320

If R 'in the oxazolidine (e.g. formula Vili, IX or X) has a meaning other than hydrogen, in addition to the chiral center at the oxazolidine position 5 there is a second chiral center at the position 2. However, if the oxazolidine is e.g. (S), (R) or (R, S), this designation only concerns the optical configuration around the carbon atom in the 5-position.

Using a single optical isomer of oxazolidine of formula VII or X in the above reactions, the naphthyridine product can be obtained directly as the only enantiomer. Therefore, when the S-isomer of oxazolidine is used, the product obtained becomes that

S isomer. This enables an expedient route for the direct production of individual isomers of the naphthyridines according to the invention.

The naphthyridines according to the invention, in which R has a meaning other than hydrogen, are useful by treating the corresponding compound, in which R is hydrogen, with a suitable acylating agent, such as acyl halide, e.g. Undecanoyl chloride, pivaloyl chloride, benzoyl chloride, p-methoxybenzoyl chloride, io an anhydride, e.g. Acetic anhydride, etc. produced. The reaction is illustrated by the following equations:

OH

h o-ch2-ch-ch2-n-r1 +

V

O H

ch3-c-c1

O

II

o-c-ch.,

I 3

OCK2_Cf ~ CH2 ~ NHRl

H

The compounds according to the invention also comprise further processes for the preparation of naphthyridines, the salts of the new naphthyridines. These salts will become 35 with certain other substituents useful by the following e.g. represented by treatment of the naphthyridine with given reaction equations. A suitable amount of a useful acid known per se, in general reaction conditions can be used.

mine in a suitable solvent.

Hydrolysis coor.

RaOH

Scheme 2

coor y 4th

0

c-N (c2H5) 2

634320

8th

> 1 atm

The naphthyridines are provided with an alkylsulfinyl or alkylsulfo. Any suitable oxidizing agent, e.g. nyl substituents can be used by oxidation of the corresponding H2O2. The following equation-containing compound containing Ci-Cs-alkylthio explains the reaction:

soc3H7

(or

-S ° 2C3H7)

Certain naphthyridine intermediates can be obtained using the 2s procedure. Usual methods and use of the reagents shown in the following reaction scheme are generally used.

Scheme A

HNO2 / H2SO4

PCls / POCh

NH-

Sn Ch / HCl

> NaN02 / H + 5 Cu CN

9

634 320

Scheme B

hydrolysis

^ N /% î

SF4 / HF

Scheme C

"N N

-NaNCh / H4

^ HPFV.A

CNaN02 / H +

^ HBFVEtO

ïNaS-CHî

tf

V> - SCH.

nN xNx ci

Scheme D

N N OH

Halogenating agent

X (Cl or Br)

POCb / PCls

'N N

The compounds according to the invention show an anti- that this antihypertensive activity is due to the peripheral hypertensive activity with a rapid onset, and they are due to vasodilation by a mechanism, also ß-adrenergic blocking agents. One does not directly deal with the ß-adrenergic blockage

634320

Relationship. An advantage of the naphthyridines according to the invention over conventional β-adrenergic agents is that the antihypertensive effect begins immediately and generally has an extended duration.

This rapid onset of antihypertensive activity is determined by administering an exemplary compound according to the invention to spontaneously hypertensive (SH) rats and measuring the effect on blood pressure. Using this test method, it is found that an exemplary compound of the invention exhibits this anti-hypertensive activity with immediate start upon oral administration.

The β-adrenergic blocking activity of the naphthyridines according to the invention is determined by measuring the ability of an exemplary compound to block the isoproterenol-induced β-adrenergic stimulating effect, such as increasing the heart rate, negative pressure and bronchodilation, in vivo. An exemplary naphthyridine was shown to have a beta-adrenergic blocking activity using this in vivo test procedure.

The ability of the naphthyridines according to the invention to rapidly reduce the blood pressure in an SH rat shows

that the compounds according to the invention are suitable for the treatment of overpressure in humans. Similarly, the observed beta-adrenergic blocking activity of these compounds suggests that they are useful to humans as beta-adrenergic blocking agents for the therapeutic treatment of cardiovascular conditions such as angina pectoris, arrhythmia, etc.

For use as antihypertensive agents and / or β-adrenergic blocking agents, the compounds according to the invention can be administered orally or parenterally, i.e. intravenously, intraperitoneally, etc., in any suitable dosage form. The compounds can be presented in a form (1) for oral administration, e.g. as tablets together with other processing components (diluents or carriers) which are usually used, such as talc, vegetable oils, polyols, benzyl alcohols, starches, glycerol and the like, or dissolved, dispersed or emulsified in a suitable liquid carrier, or in capsules or encapsulated in a suitable encapsulation material; or (2) for parenteral administration, dissolved, dispersed or emulsified in a suitable liquid carrier or diluent. The ratio of active ingredient (naphthyridine according to the invention) to processing ingredient (s) will vary according to the dosage form and the required pharmacological effect. Known methods can be used to produce the pharmaceutical preparations.

The daily dose content for the compounds according to the invention can vary from about 0.02 mg to about 50 mg / kg of body weight. Daily dose levels in the range of about 0.05 to about 25 mg / kg are preferred, with about 0.1 to about 15 mg / kg being a more preferred range. Oral administration is preferred. Depending on the unit dose, single or multiple daily doses can be administered.

The invention also relates to pharmaceutical preparations which contain a therapeutically effective amount of a compound according to the invention.

The following examples illustrate the preparation of the naphthyridines according to the invention. Unless otherwise stated, all parts are expressed by weight. All temperatures are given in ° C. Some intermediate products suitable for the preparation of the naphthyridines according to the invention are described by Hawes et al., J. Med. Chem., 16, 849-853 (1973).

example 1

A. 2-Hydroxy-3-cyano-1,8-naphthyridine A mixture of 2.44 g (0.02 mol) of 2-aminonicotinaldehyde, 4.52 g (0.04 mol) of ethyl a-cyanoacetate, 50 ml of absolute ethanol and 0.5 ml of piperidine are stirred under reflux. After 1 h the solution is cooled to 0 to 4 ° C. The yellow solid is filtered off and dried; 2.5 g (73%) of 2-hydroxy-3-cyano-1,8-naphthyridine are obtained; Mp 300 ° C.

B. 2-Chloro-3-cyano-1,8-naphthyridine A mixture of 12.2 g (0.059 mol) of phosphorus penta-chloride, 44 ml of phosphorus oxychloride and 2.3 g (0.013 mol) of 2-hydroxy-3-cyano- 1,8-naphthyridine is stirred under reflux. After 1 h, excess phosphorus oxychloride is distilled off under reduced pressure (20 to 30 mm). The residue is treated with ice and the solution is neutralized with solid NaîCCb. The aqueous solution is extracted with 3x 100 ml CHCb. The organic extracts are dried over NazSCk, filtered and concentrated to dryness. The residue is sublimed at 140 to 150 ° C and 0.3 mm; 1.2 g (81%) of 2-chloro-3-cyano-1,8-naphthyridine are obtained; Mp 273 ° C.

C. (S) -3-Cyano-2- (3-tert-butylamino-2-hydroxypropoxy) -1,8-naphthyridine

2.4 g (0.01 mol) of (S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine, 15 ml of dimethylformamide and 0.5 g (0.01 mol ; 50% mineral oil) NaH and the mixture heated for 5 min on a steam bath. After cooling to room temperature, 1.89 g (0.01 mol) of 2-chloro-3-cyano-1,8-naphthyridine are added and the solution is stirred at room temperature. After stirring overnight, the mixture is poured into 200 ml of water and extracted with 4x 100 ml of ether. The organic layer is washed with 2 x 50 ml of water and then washed with 2x 100 ml of cold IN HCl. The acidic layer is poured into 17 g (0.2 mol) of NaOAc-3H2O and the solution is stirred at room temperature. After 5 h the solution is extracted with 2x75 ml ether. The aqueous layer is neutralized with saturated NaaCCb and extracted with 3 x 100 ml CHCb. The organic layer is dried over Na2SO4, filtered and concentrated to dryness. The residue is crystallized from CH3CN; 0.85 g (20%) is obtained. (S) -3-cyano-2- (3-tert-butylamino-2-hydroxypropoxy) -l, 8-naphthyridine; Mp 152-153 ° C.

Using 2-chloro-3-cyano-1,6-naphthyridine instead of 2-chloro-3-cyano-1,8-naphthyridine in Example 1, stage C, (S) -3-cyano-2- (3-tert-butylamino-2-hydroxypropoxy) -1,6-naphthyridine.

Example 2

(S) -3-cyano-2- (3-tert-butylamino-2-hydroxypropoxy) -1,6-naphthyridine dihydrochloride

4 g (0.07 mol) of (S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine, 25 ml of DMF and 0.85 g (0.018 mol) of NaH (50 % Mineral oil) and heated for 5 min on a steam bath. After cooling to room temperature, 3.3 g (0.017 mol) of 2-chloro-3-cyano-l, 6-naphthyridine are added and the mixture is stirred at room temperature. After stirring overnight

10th

5

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

the mixture is poured into 200 ml of water and extracted with 4x 100 ml of ether. The organic layer is washed with 2 x 50 ml of water and 2 x 100 ml of cold 1N HCl. The acidic layer is poured into 27 g (0.2 mol) NaOAc-3H2O and the solution is extracted with 2x75 ml ether. The aqueous layer is neutralized with saturated NaîCCb and extracted with 3 x 100 ml CHCh. The aqueous layer is dried over NaîSCh, filtered and concentrated to dryness. The residue is chromatographed on silica gel 60 and the product is eluted with CHCh saturated with aqueous NH3. The crude product is crystallized from methanolic HCl and isopropanol (IPA); 0.32 g (5%) of (S) -3-cyano-2- (3-tert-butylamino-2-hydroxypropropoxy) -1, 6-naphthyridine dihydrochloride are obtained; Mp 215-217 ° C.

Using (R, S) -2-methyl-3-isopropylamino-5-hydroxymethyloxazolidine instead of (S) -2-phenyl-3-tert-butylamino-5-hydroxymethyloxazolidine in Example 2 gives the dihydrochloride of (R, S) -3-cyano-2- (3-isopropylamino-2-hydroxypropoxy) -1,6-naphthyridine.

11 634320

Example 3

(S) -1 - (3-tert-Butylamino-2-hydroxypropoxy) -2,7-naph-thyridine hydrogen maleate salt

2.5 g (0.01 5 mol) of (S) -2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine, 50 ml of tert-butanol, 1.3 g ( 0.011 mol) of potassium tert-butoxide and 1.67 g (0.01 mol) of 1-chloro-2,7-naphthyridine and heated with stirring at 40 ° C. After 15 h, the solution is concentrated to dry-kene. 7.2 g (0.12 mol) of acetic acid and 120 ml of 10 water are added to the residue and the solution is stirred at room temperature. After 5 h the solution is extracted with 2x 100 ml ether. The aqueous layer is neutralized with saturated Na2CCb and extracted with 3 x 100 ml CHCh. The organic layer is dried over Na2SC> 4 15, filtered and concentrated to dryness. The residue is chromatographed on silica gel 60 and the product is eluted with 20% MeOH-CHCb. The crude product is crystallized with maleic acid in IPA; 0.4 g (10%) (S) -1 - (3-tert-butylamino-2-hydroxypropoxy) -20 2,7-naphthyridine hydrogen maleate salt are obtained; Mp 177-179 ° C.

B

Claims (9)

634320 l. Compounds of the formula 2nd PATENT CLAIMS (I) (IV) R. sN oz (II) (V) or (III) (VI) and their salts, in which Z denotes -CH2-CHOR-CH2-NHR1, in which R is hydrogen or C2-Ci2-Acy] and Ri are Ci-Ci2-alkyl and R2 is hydrogen, chlorine, bromine, fluorine, cyano, amino, nitro, trifluoromethyl or -COOR. 4 is where R4 is hydrogen, Ci-Có-alkyl or Cs-Cn-aryl, or R2 is CONRsRe, where Rs and Ró are individually hydrogen or Ci-Cs-alkyl or together for -CH2- (CH) 3-CH2 -, -CH2-CH2- O-CH2-CH2-, -CH2-CH2-NH-CH2-CH2- or -CH2-CH2-N (CH3) -CH2-CH2-, Ci-Cs-alkylthio, Ci-Ce-alkylsulfinyl or Ci-Có- Alkylsulfonyl stand. 2. Compounds according to claim 1, characterized in that R stands for hydrogen. 3. Compounds according to claim 1, characterized in that they have the formula or. 4. Compounds according to claim 3, characterized in that they have the formula 634320 0-ch2-ch0r-ch2-NHR1 have. stand. 5. Compounds according to claim 4, characterized 6. Compounds according to claim 3, characterized in that R represents H, Ri for C3-C4-alkyl and R2 for -CN that they have the formula 10th O-CH —CHOR-CH ^ .- NHR 2 z 1 have. -CN stand. 7. Compounds according to claim 6, characterized 8. Compounds according to claim 3, characterized in that R represents hydrogen, Ri represents C3-4-alkyl and R2 represents that they have the formula. 30th 9. Pharmaceutical preparation which is suitable for the production of hypertension, characterized in that a β-adrenergic blocking or for the treatment it an effective amount of a compound of the formula 634 320 wherein Z denotes -CH2-CHOR-CH2-NHR1, in which R is hydrogen or C2-Cn-acyl and Ri Ci-Ci2-alkyl and R2 is hydrogen, chlorine, bromine, fluorine, cyano, amino, nitro, trifluoromethyl or -COOR4, wherein R4 is hydrogen, Ci-Có-alkyl or Có-Ci2-aryl, or R2 is CONRsRg, wherein R5 and Rfi are individually hydrogen or Ci-Cö-alkyl or together for -CH2- (CH2) 3-CH2-, CH2 -CH2-0-CH2-CH2-, -CH2-CH2-NH-CH2-CH2- or -CH2-CH2-N (CH3) -CH2-CH2-, Ci-Ce-Alkylthio.Ci-Ce- 1 alkylsulfinyl or Ci-Có-alkylsulfonyl, or contains pharmaceutically acceptable salts thereof.