DD154490A5 - PROCESS FOR THE PREPARATION OF DIPHOSPHONATE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of diphosphonate derivatives with valuable pharmacological properties for the treatment of cardiovascular diseases. The aim of the invention is to provide novel compounds with rapid and effective activity for lowering the cholesterol content in the blood and in the tissues. According to the invention, hydrodiphosphonate derivatives of formula Ia are prepared in which R and R 'are the same or different and H, CH is deep 3, C is deep 2 H deep 5 or C deep 4 H deep 9 and A is selected from one of the groups wherein n is one is integer from 1 to 6 and Y, H, CH is deep 3, OCH is deep 3 or a halogen atom, especially CL or F.

Description

Berlin, 9.1 »1981 57 909/18

Process for the preparation of diphosphonate derivatives

The present invention relates to processes for the preparation of novel diphosphonate derivatives, and in particular of hydroxydiphosphonates, phosphonophosphates and gem-diphosphonates, which are useful as äntiatherogenic drugs for the treatment of human cardiovascular diseases

^ L ^

Until a few years ago, studies on the prevention of coronary vascular disease have been carried out with conventional hypolipidaemic agents, such as olofibrates. Recently, the results of these studies have called into question the therapeutic efficacy of these compounds (see, eg, B ₆ New Engl. J ₀ Med. £ 96, 1185 to 1190, 197Q; Atherosclerosis Rev., 2 _S 113 to 153 _S 1977; The Lancet 81JDQ, 1131 to 1132, 1978; Brit, Med. Jo, £ L52j 1585, 1978) ₆

The object of the invention is to provide compounds which have a rapid and effective activity in lowering the cholesterol content directly in the tissues and not only in the blood, as is the case with most conventional hypolipidemic agents. "

Explanation of the invention of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation «,

9 · 1.1981

57 909/13

In accordance with the present invention, studies have been made on diphosphonic compounds and it has been found that diphosphonates represented by the general formula (I) have notable activity as antiatherogenic agents as well as the ability to alter the lipoprotein profile in favor of high density lipoproteins ( Density y 1jO65 g / cm) and for direct discharge of cholesterol ^ from various tissues have »

PO-R ₀

A-

C-X

PO ₃ R '

(D

In the above formula (I), X is H or OH; R and R ¹ , which are identical or different, stand for H, CH-, CpHp-, C JHL or C ^ Hq; m is lull or 1> and 'A becomes one of the following groups

selected

where η is an integer from 1 to '6 and Y is H, CH-OCH- or a halogen, in particular Cl or P ₉ ©

The ability to separate cholesterol from tissues gives these compounds (I) the opportunity to

diseases caused or caused by abnormal cholesterol synthesis, metabolism and deposition. Z ₀ B _e cardiovascular diseases which are accompanied on the walls of arteries, in general, of a cholesterol deposit (atheroma), familial Hypercholesterinäinie and cholesterol deposition in the subcutaneous tissues (xanthomatosis), gallstones (cholesterol precipitation), cancer tissues in which the cholesterol metabolism is disturbed, and thrombosis as a result of high cholesterol hypersensitive platelets (?) (Shattil, S _e J ₀ et al, The Journal of Clinical Investigation 55, 636-643, 1975)? Etc*

Since cholesterol is the precursor for steroid hormones (male and female sex hormones and for corticosteroids), the abnormal synthesis of these hormones can be regulated by the use of such compounds. * The applications of phosphonates in the above-described fields are currently investigated. Some of the compounds of formula ( I) also have activity as a hypoglysemic agent «

Diphosphonate derivatives of the formula (I) can be classified as a result of three types of compounds, namely hydroxydiphosphonates (Ia), phosphonophosphates (Ib) and gem-diphosphonates (Ic).

  ι ^{3 d} ι ι* ^ά

A-C-OH (Ia) A A-C-H (Ib) A-C-H (Ic)

I i i

P0oR ^! ₂ POoR'2 PO ₃ R ¹ ₂

wherein Aj R and R ^{1 have} the meaning defined above. According to a first aspect of the invention, the compounds (Ia) and (Ib) can be readily prepared from the same starting materials by the reaction of a dialkyl acyl chloride.

phosphonate of the formula (II) with a dialkylphosphite of the formula (III) in the presence of a base, preferably an amine. The course of the reaction can be controlled by varying the amount of the base used, ie a catalytic amount ( about 5 mole%) of the base, e.g. B, di-n-butylamine gave hydroxy diphosphonate compounds (Ia), while use of about 80-100 mol% of the same base gave the phosphonophosphates; the reaction proceeds according to the following scheme:

HP 5 % Bas e A - C - 0 OC - PO ₃ R ₂ + (0) (0R ^f ) ₂ / PO 3 ^R 2 (H) (III) 80 I 0 3 2 - 100 % Base 'A - i C 1 - H I PO 3 ^R 2

(Ia)

(Ib)

The starting materials, ie. Dialkyl acyl phosphonates (II) are known compounds and can be synthesized by a well-known method by the reaction of an acid halide with a trialkyl phosphite,

0. '0

AC-Cl; + P (OR) ₃ - ~ - ACPO ₃ R ₂ (II)

The advantage of the process is mainly that the starting materials (acyl phosphonates, dialkyl phosphites, base) are soluble in cold ether, while the compounds (Ia) and (Ib) are insoluble and therefore from the reaction mixture in a conventional manner Separate filtration, which allows

For this reason, the process of the present invention is preferably carried out in ether as a solvent at a temperature of about 0 ^° C. In some cases, a small amount of methylene chloride may be added to the ether.

The structure of the compounds (Ia) and (Ib) has been elucidated by IR or * NMR spectroscopy. For all hydroxydiphosphonate compounds (Ia), absorption at 3260-3300 cm ^-1 H (OH) was observed; this pic was missing All of the phosphonophosphates (Ib), both series (Ia) and (Ib) show intense phosphonate absorption by 1260 cra ~ (P = O group) and 1060 cm * " ¹ (POC). ^N

A second object of the invention is a method for the preparation of gem-Diphosphonatverbindun gene (Ic) by reacting an aralkyl halide of the For mel (IV) with a Tetraalkylmethylendiphosphonat of formula (V) at high temperature (about 120 ⁰ C) and Ge genwart an alkaline condensing agent,

base

PO ₃ R ₂ I

, A - Z + CH ₂ - ns »ACH

PO ₃ R! ₂ PO ₃ Rf ₂

(IV) (V) (Ic)

wherein Z is a halogen / in particular Br or Cl ₅ and A, Z, R and R 'have the meaning defined above.

Several bases can be used for the above reaction, namely sodium metal, potassium metal, sodium amide5 sodium hydride, the latter being the most suitable. "

223246 _ ₆ _

The starting materials, d. The tetraalkylmethylene diphosphonate (IV) can be prepared according to the method described in Monatshefte Chemie 81_, 202 (1950) as follows: PO R

R - OH

Cl - CH ₂ POCl ₂ --β- Cl-CH ₂ PO ₃ R ₂ ± -4- CH

(IV) The sodium salt of tetraalkylmethylene diphosphonate (IV)

o ₀

¹ A

(IV)

PO ₃ R '

the in the solvents used (e.g. "B _e toluene, tetra hydrofuren) is highly soluble, can be used in the inventive method as a starting material, in particular when R and R ¹ is higher alkyl than methyl, that is, CpH _r, iG -Ji ^ etc. _e . are"

Tetramethyl gem-diphosphonates according to (Ic), wherein R = R ¹ = CHo, are preferably prepared by the reaction of the trimethyl orthoformate of the formula (VII) and a gem-diphosphonic acid of the formula (VI), the latter being prepared by hydrolysis of tetraalkyl gem-disphosphonate ge, wherein the alkyl is not a methyl group

A PO ₃ R ₂ - CH 1 .HCl A - CH J + HC (OCH ₃ ) - I ^p0 3 ^Rt 2 PO ₃ H ₂ (VI) , (VII) (R, R ' φ CH ₃ )

Poo (CHO)

- C - H

(R = R '= CHo

Z d. ΰ - <* Ό ^ y_ 9 «1.1981

57 909/13

The structures of the preferred diphosphonate compounds (Ic) which are obtained by the process according to the invention have been clearly elucidated by IR, MS and IflvIR spectra, the purity of the gem-Diphosphonatester has been controlled by gas chromatography (3 % SE 3.0 column, 150 ζ 3 mm) »

The process of the present invention will now be further described with reference to the following Examples 1 to 8, which are directed to the preparation of some of the diphosphonate derivatives of general formula (I)

phon at (connection 4)

(Method developed by D _e A · Nicholson and H ₈ Vaughn, Journal of Organic Chemistry, 36, 3843, 1971)

PO ₃ (CH ₃ ) ₂

4.40 g (40 mmol) of dimethyl phosphite and 0.24 g (2 mmol) di (n ~ butyl) were AlNiN afgelöst in 90 ml ether a ^n, and the resulting solution was cooled to ⁰ ° C, _"S 3 96 g (40 mmol) of dimethyl-p-chlorbenzoylphosphonat (made nach.Journal of American Chemical _Society? 86, 3862, 1964) wui'den under rapid stirring added dropwise »Past instantly fell a white plague material from". The mixture was stirred for one hour at 0 C; after filtration, 13.0 g (36 mmol) of the title compound were obtained »

The cleaning was carried out by dissolving the crude compound

in acetone at room temperature and addition of ither for crystallization (acetone ι ether ratio = 3ϊ1) · There were 7 _? 9 g (22 mmol) of white crystals with a yield of 55% (pure compound),

Yield (crude product)

Kp. '

IR (IiBr): 3260 cm " ¹

2880

I5OO

1280 + 1240

1060 MS: m / e = 360 (+ 2) ⁺

358 (M) ⁺

251 (M + 2-P0, Me _? ) ⁺

249 (M-PC

6 = 7.90 4.50

3.90

= 90% = 119-123 ° C OH

aliphatic C-Il aromatic CC P = O POC 17 % 52 % 33 % 100 %

7,20 (multiplet, 4H); Phenyl group.

4.20 (triplet _s 1H, J = 7Hz) χ

H of the! -Hydroxyl group, removed by exchange with deuterium oxide.

3.50 (multiplet, 12H) % H from the methyl groups.

Analyzes

Calculated; C 36.84 »H 4.78, P 17.27% Found; C 36.81, H 4.78, P 17.26 %

In order to prove its structure, compound 4 was converted to the corresponding hydroxydiphosphonic acid monosodium aj-z (Compound 10) 5

Cl

C \ -C - OH

PO ₃ H ₂

A mixture of 3.59 g (10 ramol) of the compound 4 and \ 5 g 37 ~% hydrochloric acid was boiled for 3 hours under reflux After evaporation of HCl and HPO remaining 3) 2 g (10 mmol) of white solid as the residue .

Pp .: 192-194 ⁰ G (crude product) Yield: 100% (crude)

For the purpose of purification, the hydroxy- (p-chlorophenyl) methylene diphosphonic acid was converted to its monosodium salt according to the following method developed by P _e P. Pflaumer and J. P _e Filcik, Chemical Abstracts 72, 55656 k, 1970:

The pesticide obtained as described above was dissolved in a mixture of 4.8 g (80 mmol) of acetic acid and 0.7 g (39 mmol) of water at 95 ° C. Then, 1.36 g (10 mmol) of sodium acetate trihydrate was added gradually instantaneously a voluminous white precipitate formed "He was filtered and abundantly washed with ether until the smell of acetic acid disappeared" the • rinsed precipitate was dissolved in a mixture of ethanol% water (20: 80) to give .wobei 1.94 g (6 mmol) of white powder of 1-hydroxy-1 (p-chlorophenyl) methane-i, 1-diphosphonic acid monosodium salt (Compound 10)

Yield: 60 % "

Example 2

T_etramethyl ~ 2 _iX 2-di

Ij2r ^ i ^ h ^ ßJr ^ P ¹¹ ^ (compound 7)

(Method developed by K _e D. Berlin et al., Journal of Organic Chemistry 30, 1265, 1965, and D _e Α _β Nicholson and H. Vatfghn, Journal of Organic Chemistry 36, 3843, 1971).

- 10 CH-. PO- (CH-J ₉

"0-0 - C- OH

PO ₃ (CH ₃ )

First, by alkaline hydrolysis of ethyl p.TM. chlorophenoxyisobutyrate and boiling of the recovered acid in thionyl chloride under reflux following standard procedures p-chlorophenoxyisobutyryl chloride was prepared.

An amount of 10.6 g (86 mmol) of trimethylphosphite was added dropwise to 20.0 g (86 mmol) cooled to 0 ° C. p-Chlorophenoxyisobutyrylchloride added As a result of the reaction, the evolution of methyl chloride could be "observed." Distillation under reduced pressure gave 19.0 g (62 mmol) of dimethyl p-chlorophenoxyisobutyrylphosphonate as a nearly colorless oil.

Kp. = 115-118 ⁰ C / 5.1O ~ ² torr • aliphatic C-H yield »72 %. : C = O IR (PiIm): 3000 cm "" ¹ ί aromatic C-C 1740 • P = O 1500 : P-O-C 1250 : 1,4-disubstituted phenyl 1050 , 830

Then a solution of 2.86 g (26 mmol) of dimethyl phosphate and 0.18 g (1.4 mmol) of di- (n-butyl) amine in 65 ml of ether was cooled to 0 ⁰ C and with rapid stirring slowly 7.97 g (26 mmol) of dimethyl-p-chlorphenoxyisobutyrylphosphonat * added Past instantly a white Peststoff began to form · the reaction mixture was stirred for one hour at 0 ⁰ C for ·, after which the solid was separated by filtration "the recrystallization in benzene: hexane ( 60:40) gave 7.18 g (17.2 mmol) of white, feathery

Crystals of the title compound, d. of tetramethyl-2,2-dimethyl-2 (p-chlorophenoxy) ethene-1-hydroxy-1,1-diphosphonate »

Pp _β = 137 - - 139 C OH yield = 66 % 'aliphatic ^ C-H IR (KBr) : 3360 cm" aromatic C-C 3000 , P = O 1500 ί P-O-C 1250 + 1220 1,4-disubstituted 1070 860

phenyl

7.4 - 7.0 (multiplet, 4H): phenyl group

4.0-3.70, (multiplet, 12H): H bound from the methyl groups to the phosphonate moieties

3.5 - 3.4 (sharp spiked, 1H): H of the hydroxyl

Group J is removed by exchange with D ₂ O

1.58 (singlet 6H): H from the branched methyl groups »

Analysis: C

, JrIp

Calculated: C 40.45 H 5ί58 Ρ 14.90 % Found: C 40.29 H 5.94 P 14.93 %

Tetramethyl-1 [4 (4 ^f -chlorbensoyl) - phenyl! Me than-1-hydroxy-1, 1-diphosphonate (Compound 8). · (From T) * A «. Mcholsen and H. Vaughn, Journal of Organic Chemistry 36, 3843, 1971). "

2232 4 6

PO ^ (OH

G-OH PO ₃ (CH

The starting compound 4 (4 '~ chlorobenzoyl) benzoyl chloride by G _e E, Robinson and J. M ₀ Vernon, Journal of Chemical Society (C), 2586, 1970 and E. Wertheim, Journal of Americal Chemical Society 55s 2540 1933 * manufactured*

10.9 g (88 mmol, 10 % excess) of trimethylphosphite were added dropwise to 22.4 g (80 mmol) of acid chloride and heated to just below the melting point (about 100 ^° C.). "The reaction was exothermic and the white crystals The reaction mixture was stirred at 100 ^° C. for 30 minutes. On standing and cooling the oily material, it was converted to an orange solid. Recrystallization in a mixture of chloroform; Petroleum ether (60:40) gave 20 g (56.7 mmol) of pure dimethy1-4 (4 ^f -chlorobenzoyl) benzoylphosphonate _e

Mp = 95-97 ⁰ * C (yellow powder). , Yield - 71% •. IR (KBr) 296Ο cm "* ¹ : aliphatic CH

1665 + 1650: C = O (belongs to the Benzoylphos-

phonat and benzophenone components)

1590: aromatic C-C I25O + 1250: P = O 1050 + 1030. : P-O-C

Then a mixture of 2 _? 20 g (20 mmol) of dimethyl phosphate and 0.144 g (1.10 mmol) of di (n-butyl) amir) in 40 ml

2 <5Q 4L O

Ether cooled to above and a filtered solution of 7 * 04 g (20 mmol) of dimethyl »-4 (4 ^f -chlorobenzoyl) benzoylphosphonat in 40 ml of dichloromethane added dropwise» from the yellow mother liquor soon separated a white precipitate from »The reaction mixture was Stirred at 0 ⁰ G for one hour and then the precipitate was filtered off and washed with ether. Recrystallization in acetone gave 2.4 g (5.2 mmol) of white crystals of tetramethyl-1 pU4 '~ chlorobenzoyl) -phenyl] methane -1 "· hydroxy-1,1-diphosphonato

Pp.

Yield IR (KBr)

153 ⁰ C.

/O

-1

MS (m / e)

= 150

- 26

i 3280 cm "

1670

1600

1260 + 1240

1050 + 1030

: 464 (M + 2) ⁺ .

462 (M) ⁺ 355 (M + 2

OH C = O

aromatic C-C P = O P-O-C

14 % 42 %

PO ₃ Me ₀ ) +

353 (M-PO ₃ Me ₂ )

NMR _(CDCl3) S = 8.10

32 % 100 %

H from the two

7.30 (multiplet, 8H) phenyl groups

4.5-4.3 '(triplet, Ίη, J = 7 Hz): H out

the hydroxyl group, removed by exchange with DpO

3 * 95 - 3 _s 6O (multiplet, 12H): H from the methyl groups

(Compound 12)

^a '- 14 -

In a solution of equi-polar amounts of 4.40 g (40 mmol) of dimethylphosphite and 5? 17 g (40 mmol) of di (n-butyl) amine were added dropwise to 9.96 g (40 mmol) of dimethyl p-chlorobenzoylphosphonate, the solution being previously cooled to ⁰ ° C. After stirring for 1 hour at OC, the precipitate was separated by filtration. The uncrystallization at room temperature in a mixture of dichloromethane ί ether (1: 3) gave 12.0 g (33 mmol) of white crystals ,

Pp. 81 - 82 ⁰ C = yield 82 = IR (KBr) = 2980 cm ~ 1 1500 - 1290 + 1 260 1050 MIR (CDCl ₃ ):

aliphatic ^ C-H aromatic C-C P = O P-O-C

S ~ 7.5 ~ 7.3 (multiplet, 4H): phenyl group

5.85 - 5.40 (double doublet, J ^ 11 and 13 Hz, 1H): H from the methine group (not removable by exchange with deuterium oxide 3.95 - 3.50 (multiplet, 12H): H from the methyl groups ·

Elemental analysis: C H ClO P

'11 17 7 2

Calculated: C 36.84 H 4.76 P 17.27 % Found: C 36.71 H 4.86 P 17.33% Example 5.

X ^ - ^^^) 2,2-dimethyl-2 (p-chloro)

(Compound 16)

Dimethylation of p-chlorophenylacetonitrile with the aid of sodium amide and methyl iodide in ether gave p-chlorophenylacetonitriles. Hydrolysis of this ititrile and subsequent boiling of the resulting acid in thionyl chloride under reflux gave p-chlorophenylisobutyryl chloride *.

With a yield of 90%, dimethyl p-chlorophenyl isobutyrylphosphonate was obtained by adding an equivalent molar amount of trimethylphosphite to the above-described acid chloride which had been cooled to ⁰ ° C.

. Bp = 103-110 ⁰ C / 5.1O * ^"2 Torr (white oil) IR (film); I69O cm"^"1: C = O

1270: P-O

1070 + 1040: P-O-C

Then, a solution of 3.30 g (30 mmol) of dimethyl phosphite and 3.1 g (24 mmol) of di (n-butyl) amine was cooled to 0 ⁰ C and with rapid stirring 8 _S 72 g (30 mmol) Dimethylp-chlorphenylisobutyrylphosphonat Added soon after a white solid precipitated. After stirring at ⁰ ° C for 1 h, the gum was separated by filtration. Urinalysis in Ä'.ther gave 9 _s 0 g (75 %) of white crystals of the title compound, dimethyl 1 (dimethoxyphosphinyl) 2,2-dimethyl-2 (p-chlorophenal) ethyl phosphate "

Mp ₀ = 62 - 63 ^u C cm"" 1 β- ♦ aliphatic C-H IR (KBr) = 2980 : aromatic C-C 1500 + 1 260 * P = O 1280 + 1 030 t p-O-C 1080 (M + 2 N + : 0 _s 5 % MS (M / e) «402 (M) ⁺ : 1, 5% 400

^ & ^ 9 | ΐύί ^ TfiE '€ iSfc W ^ ^^ J' _Λ f *

CHO

248 (M - Cl - \% - C + H) ⁺ % 100%

CHO

MR (CDCIo):

I = 7.5-7 _V 25 (Multipiett, 4H): phenyl group

5.05 - 4.80 (double doublet, J = 9 and 12 Hz ₃ 1H): H from the methine group (not removable by substitution with DpO) 3.85 - 3.50 (Multipiett, 12H) .: H out the four

Methyl groups5 attached to the phosphate and phosphonate moieties 1.58 - 1.54 (two partially overlapped singlets, 6H): H from the two branched methyl groups »

Example Yes

Tetraethyl-4-phenylbutylidene-1,1-diphosphonate (Compound 21)

(Method developed by HR Hays and T _e J, Logan, Journal of Organic Chemistry 31, 3391, 1966 and 0. Quimby et al., Journal of Organometallic Chemistry 13, 199, 1968) *

- (CH ₂ ) ο - CH

23, O6 g (80 mmol) of tetraethylmethylendiphosphonate, prepared according to Monatshefte Chemie 81, 202, 1950, was added dropwise to a dispersion of 1.92 g (80 mmol) of sodium chloride in 30 ml ToD, uol. As soon as the reaction had subsided, 19.9 g (100 mmol) of 3-phenylpropylbromide were added and then the

The mixture was heated at 90 ^° C. for 14 hours and then at 110 ^° C. for a further 2 hours. After removal of the toluene under vacuum, the residue was dissolved in chloroform, washed repeatedly with a saturated sodium chloride solution and dehydrated by passage through a silicone-treated filter. Distillation under reduced pressure gave a colorless, at 135-145 ° C /

- 2

5 x 10 "01 Torr boiling were With careful rectification 10 _s 4 g (26 mmol) of tetraethyl 4-phenylbutylidene-1 ₅ 1-diphosphonate obtained"

Kp, = 141-143 ⁰ C / 5 * 1 O * " ¹ Torr Yield = 32 % .

IR (film): see Table III

MS (m / e): 406 (M) ⁺ : 61 % 301: 100 %

269 (M-PO ₃ AtIi ₂ ): 23 %

HMR (GDCl,):

£ = 7.35-7.2 (multiplet, 5H): phenyl 4.45 to 3.90 (quintet, 8H ₅ 8 Hz J =): H bound to the Phosphonatkomponenten of the four methylene groups,

2.80-1.70: (multiplet, 7H): H from the unpaired hydrogen atom and from the methylene groups of the side chains

1.50 - 1.20: (triplet, 12H, J = 7 Hz): house the four methyl groups

4-phenylbutylidene-1,1-diphosphonic acid (compound 24)

CH

Pooh.

2 2 3 2 Λ 6 _ ₁₈ _

A mixture of 8.15 g (20 mmol) of tetraethyl-4-phenyl-butylidene-1,1-diphosphonate and 40 g of 37% hydrochloric acid was refluxed for 15 hours. * Concentration of the clear acid solution to dryness gave a white, sticky pesticide "The compound was repeatedly triturated with ether to remove its stickiness." Recrystallization from a mixture of ether: acetone: hexane (30: 40: 30) gave 3.8 g (13 mmol) of white powder.

Pp. = 190 - 192 ⁰ C

Yield = 65 %

IR (KBr): see Table III

5 ^ JL £ iSli! D ^ (verb in

Education 27)

(Method elaborated by D, A _e Nicholson et al., Journal of Organic Chemistry 35, 3149s 1970) "

PO ₃ (CH ₃ )

A suspension of 4.5 g (15 mmol) 4 ™ phenylbutylidene-1,1-diphosphonic acid and 9> 8 g (92 mmol) trimethyl orthoformate was refluxed for ninety minutes. Rapid stirring was necessary to maintain intimate contact of the two phases Then an excess of 9.8 g (92 mmol) of trimethyl orthoformate was added and. the mixture was refluxed for a further 30 minutes. The methanol and methyl formate formed was removed by distillation allowing the reaction temperature to rise. The heating was continued until one phase remained and trimethyl orthoformate was removed

4 6

After distilling off this product, the residue was subjected to vacuum distillation to give 3.3 g (9.3 mmol) of colorless oil.

Kp = 135-138 ⁰ C (5.1O * ^"2 mm Hg) yield = 62% -

IR (PiIm): see Table III

NMR _(CDCl3):

& = 7.35 - 7.20 (multiplet, 5H): phenyl group 3.95 - 3.60 (doublet, 12H, J = 11 Hz): H from the methyl groups attached to the phosphonate components «2.80 - 1 , 60 (multiplet, 7H): H from the unpaired hydrogen atom and from the methylene groups of the side chains ·

The other compounds of formula (I) were prepared according to similar procedures as above; the physical properties of the compounds shown. (I) are listed in Tables I, II and III below.

MB show the spectra of the Hydroxydiphosphonatesterverbindungen (Ia) (Compounds 1 to 8) all the characteristic absorptions of a hydroxy groups a sharp spades (for the compounds 1 and 7) or a triplet (compounds .2, 3 ,, 4, 5, _S 6 and 8) _s were all removed by exchange with deuterium oxide.

The absorption of the methine Y atoms was found to be a double doublet (J ^ 10 and 12 Hz), which is characteristic of a proton coupled to two different phosphorus atoms P- and Pp:

2 2 3 2 4 6

~ 20 -

\ y 4- .a

- O - H

^P 2

The structure of the hydroxydiphosphonate ester compounds (Ia) was further confirmed by acid hydrolysis of compounds 2 and 4: the corresponding hydroxydiphosphonic acids were obtained, which were then isolated in the form of their monosodium salts to facilitate purification (compounds 9 and 10).

The IMR spectra of the Phosphonophosphatverbundungen (Ib) also show a characteristic image:

ί> - 7.5 - 7.3 Multipletyphenyl group ί- 5.8-5.4 (compounds 11, 12, 13 and 14) 5.1-4.8 (compounds 15, 16 and 17), double Doublet, J ^ 10 and 12 Hz, corresponding to the absorption of the unpaired hydrogen atom, can not be removed by exchange with deuterium oxide. "

i- 3.9 - 3.5 multiplet, methyl ester groups £ = 1, 60 - 1.55 only for compounds 15, 16 and

17 two singlets, branched 'methyl groups CHo

The MS spectra of all diphosphonate ester compounds (Ia-Ic) show a characteristic image: a molecular ion (M ⁺ ) of significant intensity (10-30 %) and a base peak (100 %) corresponding to the loss of a phosphonate ester group (M-PO ^ Rp) ,

The sole exception is the mass spectrum of compound 7 $ which does not correspond to a molecular ion _f but to spikes.

'The cleavage of the molecule shows cliend' The structure of the compound was clearly elucidated by microanalysis ο

TABLE 1 Physical Properties of Hydroxydiphosphonates of Formula (1a)

verbin Formula (1a) A R, R Fp. ( ⁰ C) Wf [IR absorptions (cm) 3250 : OH Itfr « '(CH ₃ ) O ₁ C- CH ₃ 110 - 112 -τ 2980 I aliphatic ^ C-H 1 Q CH ₃ 129 - 131 ! ^y 1260 +1240: P = O 2 VO CH ₃ 110 - 113 I 1050 : P-O-C 3 CH ₃ 119 - 123 4 "-O CHO 118 - 122 3340 1070 , 1500, 1260, 1240, 5 CH ₃ Q,. CH ₃ 120 - 123 3280 , 1670 (C = O) 6 Cl - / "^ - O-C- CH ₃ 137 - 138 1600 1050 , 1260 + 1240 + 1030 C ₁ ^ ^ CH ₃ 150 - 153 σ 8th

Table 1

page 2

jVerbinjdung No.

Formula (1a)

R, R ^f

Pp. ( ⁰ C)

- 1

IR absorptions (cm)

O-

3/4 H 1/4 H

> 300

3460, 3000 (wide) P-O-H-1200 - 1080 - 950

Φ A ¹ TVTJ

SBEI

(Continuation)

Physical properties of the hydroxydiphosphonates of the formula (Ia)

Connection | dung

Formula (la)

A Rj R '

IR options (cm ")

3460

3000 (wide) P-O-H-

1200 -1080 - 950

TABLE II Physical Properties of Phosphonophosphates of Formula (1b)

Connection no I A ψ 1 i Forr 3 ael (1b) R ₉ R ' " Mp. ( ⁰ o IR absorptions (cm ") > 2980 1500 • • * aliphatic ^ aromatic C-H C-C 11 O 3 CH ₃ oil - 1290 + 1260: P = O 12 CX-Q 3 CH ₃ 81 - 82 ί ( 1050 • • P-O-C · j 13 3 CH 48 - 49 14. CH ₃ oil 2980 1500 1280 1200 * T + + aliphatic CC aromatic CC 1260: P = O CH ₃ ' ^1180: _c group 15 ι O CH ₃ 47 - 48 1050 * • CHo, POC ^J I 16 ^ci -Q CH ₃ 62 ι - 63 5.10 -2 Torr) 17 ^3Η 3 ° "/ CH ₃ φ; ] £ τ) = ϊ 1 52 - 155 ⁰ C Y- H- X CH ί -C- A-

Physical properties of the diphosphonates of üOrrnel (Ic)

Verbin , ... Formula (ic) I 01 - / - VoH ₂ - R, R ^f Kp. (° C / torr) Pp. ( ⁰ C) -1 IR absorptions (cm) 2980 5 · aliphatic ^ C-H Training Hr. f. TV C ₂ H ₅ 135-138 / 5.10 "" ² 1500 ^> 1260 ί aromatic C-C 18 C ₂ H ₅ 153-156 / 5.1Ο "" ² Ii 70, ι P = O 19 V - == / ^{2 3} 1050 ί POC ₂ H ₅ C ₂ H ₅ 137-140 / 5.10 " ² ί P-O-C- 20 A Λ C ₂ H ₅ 141-143 / 5.10 " ² 21 Cl- / VcH ₂ - H 210-212 3400-3200 (wide) s OH 22 f v> - (CH _o ) _o - "1500 X = / ^c -> H 237-239 1230 p 23 H 190-192 1040: 24 Pl-./ '\ -CH ^ - 2980! (3 "(CH ₂ ) ₃ - CH ₃ 130-1 32 / 5.10 " ² 1500 5 > 1270 y 25 CH ₃ 141-144 / 5.10 ~ ² 1195 \ 26 CH- 135-1 38 / 5.10 ~ ² 1050: 27 J S aromatic C-C P = O ί P-O- , aliphatic ^ C-H ί aromatic C-C ί P = O PO-CH ₃ - P-O-C

2 ^ 32 4 6 ^ 2 ^ _ 9.1.1981

57 909/18

The present invention will now be further illustrated by the following Examples 9 to 11 for the pharmacological activity of the compounds of the formula (I)

Example 9 ^

Effects of bisphosphonates ^ _m ffqrmel (I) ^, ^ on the

metabolism in normal rats

Applied method:

Groups of 4 or 5 normal male Wistar rats weighing approximately 200 g were treated with diphosphonates for 4 to 21 days (200 mg / kg / day). "Water-soluble substances were dissolved in water or in solution in a 24 mM The rats were weighed, they remained laughing without food. Afterwards they were killed by decapitation under mild ethereal anesthesia. The blood was collected and the serum used for the analysis. The following blood parameters were the changes reflected in lipid metabolism ;, are described in:

- free fatty acids _s determined according to Y / # G _e Buncombe (Cliii * Acta, 9, 122, 1964)

- Triglycerides ₉ enzymatic method (Boehringer Mannheim Kit 126'012)

Phospholipids molybdate / vanadate reaction (Boehringer Mannheim Kit 124 974)

- ß-lipoprotein cholesterol was determined after CaGlp precipitation of heparin according to M, Burstein et al. (La Presse Medicale, p. 1, 974, 1958) and myself D ₉ Watson (GHn ₈ Chiiru Acta,! 5 * 637, 1960). "

Achieved results?

With the exception of compounds 1 and 3, all were lowered

diphosphonates tested (I) serum free fatty acids as determined in normal rats or in cholesterol-fed rats. "This activity appears to be more of a general feature of these diphosphonates having a p-chlorophenyl moiety, as is their intervention in lipid metabolism shows. Similar properties have been described for various hypolipidemic agents ("Hypolipidemic Agents", Ed. David Kritchevsky, Volume 41, Handbook of Experimental Pharmacology ₅ Springer-Verlag, 349-4O8, 1975). Significant decreases in serum triglycerides were determined with compounds 2, 4, 7, 8, 10 and 10, as well as with the acid form of compound 4 in several cases in compounds 2, 4, 7s 8, 11, 12 , 15, 16, 21 and 27, there was an increase in serum phospholipids. In particular, it has been found that compound 4 is the most active at least twice the increase. Cholesterol contained in the β-lipo protein fraction (very low density lipoproteins VLDL and low density lipoprotein LDL) decreased while lipoproteins (high density lipoproteins, y 1.065 g / cm - high density liproproteins HDL) increases the cholesterol level; in this' manner, which leads to a favorable increase of the oil, ~ Oholesterin / ß ~ ~ cholesterol ratio _e This effect was associated with long-term therapy with a reduced hepatic and aortic cholesterol content. Clofibrate was tested for comparison, and phospholipids decreased by 33.3 % and the ratio by 52.2%. The results are consistent with those reported by CE Day et al. (Artery 5, 90 - 109, 1979) and KR Muller and G. G ₈ Cortesi (Artery 4, 564-577, 1978), which provide evidence that clofibrate degrades HDL choleaterin in rats.

The results described above show that these di-

(mostly cholesterol) to increase and decrease the amount of by ß-lipoproteins borne lipids (mainly triglycerides) phosphates the property have to change Lipid-Vi / echsel, in particular the amount of carried by a> lipoproteins lipids "Since then, it has been found that the amount of HDL cholesterol is related to the risk of cardiovascular disease in opposed relation to each other (see H. e ₀ Miller, Lipids 13, 914-919, 1978), could diphosphonates which have the property · HDL It is important to note that the acid or salt form of Compound 4 and the fairly simple diphosphonate Compound 1 do not possess these properties. In addition, it is important to know that Dipliosphonates structurally different from compounds 2, 4, 7, and 8 and tested by others are not the proper ones to affect lipid metabolism (see W. Hollander et al., Atherosclerosis 31, 307-255, 1978 and Mellies et al., Artery 6, 38, 1979).

Example 10

Effects of diphosphonates of formula (I) on cholesterol-fed rats

Applied method;

To increase tissue cholesterol, especially in the liver, the rats were fed a high fat cholesterol diet for a period of 10 days to 3 months; The diet had the following composition: 20% casein, 37 % butter, 9.1 % cellulose, 18.9 % dextrose, 4.5 % cholesterol, 1.8 % sodium cholate, 7.3 % minerals, 1 % vitamins and 0.4 % choline *

Then the rats were fed normal diet and treated with different compounds (200 mg / kg / day) for a period of 10 days to 3 months. The serum parameters described at the beginning were determined. The liver and aortalipids were extracted according to J. Folch et al. (J. Biocheiru 226, 497, 1957). The total lipids were determined by the sulphofosphovanillin reaction (See Zölner and IU Kirsch, Z _e G es, Exp. Med. 135, 545, 1962) and cholesterol by the Liebermann-Burchard reaction. "

Achieved results;

The diet described above increased total liver lipids, especially triglycerides and cholesterol, 8 to 10 fold. Treatment with compounds 2, 4, 7, 8, 11, 12, 16 and 19 significantly reduced total liver lipids and / or liver cholesterol. After testing, the same effect could be observed in the aortic tissue »This shows that these individually tested diphosphonates have the property of removing C-ewebecholesterol. Since it has been clearly established that cholesterol deposition is an essential step in the onset and / or onset of arteriosclerosis, these compounds could be useful in preventing or treating pathological atherosclerotic changes in that they reduce cholesterol deposition in tissues such as tissue. As the aorta prevent.

Example ^ 11.

Effects of Acid and Salt Formation of Diphosphonates of ZLJ "J" Jiichi Hypercalcemic Rats ___ __________

Applied method:

In recent years it has been proved that diphosphonic acids are effective in the hypercalcemic animal model, in

which counteract aortic and renal calcification (see M. Potokar and M * Schmidt-Dunker, Athoroaclerosis 30, 313-320, 1978). Evidence has also been provided that they prevent the increase in plasma calcium induced by vitamin D. This activity might be useful for the regression of foreseeable arteriosclerosis (see I., Rosenblum, et al., Atherosclerosis 22, 411-424, 1975). Since diphosphonates have these activities when administered as acid or sodium salts, the acid and monosodium forms of compound 4 were also tested using a protocol similar to that of Potokar (supra). Briefly, groups of 4 males Wistar rats received the acid or salt form of the compound as a 0.05% solution in drinking water equivalent to about 50 mg / kg / day. The rats were treated with the compounds for 15 days. From the fifth to the tenth day, hypercalcaemia was caused by administration of 75,000 units of vitamin DU / kg / day. From the tenth to the fifteenth day, the diphosphonate treatment was continued. Then the animals were sacrificed under mild ether anesthesia and the serum calcium was determined according to BC Ray Sarkar and U, P * S. Chanham (Anal _e Biochem, 20, 155, 1967)

Results achieved: ·.

It has been suggested that calcium deposition plays a role in the late stages of arteriosclerotic disc development (see W. Hollander, Exp. Mol., Path., 25, 106, 1976), and it has been found that some diphosphonic acids or salts have an effect on the calcium metabolism, and that this property may be of particular use in the treatment of the later stages of arteriosclerosis. "The fact that none of the esterified forms

- 3 «

serum calcium is reduced, except for the acid and salt forms of Compound 4, which 14% decrease, shows that the non-esterified diphosphorates can intervene in the calcic metabolic pathway and reduce calcification of the atheromas.

Some results of the above-described pharmacological activity tests of the diphosphonates of the formula (I) according to the present invention are shown in the following Table IV.

Table IVi Pharmacological activity of the diphosphonates of the formula CQ ·

Connect. Serum free CN, ! Serum tri- CN, Serum phosphorus CN. Serum Cho CN. > +169 * -35 {Liver Liver- aorta aorta Serum- ! Unladen Swallow " , No. fatty acids -56 glycerides -15 pholipide unb. lesterin +88 +25 Total lipids Choester Total lipids Cholesterol calcium - N -67 N -21 N +21 N +220 * CN ". CN. · CN. ¹ CN " - 2 unb. -40 -21   unb. +25 unb. +27 » -32 -24 -50 -30 unb. unb o - 4 -48 -52 -24 -17 +43 +36 +51 -31 -56 -47 Unladen Swallow " unb. - 7 +28 -33 +26 unb. -25 -27 -19 unb. - S -38 -16 unb. -25 unb. Unladen Swallow ". -39 unb β unb. 5 - +27 - +64 - - - - - unb. 3 unb. unb. unb. Unladen Swallow " - - - - UQb · - 1 . unb o +24 -43 Unladen Swallow " - - - unb. - 4 acid -17 -29 unb · Unladen Swallow " unb o unb · unb. unb. -20 years 10 -27 -17 unb. Unladen Swallow " Unladen Swallow " unb. unb β unb o -14 Clofibre unb o +19 -34 unb. - unb. - - 12 -50 unb. +26 -32 -57 -37 -30 11 -21 +32 +28 +21 + 24 -18 -51 - - 15 - +36 +15 +25 - - - - 16 - - -36 -46 - - 13 - unb. unb * +81 - _ - - 14 - -65 years unb. -24 unb. unb. +15 - j - - - 26 -44 j +36 -18 unb. I - - - 19 -44 j -16 unb. unborn unb -6.0 unb. 21. - +46 +17 +33 - I , - - 27 - +42 +33 +49 - -

Note: - In the above Table IV, the results are reported as % control values. With the exception of the serum calcium, the values differing from the control values by less than 15% have been considered insignificant (urib.).

- Free fatty acids in serum, serum triglycerides and phospholipids were determined in normal Eatten (K) and in rats fed cholesterol (GN cholesterol diet) for 10 days.

- Serum-06 / β-cholesterol ,. Total lipid and cholesterol of the liver and aorta were determined in normal rats and in bats previously fed a high-cholesterol diet. "

- ·. Serum calcium was determined in hypercalcaemic rats.

The pharmacological selection of diphosphonate derivatives of the formula. (1) According to the present invention, it has been shown that said compounds possess specific properties and activities against lipids and lipid metabolism, and that it is possible to use them in the treatment of cardiovascular diseases for the following reasons:

- They / work on the lipid metabolism in normal rats by reducing the content of free fatty acids in the serum, reduce triglycerides and increase the content of phospholipids. The latter may be associated with the increased content of HDL lipids, in particular HDL cholesterol, as is most impressively with the compounds 2 _? 4, 5? 12 and 13 is watching.

- They have the important property of significantly reducing and removing liver and aortalipids, especially cholesterol, as detected in cholesterol-fed rats. Experiments not reported herein have also shown that compounds such as 2 and 4 increase cholesterol / gland and fecal secretion, resulting in detectable degradation of tissue cholesterol.

Accordingly, it should be noted that the primary effects of said diphosphonates (I) are different and novel compared to the classical Jaypolipidemic agents. The specificity of these activities (increased HDL and cholesterol release from the tissues) is convincing evidence of possible pharmaceutical use in atherosclerosis. "Experiments conducted on rabbits in which arterial sclerosis has been induced experimentally by cholesterol feeding confirmed the earlier observations that Compound 4, which carries the p-Cl component, which is the most active.

In addition, the fact that the acid and salt forms of compound 4 act on the calcium metabolism gives rise to the suggestion that all non-esterified forms of the described diphosphonates should also be used to treat the late stages of atherosclerosis, even if they also have this ability.

At game 12

gypoglyzemic activity of diphosphonates djgr_fformel (I)

Male Wistar rats (5 / group) weighing between 150-200 g were treated with selected phosphoramates for 4 days. "Overnight, they remained without food and were sacrificed by decapitation on the fifth day under mild ether anesthesia. The blood was collected, taking

ID TA was used as an anticoagulant. The results are given as mean values ± (?). The results shown in Table YI show that the p-chlorophenyl diphosphonate, especially when administered intraperitoneally, was the most effective. "

Table VI

Hypoglycemic activity

3 words of input _s dose and solvent (vehicle) Controls Plasmasluko s (mg / 100 m3.) Verb. 4 Verb. 2 Verb, 21 Verb 2p i «p» 50 mg / kg aq "buffer ρ" ο * 50 mg / kg aq "buffer * p o _t 50 mg / kg corn oil p> 0. 100 mg Ag aq. Buffer po 50 mg Ag maize germ oil po "200 mg Aga» buffer p · 0. 200 mg Ag 'aq. buffer 87 + 3 132 i 8 125 ί ίο 111 1 7 125 I 10 131 + 4 Treated with ' 36 ± 1 10OiI2 90 ± 5 93Ϊ12 110 + 10 88 ± 5 102 + 9

The glucose concentration was determined by the enzymatic method of W. Werner and H ₉ G. Wielinger (Z, Analyt, Ghem «252 , 2.2 ¹ I, 1970) (taken from Boehringer Mannheim, Kit No. 124036).

The present invention includes, as subject of the invention further hypoglyzeiaische and antiatherogenic preparations comprising a pharmaceutically as an active ingredient

effective amount of one or more diphosphonate derivatives of formula (I).

In order to produce a desirable success in an acceptable ratio of risk to risk associated with any medical treatment, reliable and effective amounts of the phosphonate compound are sufficiently produced. Within the acceptable and thorough medical opinion, the dose of the phosphonate compound will vary with the particular condition being treated, the severity of the condition, the duration of the treatment and the specific phosphonate compound employed.

The phosphonates are prepared as pharmaceutically acceptable products containing all of the ingredients used in the compositions used and which are suitable for use in contact with human and animal tissues without undue toxicity, irritation, triggering of allergic reactions with a reasonable benefit ratio Risk are equally suitable »

The preparation of the pharmaceutical compositions of the present invention in the form of oral unit dosages can be accomplished by the preparation of a solid solvent (vehicle) mixture containing lactose, sucrose, sorbitol, mannitol, arnidone, amylopectin, cellulose derivatives and / or gelatin , which may be prepared with lubricants such as magnesium stearate, Kai ζ rumste ar at,. forms of "garbowax" and / or polyethylene glycol. For some cases it may be advisable to use a capsule and the ingredients may then consist of a mixture containing syrup, gum arabic, talc and / or titanium dioxide,

• 36th

For some specific cases, the phosphonates may be mixed with a buffer solution, corn oil oil, olive oil and conventional glycerine excipients and administered in a closed, hard gelatin capsule, as drops or syrup forms,

In addition, the phosphonates can be processed with "Imhausen H" for the production of suitable suppositories.

For example, compounds 4- and 9 were tabletted with 10% magnesium stearate and 25 % amidone in tablet form to give a final consensus of about 100 to 300 .mg active ingredient. In addition, compounds of formula (I) have been used in a drinking or corn germ oil solution at concentrations between about 2 mg / ml and 100 mg / ml *

Claims (12)

1 »Process for the preparation of a diphosphonate derivative de] Formula (I) POJR ₀ j 3 2 (D ACX I
PO ₃ R ¹ ₂ wherein X is OH or H, R and R ^{1 are the} same or different are. H and CH ₀ or C ₀ H ₁ - mean "m is zero or 1 is" 3 2 5 ^y and A from one of the groups CH ₃ CH ₃ CH ₃ ^Y CH ₃ where η is an integer from 1 to 6 and Y is H, CH ₃ J is OCH ₃ or a halogen atom, in particular chlorine or fluorine, characterized in that a dialkylazylphosphonate of the formula (II)  n ACPO ₃ R ₂ (II) with an equimolar amount of dialkyl phosphite of the formula (III) HP (O) (0R) ₀ (III) 2. Method according to item 1 for the preparation of hydroxy diphosphonate derivatives of the formula (Ia) 3. The method according to item 1 _9, characterized in that the molar amount of the base used corresponds to 5 ° b of the molar amount of each of the reactants » ₃ AC OH wherein A, R and R 'are as defined in item 1, characterized in that an oialkylazylphosphonate of the formula (II) is reacted with an equimolar amount of a dialkylphosphite of formula (III) as defined in point 1 in the presence of a catalytic amount of Base brings to reaction. 4. Method according to item 1 for the preparation of phosphonophosphate derivatives of the formula (Ib) ? OH 57 909 18 wherein A, R and R ^{1 are} as defined in item 1, characterized in that a dialkylazylphosphonate of the formula (II) is reacted with an equimolar amount of dialkyiphosphite of the formula (III) as defined in point 1 in the presence of an amount of Base which corresponds to 80 to 100 ° h of the molar amount of each of the reactants η (II) or (III) in Re aid: ion brings. 5. The method according to item 1 to 4, characterized in that the base used is an amine. 5? 909 18 223246 _1 ° _ in the presence of various amounts of a base for the reaction "brings. 6. Method according to one of the items 1 to. 5, characterized in that the reaction takes place in diethyl ether as a solvent at a temperature of about _e 0 ° G * 7. The method according to item 1, characterized in that tetramethyl-1 (p-chlorophenyl) methane-i-hydroxy-1,1-diphosphonate is prepared. 8. The method according to item 1, characterized in that tetramethyl ~ 2-2-dimethyl-2- (p-chlorophenoxy) ethane-1 ~ hydroxy-1,1-diphosphonate is prepared » 9. The method according to item 1, characterized in that tetramethyl-1- / 4 (4 ^f ~ chlorobenzoyl) phenyl7 - methane - 1-hydroxy-1,1-diphosphonate is prepared. 10, "Process for the preparation of dimethyl 1 (dimethoxyphosphinyl) -p-chlqrbenzylphosphat according to item 3. 57 909 18 223 24 6 11. The method according to item 4, characterized in that Dimethyl- / T (dimethoxyphosphinyl) 2,2-dimethyl 2-phenyl-7-ethyl phosphate is produced « 12 "procedure according to point 4 _? characterized in that dimethyl / T (dimethoxyphosphinyl) 2 ₅ 2-dimethyl-2 (pohlorphenyl7äthylphosphat is prepared.