DD283821A5 - METHOD FOR PRODUCING MEVALONOLACTONS WITH A PYRAZOLOPYRIDINE RING - Google Patents

Abstract

The invention relates to a process for the preparation of mevalonolactones having a pyrazolopyridine ring of the formula I in which the substituents R 1, R 2, R 3, R 4, R 5, Y and Z have the meaning given in the description. The compounds according to the invention have a high inhibitory action on HMG-CoA reductase in cholesterol biosyntheses and are used as medicaments, in particular against hyperlipidaemia, hyperlipoproteinemia and atherosclerosis. Formula I {Mevalonolactone Preparation; Pyrazolopyridine ring; Inhibitory effect HMG-CoA reductase; Drug; hyperlipidemia; hyperlipoproteinemia; atherosclerosis}

Description

Process for the preparation of mevalonolactones with a pyraalopyridine ring

Field of application of the invention

The invention relates to a process for the preparation of novel mevalonolotones having a pyrazolopyridine ring, pharmaceutical compositions containing them and their pharmaceutical use, in particular as anti-hyperlipidemic agents, hyperlipoproteinemic agents

and anti-atherosclerosis agents. Furthermore, the invention relates to intermediates which are useful in the preparation of the novel compounds, as well as processes for the preparation of such intermediates.

Characteristic of the known state of the art:

It is known that some fermentation metabolites such as compactin, CS-513, mevinolin or semi-synthetic derivatives or fully synthetic derivatives thereof are inhibitors of HMG-CoA reductase, which is a rate-limiting enzyme in cholesterol biosynthesis [A Eno J.Med. Chem., 28 (4), 401 (1986)].

CS-514 and mevinolin have been shown to be potently useful anti-hyperlipoproteinemia agents in clinical trials, and are believed to be effective in curing or preventing diseases such as coronary atherosclerosis or atherosclerosis (iXth Int.Symp.Drugs Affect., Lipid Metab., 1986, pages 30, 31 and 66).

With regard to the fully synthetic derivatives, in particular heteroaromatic derivatives, of inhibitors of HMG-CoA reductase, however, little information is found in the following references:

WPI ACC Nos. 84-157675, 86-028274, 86-098816, 86-332070, 87-124519, 87-220987, 88-07781, 88-008460, 88-091798, 88-112505, 88-182950, 88- 205067, 88-234828, 88-258359 and 88-300969.

-3-

Object of the invention

The invention provides a process for the preparation of mevalonolactone derivatives with a pyrazolopyridine ring, their corresponding dihydroxycarboxylic acids and their salts and esters.

The compounds produced according to the invention have a high inhibitory effect on cholesterol bio-syntheses in which HMG-CoA reductase acts as a rate-determining enzyme.

Explanation of the essence of the invention

The present invention has for its object to produce new mevalonolactones, which are suitable inhibitors of HMG-CoA reductase.

According to the invention, new mevalonolactone derivatives of the formula I are prepared,

Y Z

(D

wherein R ^{1 is} hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-7

alkyl, C _2-6 alkenyl, ε- or β-naphthyl, 2-, 3- or 4-pyridyl,

2- or 3-thienyl, 2- or 3-furyl, fluorine, chlorine, bromine,

-3a-

where R, R 1 and R ^{8 are} each independently hydrogen, C ₁ -alkyl,

i ~ ö & in

C ₁ o -alkoxy, C ₁ , -alkylthio, chloro, bromo, fluoro, -NR ⁵ R ¹ (where B / and R are independently C 1-10 -alkyl), chloromethyl, trichloroethyl, trifluoromethyl, trifluoromethoxy, trio-chloromethoxy, difluoromethoxy, phenoxy,

Benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-t-butylsilyloxy, hydroxymethyl or -O (CH ₂ ) ↑ OR ¹⁸ (wherein R is hydrogen or C ₁ , alkyl and k is 1, 2 or 3); and when R ^{8 is} hydrogen and R and R are ortho to each other, they may together form -OC (R 1) (R) O-

<| q PO

(wherein R * and R are independently hydrogen or C ₁ , alkyl); or if R ^ and R ^{8 are} simultaneously hydrogen, R is

(where R 1 is hydrogen, C 1 -C 4 -alkyl, C ₁ -C 6 -alkoxy, trifluoromethyl, chlorine, bromine or fluorine)], phenyl-C ₂ , -alkenyl, the phenyl group of which is unsubstituted or substituted by C 1 -C 4 -alkyl, C ₁ , alkoxy, fluoro, chloro or bromo, or C ₁ , alkyl substituted by a member selected from the group C ₁ , alkoxy, naphthyl and

R ⁶ R ⁷

(wherein R, R ^ and R ^{8 are} as defined above), and by 0, 1 or 2 members selected from

A group consisting of C ₁ "alkyl;

ρ R is attached to the nitrogen atom in the 1- or 2-

Bonded position of the pyrazolopyridine ring and is hydrogen, C _1-8 -AllCyI, C ₁ , alkyl, substituted

5 283621

with 1 to 3 fluorine, C * -Cycloalkyl, α- or ß-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl or

R ⁶ R ⁷

(wherein R, R 'and R are as defined above) or C ₁ , alkyl substituted by a member of the group consisting of C ₁ ''- alkoxy, hydroxy, naphthyl and

C. Π Q

(wherein R, R 'and R are as defined above), and by 0, 1 or 2 members of the group consisting of C, Q-alkyl;

R * and R are independently hydrogen, C _1-8 -

Alkyl, C ₁ -C 6 -cycloalkyl, C ₁ -alkoxy, n-butoxy,

27> 2.Ut 2. ~ *> 24

Butoxy, sec-butoxy, R 1 R N- (wherein R and R are independently hydrogen or C ₁ , alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy , Diphenyl-t-butylsilyloxy, hydroxymethyl or -O (CH ₂ ) _l 0R ¹ ^ (where R ¹ ^ is hydrogen or C _1-7 -alkyl and 1 is 1, 2 or 3)

hen; or, when R and R are ortho to each other, they may together form -CH = CH-CH = CH- or methylenedioxy;

Y is -CH ₂ -, -CH ₂ CH ₂ -, -CH = CH-, -CH ₂ -CH = CH-, -CH = CH-CH ₂ -, -C (CH ₃ ) = CH- or -CH = C (CH ₃ ) - stands; Z is -Q-CH ₂ WCH ₂ -CO ₂ R ¹² ,

or

CO ₂ R ¹²

[wherein Q is -C (O) -, -C (OR ¹ ^) ₂ - or -CH (OH) -; W is -C (O) -, -C (OR ¹³ ) ₂ - or -C (R ¹¹ ) (OH) -; R is hydrogen or C ₁ , alkyl; R ^{12 represents} hydrogen or R (wherein R represents the alkyl moiety of chemically or physiologically hydrolyzable alkyl ester or M (wherein M is NH 3, sodium, potassium, ½ calcium or a hydrogen addition product to nitrogen of lower alkylamine, di-lower alkylamine or tri lower R ₂ ) independently represent primary or secondary C _1-6 alkyl, or two R 'together - (CH ₂ ) ₂ - or

- (CH ₉ ), - form; R and R ^{17 are} independently hydrogen

16 17

or C ₁ , alkyl; or R and R together form - (CH ₂ ) ₂ - or - (CH ₂ ), -]];

R? is hydrogen, chloro, bromo, hydroxy, C _1- , alkoxy, R ²³ R ²⁴ N- (wherein R ²³ and R ^{24 are} independently hydrogen or C _1-3 alkyl), C ₁ -Q alkyl, C _{2 -6} alkenyl, C _3- y cycloalkyl, Cc- ₇ cycloalkenyl, trifluoromethyl or

R ²⁵

O "

Λ *

(wherein R- * is as defined above) or "C 1-6 alkyl substituted by a member of the group consisting of

& 7ft

(wherein R, R 'and R are as defined above), and by 0/1 or 2 members selected from the group consisting of C 1 -C 4 alkyl.

Various substituents in Formula I are explained in detail with reference to specific examples. It should be noted, however, that the present invention is not limited to these specific examples.

C _1-8 -alkyl for R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ includes, for example, methyl, ethyl, n-propyl, i-propyl, η-butyl, Butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl. C, ₇ for R ¹ , R ² , R ⁵ , R ⁴ and R ^J includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-methylcyclohexyl and cycloheptyl.

C _1-8 alkoxy for R, R ⁷ and R ⁸ includes, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, n-pentoxy, n-hexyloxy, n-heptyloxy and n-octyloxy.

C 1 -C 4 alkylthio for R, R ⁷ and R ⁸ includes, for example, methylthio, ethylthio, n-propylthio and i-propylthio.

Q 10

^c 1-3 " ^{alkyl for} " ¹ ^ ^R u ^ ⁰⁰ * * for example, methyl, ethyl, n-propyl and i-propyl.

C ₁ alkyl for R ¹¹ includes, for example, methyl, ethyl, n-propyl and i-propyl.

C _1-6 alkyl for R ¹ ^ includes, for example, methyl, ethyl, n-propyl, i -propyl, η-butyl. i-butyl, sec-butyl, n-pentyl and n-hexyl.

C _1-3 alkyl for R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²⁵ and r24 includes, for example, methyl, ethyl, n-propyl and i-propyl.

C 1-4 alkyl for R ²⁵ includes, for example, methyl, ethyl, n-propyl, i -propyl, η-butyl, i-butyl, sec-butyl and t-butyl.

Further, these compounds may have at least one or two asymmetric carbon atoms and may have at least two to four optical isomers. The compounds of formula I include all of these optical isomers as well as all mixtures thereof.

Among the compounds with carboxylic acid units, the

12

are outside the definition of -CO ₂ R of the carboxylic acid moiety of the substituent Z in the compounds of the invention are those which, after taking a physiological hydrolysis to form the corresponding carboxylic acids (compounds in which the -C0 ₂ R ¹² - unit for CO ₂ H) are equivalent to the compounds of the invention.

In the following, preferred substituents of the compounds of the invention will be explained.

In the following examples of preferred, more preferred, even more preferred, and most preferred substituents, the numerals for the positions of the substituents indicate the positions on the pyrazolopyridine ring.

Preferred examples of R and R are those as defined in connection with formula I.

As preferred examples of R · and R, when R is hydrogen, R ^ is hydrogen, 3-fluoro, 3-chloro, 3-methyl, 4-methyl, 4-chloro or 4 * fluoro; or R ^ and R together form 3-methyl-4-chloro, 3 »5-dichloro, 3,5-difluoro, 3,5-dimethyl or 3-methyl-4-fluoro.

Preferred examples of R- 'include primary and secondary C 1-8 alkyl and C 1-6 cycloalkyl.

Preferred examples of Y include -CH ₂ -CH ₂ - and -CH = CH ".

Preferred examples of Z include HO.sup

-CH (OH) CH ₂ CH (OH) Ch ₂ CO ₂ R ¹ Z, -CH (OH) CH ₂ C (O) CH ₂ CO ₂ R 12 and -CH (OH) CH ₂ C (OR 13) ₂ CH ₂ CO ₂ R12.

2 638 21

In the following, particularly preferred Substiti. Snten the compounds of the invention described.

Particularly preferred examples of R include hydrogen, C _1-8 -alkyl, C ^ g-alkoxy, C ^ y-cycloalkyl, C ₂ _g-alkenyl, α- or ß-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl,

(wherein R, R 'and R are as defined above) and C ₁ , alkyl substituted by a member of the group consisting of C ₁ , alkoxy, naphthyl and

(wherein R, R ⁷ and R ^{8 are} as defined above), and by 0, 1 or 2 members of the group consisting of Cjg

As particularly preferable examples of R, in the case where R ² is bonded to the nitrogen in the 1- or 2-position of the pyrazolopyridine ring, mention is made of Ch g -alkyl, C ₁ , -alkyl substituted by 1 to 3 fluorine , C _3-7 -cycloalkyl, α- or β-naphthyl, 2-, 3- or 4-pyridyl,

(wherein R, R ⁷ and R ^{8 are} as defined above), and C ₁ , alkyl substituted by a member

from the group consisting of C _1. , - alkoxy, hydroxy, naphthyl and

(wherein R, R ⁷ and R ^{8 are} as defined above) and by 0, 1 or 2 members selected from the group consisting of C _1-8

As particularly preferred examples of R * and R, if R is hydrogen, R ^{3 is} hydrogen, 4-methyl, 4-chloro or 4-fluoro; or R ^ and R together are 3,5-dimethyl or 3-methyl-4-fluoro.

Particularly preferred examples of Y include -CH ₂ -CH ₂ - and (E) -CH = CH-.

In the following, the more preferred substituents of the compounds of the invention will be explained.

Still further preferred examples of R include hydrogen, C ₁ _ _ß alkyl, C ^ y-cycloalkyl, C _2- g-alkenyl, and "r

^R 7

(wherein R, R ⁷ and R ^{8 are} as defined above).

As even more preferred examples of R may be mentioned, if R is attached to the nitrogen in the 1-position of the fyrazolopyridine ring, C _1-8 alkyl, C ₁ , allyl, substituted by 1 to 3 Fluorine, C 1-6 -cycloalkyl, α- or β-naphthyl, 2-, 3- or 4-pyridyl,

(wherein R, R ' υη <* R ^{8 are} as defined above) and Cj, alkyl substituted by a member of the group consisting of C ₁ , alkoxy, hydroxy, naphthyl

and r

(wherein R, R 'and R are as defined above), and by 0, 1 or 2 members of the group consisting of C _1-8 alkyl.

ρ Still more preferable examples of R in the case that R is bonded to the nitrogen in the 2-position of the pyrazolopyridine ring may be mentioned a- or ß-naphthyl and

(wherein R ⁶ , R ⁷ and R ^{8 are} as defined above).

As further smelled preferred examples of R? and R are mentioned for the case where R is hydrogen, as R 1 is hydrogen, 4-chloro or 4-fluoro; or R and R together represent 3-methyl-4-fluoro.

5 Further preferred examples of R include ethyl,

n-propyl, i-propyl and cyclopropyl.

Still further preferred examples of Y include (E) -

In the following the most preferred substituents for the compounds according to the invention are described.

The most preferred examples of R include hydrogen, methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, sec -butyl, t -butyl, cyclopropyl, cyclohexyl, phenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-tolyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-chloromethylphenyl, 3- or 4-ethoxyphenyl, 4- (2-methylbutyl) -phenyl, 4-n-heptylphenyl, 4-n-octylphenyl, 4-n-pentylphenyl, 4-n-hexylphenyl, 4-n-propylphenyl, 4-n-butylphenyl, 4-t-butylphenyl, 4-n-butoxyphenyl, 4-n-pentyloxyphenyl, 4-n-hexyloxyphenyl, 4-n-heptyloxyphenyl, 4-n-octyloxyphenyl, 4-phenoxyphenyl, 4-biphenyl, 4-trichloromethoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,3-difluorophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 3, 4-Difluorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl, 2,5- Dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylph enyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,5-bis (trifluoromethyl) phenyl, 3,4-methylenedioxyphenyl , 2,4,6-trimethylphenyl, 3,4,5-trimethoxyphenyl and 2,4,6-triisopropylphenyl. As the most preferred examples of R are mentioned in the case where R ^{2 is} attached to the nitrogen in the 1-position of the pyrazolopyridine ring, methyl, ethyl, n-propyl, i-propyl, η-butyl, i- Butyl, sec-butyl, t-

Butyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclohexyl, benzyl, 2-chlorobenzyl, 2-hydroxybenzyl, 3-trifluoromethylbenzyl, 2-phenylethyl, phenyl, 2-, 3- or 4-chlorophenyl, 2- , 3- or 4-bromophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-tolyl, 2-, 3- or 4-trifluoromethylphenyl, 3- or 4-methoxyphenyl, 2-hydroxyphenyl, 4 Isopropylphenyl, 4-t-butylphenyl, 4-trifluoromethoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3 ', 4-dichlorophenyl, 3,5-dichlorophenyl, 2 , 4,6-Trichlorophenyl, 2,3,4-trichlorophenyl, 2,4-Dlfluorophenyl, 3,5-bis- (trifluoromethyl) -phenyl, 3 "-chloro-4-tolyl, 3-chloro-6-tolyl, 4 -Chloro-2-tolyl, 2-chloro-6-tolyl, 2-chloro-6-fluorophenyl, 2-chloro-5-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 4-bro-3-chlorophenyl, 2-chloro 4-trifluoromethylphenyl, 3-fluoro-6-tolyl, a-naphthyl, 2-pyridyl, 3-methyl-5-trifluoromethyl-2-pyridyl, 4-pyridyl or 2,6-dichloro-4-pyridyl.

As the most preferred combinations of R

4 3

and R are those mentioned where R is hydrogen

and R is 4-chloro or 4-fluoro.

The most preferred examples of R include isopropyl and cyclopropyl.

The most preferred example of Y includes (E) - CH = CH-.

In the following, particularly preferred, specific compounds of the present invention are given. The following compounds (a) to (z) are in the form

represented by carboxylic acids. However, the present invention includes not only the compounds in the form of carboxylic acids, but also the corresponding lactones formed by the condensation of the carboxylic acids with hydroxy at the 5-position, as well as the sodium salts and lower alkyl esters (such as methyl, ethyl, isopropyl and n-propyl esters) of the carboxylic acids, which can be physiologically hydrolyzed to the carboxylic acids.

(a) (E) -3,5-Dihydroxy-7- [4 "- (4" -fluorophenyl) -1 ', 3'-dimethyl-6 ¹ - (1 "-methylethyl) -pyrazolo [3,4- b] pyridin-5'-yl] hept-6-enoic $

(b) (E) -3,5-dihydroxy-7- [6 ^l -cyclopropyl-4 ^t - (4 ¹¹ -

fluorophenyl) -1 ·, 3'-dimethylpyrazolo [3,4-b] pyridin-5'-yl] hept-6-enoic acid;

(c) (E) -3,5-Dihydroxy-7- [i "-t-butyl-4 ¹ - (4" -fluorophenyl) -3 · methyl-6 · - (1 "-methylethyl) -pyrazolo [ 3,4-b] pyridin-5'-yl] hept-6-enoic acid;

(d) (E) -3,5-Dihydroxy-7- [1'-t-butyl-6'-cyclopropyl-4 - (4 "-fluorophenyl) -3'-methylpyrazolo [3,4-b] pyridine

5'-yl] hept-6-enoic acid;

(e) (E) -3,5-Dihydroxy-7- [1 ^l -benzyl-4 '- (4 »-fluorophenyl) -3'-methyl-6 · - (1" -methylethyl) -pyrazolo [3, 4-b] pyridine-5 · -yl] hept-6-enoic acid;

(f) (E) -3,5-Dihydroxy-7- [1'-benzyl-o'-cyclopropyl-4 - (4 "-fluorophenyl) -3'-methylpyrazolo [3,4-b] pyridine-5 ' -yl] hept-6-enoic acid;

(g) (E) -3,5-dihydroxy-7- [4 ^l - (4 "-fluorophenyl) -1 ^l - (4" -methoxyphenyl) -3'-methyl-6 ^- (1 "methylethyl) pyrazolo [3,4-b] pyridin-5'-yl] hept-6-enoic acid;

(h) (E) -3,5-Dihydroxy-7- [6'-cyclopropyl-4 ^L - (4 ¹¹ -fluorophenyl) -1- (4 "-methoxyphenyl) -3'-methylpyrazolo [3,4 -b] pyridin-5'-yl] -hept-6-enoic acid 4

(i) (E) -3,5-dihydroxy-7- [3'-cyclopropyl-4 ^l - (4 "- £ luorphenyl) -1'-methyl-6 '- (1" methylethyl) -pyrazolo- [ 3 '4-b] pyridin-5'-yl] -hept-6-enoic acid; (d) (E) -3,5-dihydroxy-7- [3', 6'-dicyclopropyl-4 '- (4 " fluorophenyl) -1 · -methylpyrazolo [3,4-b] pyridin-5'-yl] hept-6-enoic acid;

(k) (E) -3,5-dihydroxy-7- [4 '- (4 "-fluorophenyl) -1'-methyl-6' - (1" -methylethyl) -3-phenylpyrazolo [3,4- b] pyridin-5'-yl] hept-6-enoic acid.

(l) (E) -3,5-dihydroxy-7- [6 ^l -cyclopropyl-4 '- (4-f ¹¹ luorphenyl) -1' -methyl-3 '-phenylpyrazolo [3,4-b] pyridine 5'-YLJ-hept-6-enoic acid;

(m) (E) -3,5-Dihydroxy-7- [3 '- (4 "-chlorophenyl) -4' - (4" -fluorophenyl) -1'-methyl-6 ¹ - (1 "-methylethyl) -pyrazol-Io [3,4-b] pyridin-5'-yl] hept-6-enoic acid; · (Η) (E) -3,5-dihydroxy-7- [3 '- (4 »-chlorophenyl) -6 · -cyclopropyl-4 ^f - (4" -fluorophenyl) -1'-methylpyrazolo [3,4 -b] pyridin-5'-yl] -hept-6-enoic acid; (ο) (E) -3,5-dihydroxy-7- [1 ^l -ethyl-4 '- (4 »-fluorophenyl) -6- ^f - (1 "-methylethyl) -pyrazolo [3> 4-b] pyridin-5'-yl] -hept-6-enoic acid;

(ρ) (E) -3,5-dihydroxy-7- [6'-cyclopropyl-1'-ethyl-4 - (4 "-fluorophenyl) -pyrazolo [3,4-b] pyridine-5-yl ] hept-6-enoic acid;

(q) (E) -3,5-dihydroxy-7- [4 '- (4 "-fluorophenyl) -6 ^f - (1" -methylethyl) -1'-phenylpyrazolo [3,4-b] pyridine-5 '-yl] hept-6-enoic acid;

(r) (E) -3,5-Dihydroxy-7- [6'-cyclopropyl-4 '- (4 "-fluorophenyl) -1'-phenylpyrazolo [3,4-b] pyridine-5- ^f- yl ] hept-6-enoic acid;

17 2 83 8 2 ί

(s) (E) -3,5-Dihydroxy-7- [4 '- (4 "-fluorophenyl) -3'-methyl-6' - (1'-methylethyl) -1'-phenylpyrazolo [3,4- b] pyridin-5'-yl] hept-6-enoic acid;

(t) (E) -3,5-Dihydroxy-7- [6-cyclopropyl-A '- (4-fluorophenyl) -3'-methyl-1'-phenylpyrazolo [3,4-b] pyridine-5 '-yl] -hept-6-enoic acid j

(u) (E) -3,5-Dihydroxy-7- [3'-cyclopropyl-4 ^L - (4 ¹¹ -fluorophenyl) -6 · - (1 "-methylethyl) -1- ^f -phenylpyrazolo [3 1 4 -b] pyridin-5'-yl] hept-6-enoic acid; (v) (e) -3,5-dihydroxy-7- [3 ^f, 6 '-dicyclopropyl-4 ^f - (4H-fluorophenyl) - 1'-phenylpyrazolo [3,4-b] pyridin-5'-yl] hept-6-enoic acid;

(w) (E) -3,5-Dihydroxy-7- [i.-t-butyl-3-cyclopropyl-41- (4'-fluorophenyl) -6 • - (1 "-methylethyl) -pyrazolino [3 , 4-b] pyridin-5'-yl] -hept-6-enoic acid ;

(x) (E) -3,5-dihydroxy-7- [1'-t-butyl-3 ^f, 6 x -dicyclopropyl-4 '- (4 "-fluorophenyl) pyrazolo [3,4-b] pyridine -5'-yl] hept-6-enoic acid;

(y) (E) -3,5-dihydroxy-7- [i'-t-butyl-4 '- (4 "-fluorophenyl) -6 ^f - (1" -methylethyl) -3'-phenylpyrazolo [3, 4-b] pyridin-5'-yl] hept-6-enoic acid;

(z) (E) -3,5-Dihydroxy-7- [i'-t-butyl-e'-cyclopropyl-4 - (4 "-fluorophenyl) -3'-phenylpyrazolo [3,4-b] pyridine. 51_yi] hept-6-enoate.

The mevalonolactones of formula I can be prepared according to the following reaction schemes.

Further, the compound of the formula X can be prepared by a method described in J.Prakt. Chem., 79 t 1 (1909), or in Japanese unexamined

is 28382t

Or may be prepared from 3,3-dichloroacrylonitrile [J.Org.Chem., ^ 4, 3410 (1969), ibid. $ 6, 3386 (1971)] as a starting material via cyanoketene acetal obtained by a method described in J. Org. Chem., 5, 828 (1970) (Japanese Examined Patent Publication No. 2541/1973).

The compound of formula VII can be prepared from the compound of formula X [Chem.Pharm.Bull., 35 , 3235 (1987), and Japanese Unexamined Patent Publication No. 65089/1984].

The Enal III can also be prepared by the process stages K, L and M.

Further, the primary alcohol VI can also be prepared by the process steps P, S and T.

19

^ x

K \ . .R "R ¹

CO ₂ R

2 1

JP

CO ₂ R

Z

O ^^ R ⁵ X Π

X I

CO ₂ R ²¹

20

2Θ3821

it

C = CS

23

28382f

it is approx

CO ₂ R ^{1 2}

AA

C (O) .; Y = - C f ί ₂ C f I ζ -) ^I ~ ¹ (Y = -CH = CH-)

1-7 (Y = -CH ₂ -CH ₂ -)

OO CO OO

27

X,

28

CO ₂ R

I - 1

* Ph ₃ Hal-IKO) C ^ <r "OR ¹²

XK Β ·

CC-I ~ *

XVi

Hydrolysis Oxidation

C C - 2

3 removal of the protective group

C C -

2

ι -

30

28382t

χ χ

"J

Ö OWCO

φ ~

CS CS

In the above reaction schemes, R, R, R, R, R and R are as defined above in connection with formula I

21 and R and R are independently C _{1 -Zf lower} alkyl, such as methyl, ethyl, n-propyl, i-propyl or n-butyl.

Step A is a reduction reaction of the ester to a primary alcohol. Such a reduction reaction may be carried out by using various metal hydrides, preferably diisobutylaluminum hydride, in a solvent such as tetrahydrofuran, toluene or ° M'athylenchlorid, at a temperature of -20 to 20 ⁰ C, preferably from -10 to 10 ⁰ C.

Step B is an oxidation reaction of the primary alcohol to an aldehyde, which can be carried out using various oxidants. Preferably, the reaction can be carried out using pyridinium chlorochromate in methylene chloride at a temperature of 0 to 25 ^° C. or using oxalyl chloride, dimethyl sulfoxide and a tertiary amine such as triethylamine (Swern oxidation) or using a sulfur trioxide-pyridine complex .

Step C is a synthesis of a 3-ethoxy-1-hydroxy-2-proTv-n derivative which can be prepared by reacting a compound V with a lithium compound previously formed by treating cis-1-ethoxy-2 - (tri-n-butylstannyl) -ethylene with butyllithium in tetrahydrofuran. As the reaction temperature, it is preferred to use low temperature at a level of -60 to -78 ⁰ C.

28382t

Step D is a synthesis of an enal by acid hydrolysis. As the acid catalyst, it is preferred to use p-toluenesulfonic acid, hydrochloric acid or sulfuric acid, and the reaction can be carried out in a mixed solvent of water and tetrahydrofuran or ethanol at a temperature of from 10 to 25 ^° C. The 3-ethoxy-1-hydroxy-2-propene derivative obtained in Step C can be used in Step D without purification, ie, by simply removing the formed tetra-n-butylzirn simultaneously.

Step E is a double anion addition reaction between the enal III and an acetoacetate. Such an addition reaction is preferably carried out using sodium hydride and n-butyl lithium as the base.

se in tetrahydrofuran at a temperature of -78 to ⁰ ° C, preferably from -30 to -10 ⁰ C.

Step F is a reduction reaction of the ketocarboxylate of formula II by means of various reducing agents. This reaction involves the reduction of carbonyl by, for example, sodium borohydride, sodium cyanoborohydride, zinc borohydride, disiamylborane, diborane, t-butylaminoborane, pyridine-borane complex, dicyclohexylborane, thexylborane, 9-borabicyclo [3.3.1] nonane, diisopinocamphenylborane or lithium tri sec-butylborohydride to the corresponding dihydroxycarboxylate of formula 1-1.

This reaction can be carried out in a solvent selected from hydrocarbons, halogenated hydrocarbons, C 1 -C 4 -alcohols, ethers and solvent mixtures.

thereof, can be carried out at a temperature of -100 to 5O ⁰ C, preferably from -78 to 3O ⁰ C.

Further, according to J. Amer. Chem. Soc., JK) £, 593 (1983), a trialkylborane such as tri-n-butylborane or triethylborane and sodium borohydride are used at a low temperature. Further, as described in Tetrahedron Letters, 28 , 155 (1987), the erythro-form having biologically superior activities can be advantageously obtained by using an alkoxydialkylborane such as methoxydiethylborane or ethoxydiethylborane, and sodium borohydride. This reaction kaim using a solvent mixture of a C, ^ - alcohol and tetrahydrofuran at a temperature from -80 to -50 ⁰ C, preferably from -72 to -68 ⁰ C is performed.

Step G is a step to hydrolyze the ester. The hydrolysis can be carried out using an equimolar amount of a base, preferably potassium hydroxide or sodium hydroxide, in a mixed solvent of water and methanol or ethanol at a temperature of 10 to 25 ^° C. The free acid thereby obtained can be treated with a suitable solvent Base can be converted into a salt.

Step H serves to form a mevalonolactone by the dehydration reaction of the free hydroxy acid 1-2. The dehydration reaction may be carried out in benzene or toluene under reflux and removal of the resulting water or by addition of a suitable dehydrating agent such as molecular sieve.

Further, the dehydration reaction may be carried out in dry methylene chloride using a lactone-forming agent such as carbodiimide, preferably a water-soluble carbodiimide such as N-cyclohexyl-N '- [2' - (methylmorpholinium) -ethyl] carbodiimide p-toluenesulfonate, at a temperature of 10 to 35 ⁰ C, preferably 20 to 25 ⁰ C.

Step J is a reaction to hydrogenate the double bond connecting the mevalonolactone moiety and the pyrazolopyridine ring. This hydrogenation reaction can be carried out using a catalytic amount of palladium on carbon or rhodium on carbon in a solvent such as methanol, ethanol, tetrahydrofuran or acetonitrile, .for a temperature of 0 to 50 ⁰ C, preferably 10 to 25 ⁰ C.

Step K is a reaction for synthesizing an α, β-unsaturated carboxylic acid ester, wherein an α, β-unsaturated carboxylic acid ester in the trans form can be obtained by a so-called Horner-Wittig reaction using an alkoxycarbonylraethylphosphonate. The reaction is carried out using sodium hydride or potassium t-butoxide as base in dry tetrahydrofuran at a temperature of -30 to ⁰ ° C., preferably -20 to -15 ° C.

Step L is a reduction reaction of the cc, β-unsaturated carboxylic acid ester to an allyl alcohol. This reduction reaction can be carried out using various metal hydrides, preferably biisobutylaluminum hydride, in a solvent such as dry tetrahydrofuran or toluene at a temperature of -10 to 10 ^° C., preferably -10 to ⁰ ° C.

Step M is an oxidation reaction of allyl alcohol to an enal. This oxidation reaction can be carried out using various oxidizing agents, especially activated manganese dioxide, in a solvent such as tetrahydrofuran, acetone, ethyl ether or ethyl acetate, at a temperature of 0 to 100 ^° C., preferably 15 to 50 ^° C., or according to Swern oxidation using oxalyl chloride, dimethyl sulfoxide and a tertiary amine such as triethylamine.

Step N is a reaction to synthesize an α, β-unsaturated ketone by the selective oxidation of the dihydroxycarboxylic acid ester. This reaction can be conducted using activated manganese dioxide in a solvent such as ethyl ether, tetrahydrofuran, benzene or toluene, at a temperature of 20 to 80 ⁰ C, preferably 40 to 8O ⁰ C.

Step P is a hydrolysis reaction of an ester. The hydrolysis can be carried out under various acidic or basic conditions. Preferably, a method of heating or refluxing using sodium hydroxide or potassium hydroxide in a mixed solvent of water and ethyl alcohol or ethylene glycol, a method in which refluxing is carried out using sodium ethoxide in ethyl alcohol, or a method of using wherein the hydrolysis is carried out using trifluoroacetic acid at a temperature of 0 to 70 ⁰ C.

Step S is a reaction to synthesize an acid chloride from the free carboxylic acid. The reaction can be carried out using thionyl chloride or oxalyl chloride in

36 28382t

a solvent such as benzene, tetrahydrofuran or methylene chloride, at a temperature of 0 to 80 ⁰ C are performed. The resulting acid chloride XIV can be used at the following stage without purification, ie by simply removing the solvent.

Step T is a reduction reaction of the acid chloride to a primary alcohol. Such a reduction reaction can be carried out using various metal hydrides at a temperature that does not affect the other substituents. For example, the reduction reaction may be carried out using lithium aluminum hydride in an ethereal solvent such as diethyl ether at a temperature of from 0 to about 36 ^° C., using sodium borohydride in an ethereal solvent such as dioxane at a temperature of from 0 to about 100 ⁰ C, using sodium bis (2-methoxyethoxy) -aluminum hydride in an aromatic hydrocarbon solvent such as benzene, toluene or xylene, at a temperature of from 0 ° to the boiling point of the solvent, preferably from 25 to 80 ^0th C, or using diisobutylaluminum hydride in a solvent such as tetrahydrofuran, toluene or methylene chloride, at a temperature of -20 to 20 ⁰ C, preferably -10 to 10 ° C.

Further, the compound of formula '1-6 can be obtained from the aldehyde of formula V by the Wadsworth-Emmons coupling reaction [J. Amer. Chem. Soc., 107 T 3731 (1985)]. The compound can also be prepared from the enal of formula III [Tetrahedron Letters, 26 , 2951 (1985)].

The step AA is a reduction reaction of the ketocarboxylate of the formula 1-6 or XV using various reducing agents. This reaction involves the reduction of carbonyl by e.g. Sodium borohydride, sodium cyanoborohydride, zinc borohydride, diisobutylborane, diborane, t-butylaminoborane, pyridine-borane complex, dicyclohexylborane, th.exylborane, 9-borabicyclo [3.3.1] -nonane, diisopinocamphenylborane or lithium tri-sec, butylborohydride to give the corresponding dihydroxycarboxylate of formula 1-1 or 1-7.

This reaction may be carried out in a solvent selected from hydrocarbons, halogenated hydrocarbons, C 1-4 alcohols, ethers and solvent mixtures thereof at a temperature of -100 to 50 ^° C., preferably -78 to 30 ^° C.

Fener can according to J.Amer.Chem.Soc., 105 t 593 (1983), a trialkylborane such as tri-n-butylborane or triethylborane and sodium borohydride at low temperature use. Further, as described in Tetrahedron Letters, 28, 155 (1987), the erythro-form having biologically superior activities can be advantageously obtained by using an alkoxydiaikylborane such as methoxydiethylborane or ethoxydiethylborane, and sodium borohydride. This reaction may be performed using a solvent mixture of a C ^ alcohol and tetrahydrofuran at a temperature from -80 to -50 ⁰ C, preferably from -72 to -68 ⁰ C, are performed.

The compound of formula XV can be prepared by continuous Wittig reaction of the aldehyde of formula V (V / 0-84 / 02131) and subsequent double anion condensation reaction

of the resulting aldehyde with an acetoacetate are prepared in the same manner as in Step E.

The substituents R ¹ , R ² , R · ⁵ , R and R ^ of the intermediate material of the formula VI, which is used in the reaction of the stage BB-1, CC-1 or DD-1, and the substituents of the compound XVIII, XX or XXII are the substituents defined for formula I except for substituents with hydroxyl, amino or monoalkylamino.

Steps BB-1 and BB-2 involve the reaction of the compound of formula XVII with the compound of formula XVI (wherein Hal represents chlorine, bromine or iodine) by Wittig reaction to obtain the compound of formula XVIII (step BB -1), followed by hydrolysis of the hydroxyl-protecting group (R) of the compound XVIII in the presence of a catalyst to obtain the compound of the formula 1-1.

The phosphonium compound of the formula XVI can be obtained by halogenating the hydroxyl group of the hydroxymethyl in the 5-position of the pyrazolopyridine ring of the compound of the formula VI by a conventional method and subsequent reaction with triphenyl phosphine.

The reactions of steps BB-1 and BB-2 can be carried out according to the procedure described in Tetrahedron Letters, 25, 2435 (1984), US Patent 4,650,890. EP 0 244 364A, etc. has been described.

The Wittig reaction can be carried out in a dry, inert solvent. The inert solvent may be an aliphatic hydrocarbon,

39

Call toluene or an ether-type solvent. Preferred is the ether type solvent such as diethyl ether, 1,2-diethoxyethane, 1,2-dimethoxyethane or tetrahydrofuran.

The Wittig reaction can be carried out in a conventional manner. A strong base is added to a solution of the phosphonium compound of the formula XVI, in a temperature range in which the substituents of the phosphonium compound are not affected. In this way, the corresponding ylide compound is formed. Then the aldehyde of formula XVII is added to the solution to form the desired compound. As examples of the strong base, mention may be made of sodium hydride and n-butyllithium. Preference is given to n-butyllithium.

The temperature after addition of the strong base is -40 to 25 ⁰ C and the temperature after addition of the aldehyde -35 to 3O ⁰ C.

The hydroxyl-protecting group (R) of the compound of the formula XVII or XVIII is trisubstituted silyl, preferably diphenyl-t-butylsilyl, which is usually used as a hydroxyl-protecting group. Preferred is a protecting group which can be decomposed without decomposition of the ester or lactone. The solvent used in the deprotection is an inert solvent such as tetrahydrofuran or methanol. The catalyst used in deprotection is one commonly used for the silyl removal reaction. For example, a mixture of acetic acid and tetra-

butylammonium fluoride in tetrahydrofuran or hydrochloride in methanol.

The reaction temperature for removing the protective group is 20 to 60 ^° C., preferably 20 to 30 ^° C.

If other hydroxyl protecting groups than R are present at the time of deprotection, such protecting groups can be removed to form hydroxyl groups.

Steps CC-1 to CC-3 are Wittig reactions of the compound of the formula XVI with the compound of the formula XIX (step CC-1), followed by hydrolysis of the acetal to form the hemiacetal, followed by oxidation of the hemiacetal to form of the lactone (step CC-2) and subsequent removal of the hydroxyl-protecting group (R) (step CC-3). The hydroxyl-protecting group (R) is defined as in steps BB-1 and BB-2. The reaction conditions for the CC-1 stage may be the same as for the BB-1 method.

Step CC-2 includes (1) hydrolysis and (2) oxidation. The hydrolysis may be carried out in a mixed solvent such as 10 # HCl in tetrahydrofuran or acetic acid / water / tetrahydrofuran, preferably acetic acid / water / tetrahydrofuran. The reaction temperature is 10 to 100 ^° C., preferably 20 to 60 ^° C.

The oxidation of the hemiacetal formed by the hydrolysis can be carried out under mild conditions. The reaction conditions vary depending on the type of oxidant used.

If the oxidizing agent is pyridinium chlorochromate, the reaction temperature is 20 to 3O ⁰ C, and the solvents are halogenated hydrocarbons, preferably methylene chloride, is used.

Swern oxidation is carried out using a mixing system of oxalyl chloride / dimethyl sulfoxide / triethylamine as the oxidizing agent. The reaction temperature is -60 to -40 ⁰ C, and the solvent used is a halogenated hydrocarbon, preferably methylene chloride.

If the oxidizing agent is N-methylmorpholine oxide and dichloro-tris "[(phenyl), P] ruthenium (II), the reaction temperature is 0 to 40 ⁰ C, preferably 20 to 30 ⁰ C and the solvent is dry. Dimethylformamide or acetone.

If the oxidizing agent is AgCO ^ on Celite, the reaction temperature is from 0 ° C to the boiling point of the reaction solution, preferably not more than 150 ⁰ C, and the solvent is benzene, toluene, xylene, etc.

The reaction condition for deprotection in step CC-3 may be the same as in the method of step BB-2.

Steps DD-1 and DD-2 are Wittig reactions of the compound of the formula XVI with the compound of the formula XXI (step DD-1), followed by removal of the hyrlroxyl-protecting group (R ²⁶ ) (step DD-2) The hydroxyl protecting group (R) is defined as in steps BB-1 and BB-2.

The reaction conditions for the DD-1 stage may be the same as for the BB-1 method. The reaction conditions for deprotection in step DD-2 may be the same as in the method of step BB-2.

In Table 1 and in the following description, i - iso, see - secondary, t - tertiary and c - eyeIo. Me stands for methyl, Et for ethyl, Pr for propyl, Bu for butyl, pent for pentyl, hex for hexyl and Ph for phenyl.

As specific examples of the compound of the present invention, in Table 1, the compounds of the formula 1-2 are shown together with the compounds defined in the examples below. In addition to the compounds of formula 1-2 which are shown in Table. 1, compounds of the formulas 1-1, 1-3 and 1-4 are given in Table 1, in which R ¹ , R ² , R ³ , R ^ and R ^{5 have} the same meaning as in formula 1-2 , as well as compounds of formula 1-5, which correspond to the salts of the compound of formula 1-2.

- 43 -

383821

Table 1

CO ₂ H

H 2-Ph 4-F H i-Pr H 1-Me 4-F H i-Pr H 2-Me 4-F H i-Pr H 1-i-Pr 4-F H i-Pr H 1-t-Bu 4-F H i-Pr H 1- (4-C jg -Ph) 4-F H i-Pr H 1- (4-Me-Ph) 4-F H i-Pr H 1- (4-MeO-Ph) 4-F H i-Pr H 1- (4-F-Ph) 4-F H i-Pr H 1-CH ₂ Ph 4-F n i-Pr me 2-Me 4-F H i-Pr Me · 1-Et 4-F H i-Pr

- 44 -

Table 1 (cont.)

R ¹ R ² R ³ R ⁴ R ³ Me "" 1-i -Pr " 4-F H i-Pr me 1-U-C4-Ph) 4-F H i-Pr me 1- (4-Me-Ph) 4-F H i-Pr me 1- (4-F-Ph) 4-F H i-Pr me 1- (2'-pyridyl) 4-F H i-Pr et 1-Me 4-F H i-Pr et 1-Et 4-F H i-Pr et 1-i-Pr 4-F · , H i-Pr et 1-Ph 4-F H i-Pr Cyclo-Pr 1-Et 4-F H i-Pr Cyclo-Pr 1-i-Pr 4-F H i-Pr Cyclo-Pr 1-t-Bu 4-F H i-Pr i-Pr 1-Me 4-F H i-Pr i-Pr 2-Me 4-F H i-Pr i-Pr 1-Et 4-F H i-Pr i-Pr 1-i-Pr 4-F H i-Pr i-Pr 1-t-Bu 4-F H i-Pr i-Pr 9-Ph 4-F H i-Pr i-Pr 1-Ph 4-F H i-Pr t-Bu 1-Me ' 4-F H i-Pr

-45 -

Table 1 (cont.)

^gt Rj R ³ R * rs

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr.

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

i-Pr

t-Bu Ph 2-Me t-Bu Ph 1-Et t-Bu Ph 1-i-Pr t-Bu Ph 1-t-Bu t-Bu 1-Ph Ph 1-Et Ph 1-i-Pr Ph 1-t-Bu Ph 1-Ph 4-C4 1-Et 4-Cjg 1-Ph 4-Me 1-Me 4-MeO 1-Me H 1-Ph H 1-Me H 1-Et H 1-i-Pr H 1-t-Bu H 1-Ph H J- (4-C

4-F H 4-F H 4-F. H 4-F H 4-F H 4-F H 4-F H 4-F · H 4-F H 4-F H 4-F H 4-F H 4-F H 4-C £ H 4-C jg H 4-C H 4-C £ H 4-C4 H 4-C4 H 4-C ί H

Table 1 (cont.)

R ¹ R ² R ³ R ⁴ R ^s H 1- (4-Me-Ph) 4-C £ H i-Pr H 1- (4-MeO-Ph) 4-C4 H i-Pr H 1- (4-F-Ph) 4-C4 H i-Pr H 1-CH ₂ Ph 4-CAE H i-Pr me 1-Me 4-C4 H i-Pr me 1-Et 4-C £ H i-Pr me 1-i-Pr 4-C4 .H i-Pr me 1- (4-CA-Ph) 4-C £ ' • H i-Pr me 1- (4-Me-Ph) 4-C4 H i-Pr me 1- (4-MeO-Ph) 4-C £ H i-Pr me 1- (4-F-Ph) 4-C £ H i-Pr me 1-t-Bu 4-C £ H i-Pr me 1-Ph 4-C4 H i-Pr me 1-CH ₂ Ph 4-Cjg H i-Pr me l- (2'-pyridyl) 4-C £ H i-Pr et 1-Me 4-C jg H i-Pr et 1-Et 4-C £ H i-Pr et 1-i-Pr 4-C £ H i-Pr et 1-Ph 4-C £ H i-Pr C yclo- Pr 1-Me i-C £ H i-Pr

- 47 -

Table 1 (cont.)

R *

cycl o-Pr Ph 1-Et cycl o-Pr Ph 1-i-Pr cycl o-Pr Ph 1-t-Bu i-Pr 1-Me i-Pr 1-Et i-Pr 1-i-Pr i-Pr 1-t-Bu i-Pr 1-Ph t-Bu • 1-Me t-Bu 1-Et t-Bu 1-i-Pr t-Bu 1-t-Bu t-Bu 1-Ph Ph 1-Et Ph 1-i-Pr Ph 1-t-Bu Ph 1-Ph A-Ci 1-Me A-Ci 1-Et A-Ci 1-Ph

A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr 4-ÜjG H i-Pr A-Ci " ' H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr A-Ci H i-Pr

- 48 -

Table 1 (cont.)

R ¹ R ^z R ³ R ⁴ R ^s 4-Me-Ph · 1-Me 4-C4 H i-Pr 4-Ph-Heo 1-Me 4-C £ H i-Pr H 1-Ph H H i-Pr H 1-Me H H i-Pr H l-et H H i-Pr H 1-i-Pr. H H i-Pr H 1-t-Bu H H i-Pr H 1- (4-CA-Ph) H ' ' H i-Pr H 1- (4-Me-Ph) H H i-Pr H 1- (4-MeO-Ph) H H i-Pr H 1- (4-F-Ph) H H i-Pr H 1-CH ₂ Ph H H i-Pr me 1-Me H H i-Pr me 1-Et H H i-Pr me 1-i-Pr H H i-Pr me l- (4-C. "-Ph) H H i-Pr me 1- (4-Me-Ph) H H i-Pr me 1- (4-MeO-Ph) H H i-Pr me 1- (4-F-Ph) H H i-Pr me 1-t-Bu H H i-Pr

Table 1. (cont.)

R ¹ ... me R ^z R ³ H R ⁴ R ⁵ me H me 1-Ph H H i-Pr et 1-CH ₂ Ph H H i-Pr et 1- (2-pyridyl) H H i-Pr et 1-Me H H i-Pr et 1-E t H H i-Pr Cyclo-Pr 1-i-Pr H · ' H i-Pr Cyclo-Pr 1-Ph H  H i-Pr Cyclo-Pr 1-He H H i-Pr Cyclo-Pr 1-Et H H i-Pr i-Pr 1-i-Pr H H i-Pr i-Pr 1-t-Bu H H i-Pr i-Pr 1-Me H H i-Pr i-Pr 1-Et H H i-Pr i-Pr 1-i-Pr H H i-Pr t-Bu 1- t-Bu H H i-Pr t-Bu 1-Ph H H i-Pr t-Bu 1-He H H i-Pr t-Bu 1-Et H H i-Pr 1-i-Pr H i-Pr 1-t-Bu II i-Pr

Table 1 (cont.)

R ¹ R ² R ^: I H R ⁴ R ⁵ t-Bu 1-Ph H H i-Pr Ph 1-Et H H i-Pr Ph 1-i-Pr H H'' i-Pr Ph 1-t-Bu H H i-Pr Ph 1-Ph. H H i-Pr 4-C4-Ph 1-Me H H i-Pr 4-Cjg -Ph 1-Et H · H i-Pr 4-C jg -Ph 1-Ph H , H i-Pr 4-Me-Ph 1-Me H H i-Pr 4-MeO-Ph 1-Me H i-Pr H 1-Ph 4-F H c-Pr H 2-Ph 4-F H c-Pr H 1-Me * 4-F H c-Pr H 2-Me 4-F H c-Pr H 1-Et 4-F H c-Pr H 1- i-Pr 4-F H c-Pr H 1-t-Bu 4-F H c-Pr H 1- (4-C ^ -ph) 4-F H c-Pr H 1- (4-Me-Ph) 4-F H c-Pr H 1- (4-MeO-Ph) 4-F H c-Pr

- 51 -

Table 1 (cont.)

R ¹ R ² R ³ R ⁴ R ⁵ H 1- (4-F-Ph) 4-F H c-Pr H 1-CH ₂ Ph 4-F H c-Pr me 2-Me 4-F H c-Pr me 1-Et 4-F H c-Pr me 1-i-Pr 4-F H c-Pr He 1- (4-CA-Ph) 4-F H c-Pr me 1- (4-Me-Ph) 4-F H c-Pr me 1- (4-MeO-Ph) 4-F '   H c-Pr me 1- (4-F-Ph) 4-F H c-Pr me 1-Ph 4-F H c-Pr me 2-Ph 4-F H . c-Pr me 1-CH ₂ Ph 4-F H c-Pr me 1- (2-pyridyl) 4-F H c-Pr et 1-Me 4-F H c-Pr et 1-Et 4-F H c-Pr et 1-i-Pr 4-F H c-Pr et 1-Ph 4-F H c-Pr cyclo -Pr 1-Me 4-F H c-Pr cyclo -Pr 1-Et 4-F H c-Pr cyclo -Pr 1-i-Pr 4-F H c-Pr

Table 1 (cont.)

R ¹ R ² R ³ R *

'Cyclo-Pr 1-Ph

i-Pr 1-Me

i-Pr 2-He

i-Pr 1-Et

i-Pr i-Pr

i-Pr 1-t-Bu

i-Pr 2-Ph

i-Pr 1-Ph

t-Bu 1-Me

t-Bu 2-He

t-Bu 1-Et

t-Bu 1-i-Pr

t-Bu 1- t-Bu

t-Bu 1-Ph

Ph 1-Et

Ph 1-i-Pr

Ph 1-Ph

4-C £ -Ph 1-Me

4-C jg -Ph 1-Et

4-C £ -Ph 1-Ph '

4-F H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F · , H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F " H c-Pr 4-F H c-Pr 4-F H c-Pr 4-F H c-Pr

Table 1 (cont.)

Ρ " R ² X ' F V R ⁵ 4-Me-Ph 1-Me 4 F H c-Pr 4-MeO-Ph 1-Me 4 i H c-Pr H 1-Ph 4-C i H c-Pr H 1-Me 4-C i H c-Pr H 1-Et 4-C i H c-Pr H 1-i-Pr 4-C I H c-Pr H 1-t-Bu 4-C S. ' H c-Pr H 1-Ph 4-C I   H c-Pr H 1- (4-Ci -Ph) 4-C I H c-Pr H 1- (4-Me-Ph) 4-C i H c-Pr H 1- (4-MeO-Ph) 4-C i H c-Pr H 1- (4-F-Ph) 4-C i H c-Pr H 1-CH ₂ pts 4-C i H c-Pr me 1-Me 4-C I H c-Pr me 1-Et 4-C £ H c-Pr me 1-i-Pr 4-C I ' H c-Pr me 1- (4-Ci -Ph) 4-C SL H c-Pr me 1- (4-Me-Ph) 4-C I H c-Pr me 1- (4-MeO-Ph) 4-C λ H c-Pr me 1- (4-F-Ph) 4-C H c-Pr

~ ⁵⁴ "2838 2 t

Table 1 (cont.)

R ¹ - R ² R ³ R ⁴ R ⁵ me 1-t-Bu 4-C i H c-Pr me 1-Ph K-Zi H c-Pr me 1-CH ₂ Ph K-Zi H c-Pr me 1- (2 -pyridyl ¹⁾ K-Zi H c-Pr et 1-Me K-Zi H c-Pr et 1-Bt _- . K-Zi H c-Pr et 1-i-Pr K-Zi .H c-Pr et o-Pr 1-Ph K-Zi '   H c-Pr cycl o-Pr 1-Me K-Zi H c-Pr cycl o-Pr 1-Et K-Zi H c-Pr cycl o-Pr 1-i-Pr K-Zi H c-Pr cycl 1-t-Bu K-Zi H c-Pr i-Pr 1-Me K-Zi H c-Pr i-Pr 1-Et K-Zi II c-Pr i-Pr 1-i-Pr K-Zi H c-Hr i-Pr 1 -t-Bu K-Zi H c-Pr i-Pr ! -Ph K-Zi H c-Pr t-Bu 1-ms K-Z i H c-Pr t-Bu 1-Et K-Zi H : Pr t-Bu 1-i-Pr K-Zi H c-Pr

- 55 -

Table 1 (cont.)

R ¹ R ² R ³ i R ⁴ R ⁵ i H t-Bu 1-t-Bu 4-C i H c-Pr t-Bu 1-Ph 4-C I H c-Pr Ph 1-Et 4-C i H c-Pr Ph 1-i-Pr 4-C i H c-Pr Ph 1-t-Bu 4-C i H c-Pr Ph 1-Ph 4-C ι H c-Pr AC & PH 1-He 4-C i H c-Pr A-Ci -Ph 1-Et 4-C I H c-Pr 4-C £ -Ph 1-Ph 4-C i H c-Pr 4-Me-Ph 1-He 4-C H H c-Pr 4-MeO-Ph 1 -Me 4-C H H c-Pr H 1-Ph H H c-Pr H 1-Me H H c-Pr H 1-Et - H H c-Pr H i-i-Pr H H c-Pr H 1-t-Bu H H c-Pr H 1- (4-C Ä -Ph) H H c? r H 1- (4-Me-Ph) H H c-Pr H 1- (4-MeO-Ph) H c-Pr H 1- (4-F-Ph) c-Pr

- 56 -

Table 1 (Voyts.).

R ¹ R ² R ³ H R ⁴ R ³ H 1-CH ₂ Ph H H c-Pr me- " 1-Me • H H c-Pr He 1-Et H H c-Pr me 1-i-Pr H H c-Pr me 1- (4-Ci-Ph) H H , c-Pr me 1- (4-Mo-Ph) H H c-Pr me 1 -. (4-Me (I-Ph) H H • c-Pr me 1 '(4-F-Ph) " H • H c-Pr me 1-t-Bu H H c-Pr me 1-Ph H H c-Pr me 1-CH ₂ Ph H H c-Pr me 1- (2'-pyridyl) H H H c-Pr Et Et 1-Me l-et · " H H'H c-Pr c-Pr Eh 1-i-Pr H H - 'c-Pr et 1-Ph H ,-H c-Pr Cyclo-Pr 1-Me H H c-Pr C yclo-Pr 1-Et H H c-Pr Cyclo-Pr 1-i-Pr H H c-Pr Cyclo-Pr 1-t-Bu H c-Pr

- 57 -

28382t

Table 1 (Foirta.)

R ¹ R ^z R ³ H R ⁴ R ⁵ i-Pr 1-Me H H c-Pr l-Pr 1-Et IJ H c-Pr i-Pr 1-i-Pr H H c-Pr i-Pr 1-t-Bu H H c-Pr i-Pr 1-Ph R H c-Pr t-Bu 1-Me H H c-P · t-OEU 1-Et H · H c-Pr t-Bu 1-i-Pr H • J c-Pr t-Bu 1-t-Bu H H c-Pr t-Bu 1-Ph H H c-Pr Ph 1-Et H H c-Pr Ph 1- i-Pr H H c-Pr Ph 1-t-Bu H H c-Pr Ph 1-Ph H H c-Pr 4-C i -Ph 1-Me H H c-Pr 4-Cjg -Ph 1-Et ff H c-Pr 4-C £ -Ph 1-Ph H H c-Pr 4-Me-Ph 1-Me H H c-Pr 4-MeO-Ph 1-Me H c-Pr

More finely, pharmaceutically acceptable salts such as sodium salts or potassium salts, or esters such as ethyl esters or methyl esters of these compounds can be prepared in the same manner.

The compounds according to the invention exhibit high inhibitory activity against cholesterol biosynthesis in HMG-CoA reductase as a rate-limiting enzyme. This is evident from the test results given below. The compounds are thus able to keep the amount of the present in the blood as lipoprotein cl olesterins low or reduce. The compounds of the present invention are useful as a cure for hyperlipidemia, hyperlipoproteinemia and atherosclerosis.

They may be formulated into various suitable formulations, depending on the mode of administration. The compounds of the invention may be administered in the form of the free acids or in the form of physiologically hydrolyzable and acceptable esters or lactones or in the form of pharmaceutically acceptable salts.

The pharmaceutical compositions of the present invention are preferably administered orally, in the form of the compound of the invention itself or in the form of powders, granules, tablets or capsules formulated by mixing the compound of the invention with a suitable, pharmaceutically acceptable carrier, including a binder, such as hydroxypropylcellulose, syrup, gum arabic, gelatin, sorbitol,

59 2838 2 t

Gum tragacanth, polyvinylpyrrolidone or CMC-Ca, an extender such as lactose, sugar, corn starch, calcium phosphate, sorbitol, glycine or crystalline cellulose powder, a lubricant such as magnesium stearate, talc, polyethylene glycol or silica, and a disintegrant such as potato starch.

However, the pharmaceutical compositions of the present invention are not limited to those for oral administration and may also be applicable to parenteral administration. For example, the composition may be in the form of e.g. into a suppository, formulated using oily base material such as cocoa butter, polyethylene glycol, lanolin or fatty acid triglyceride, a transdermal therapeutic base formulated using liquid paraffin, white petrolatum, a higher alcohol, macrogol ointment, hydrophilic ointment or hydrogel. A base material, an injection formulation, formulated using one or more materials selected from the group consisting of polyethylene glycol, hydrogel base material, distilled water, distilled water for injection and an extender such as lactose or corn starch, or a formulation for the Administration by mucous membranes such as ocular mucous membrane, nasal mucous membrane and oral mucous membrane.

Further, one can combine the compounds of the present invention with basic ion exchange resins which are capable of forming bile acids and yet are not absorbed by the gastrointestinal tract.

The daily dose of the compound of formula I is 0.05 to 500 mg, preferably 0.5 to 50 mg, for an adult. The compound is administered 1 to 3 times a day. The dose may of course vary depending on the age, weight or condition of the patient.

The compounds of the formulas II to VII are novel and represent important intermediates for the preparation of the compounds of the formula I. Accordingly, the present invention also relates to the compounds of the formulas II to VII and to the processes for their preparation.

Embodiment:

In the following, the invention is explained in more detail by means of test examples for the pharmacological activities of the compounds of the present invention, by means of preparation examples and formulation examples. It should be understood, however, that the present invention is not limited by these specific examples.

Pharmacological test examples

Test A: Inhibition of cholesterol biosynthesis from acetate in vitro

An enzyme solution is prepared from the liver of male Wistar rats cannulated to collect bile and deliver bile over a period of 24 hours. The liver is excised in semi-darkness and microsome and supernatant fraction, which are precipitated with 40 to 80 £ Ammon ammonium sulfate solution

can (sup fraction), be prepared from liver homogenate according to the modified method of Knauss et al .; M. Kuroda et al., Biochim. Biophys. Acta, 489, 119 (1977). For the cholesterol biosynthesis assay, microsome (0.1 mg protein) and sup fraction (1.0 mg protein) are incubated for 2 h at 37 ^° C. in 200 μl of the reaction mixture containing ATP; 1mM, glutathione; 6 mM, glucose-1-phosphate; 10mM, NAD; 0.25 mM, NADP; 0.25 mM, CoAr 0.04 mM and 0.2 mM [2-C] sodium acetate (0.2 / μCi) with 4 / μl of the test compound solution dissolved in water or dimethylsulfoxide. In order to stop the reaction and to bring about a hydrolysis, 1 ml of 15 # strength EtOH-KOH was added to the Reaktionssyotem and heated for 1 h at 75 ⁰ C. Non-saponifiable lipids are extracted with petroleum ether

14 and the incorporated C-radioactivity is counted.

The inhibitory activity of the compounds is indicated as IC50.

Test B: Inhibition of cholesterol biosynthesis in blood cells

Hep G2 cells out of the above 5. Passage be on 12 well plates (well plates) seeded with Dulbecco's modified Eagle (DME) medium containing 10% fetal bovine serum (FBS) at 37 ⁰ C, 5% CO _2, incubated, until the cells confluence for about 7 days. The cells are exposed to the DME medium containing 5% lipoprotein deficient serum (LpDS) prepared by the ultracentrifugation method for more than 24 hours. Before the assay, the medium is changed to 0.5 ml of fresh 5% LpDS containing DME and 10 μl of the test compound solution dissolved in water or DMSO is added. 0.2 / μCi of [2- C] -nitium acetate (20 / μL) becomes

Time O hours (B-1) or 4 hours (B-2) added after addition of the compounds. After another 4 h

14

incubation with [2- C) -Natriumacetat the medium is removed and the cells with phosphate buffered saline (PBS), cooled to ⁰ C 4, washed. The cells are scraped with a rubber policeman and collected into tubes with PBS and digested with 0.2 ml 0.5 N KOH at 37 ⁰ C. Aliquots of the digestive product are used for protein analysis and the remainder is used

1 ml 15% EtOH-KOH for 1 h at 75 ⁰ C saponified. Non-verseif-

bare lipids are extracted with petroleum ether and the

C radioactivity is counted. The counts were

checked by cell protein and displayed with DPM / mg protein. The inhibitory effect of the compounds is indicated as IC50.

Test C: Inhibition of cholesterol biosynthesis in vivo

Male Sprague-Dawley rats, weighing about 150 g, are fed normal Purina food and water ad libitum and exposed to a darkened 12 h (12 o'clock to 2 o'clock) dark illumination pattern before they are used for the in vivo test for the determination of cholesterol biosynthesis inhibition. The animals are divided into groups consisting of 5 rats, and zv / ar such that there is an average, average body weight in each group. Test compounds at dose levels of 0.02 to 0.2 mg / kg body weight (0.4 ml / 100 g body weight) are dissolved in water or suspended in 0.5% methyl cellulose and

Administered orally 2 to 3 hours before the middle of the dark period (8:00 pm), i. while cholesterol biosynthesis reaches a maximum in rats. As a control, advice

only administered water or vehicle orally. At 90 minutes after the sample administration, the rats are intraperitoneally injected with 10 μCi of [2- C] sodium acetate in a volume of 0.2 ml / rat. Two hours later, blood samples are taken and the serum is immediately separated. The total lipids are determined according to the method of Folch et al. extracted and saponified with EtOH-KOH. Non-saponifiable lipids are extracted with petroleum ether.

and the radioactivity incorporated into the non-saponifiable lipids is counted.

Inhibitory activity is reported as the percent decrease in counts in the test groups (DPM / 2 ml serum / 2 h) versus that in the control group.

In the compounds according to the invention, the inhibitory effect on cholesterol biosynthesis, in which HMG-CoA reductase serves as a rate-determining enzyme, is measured by the above tests A and B. The results are shown in Tables 2, 2-2, 3, 3-2 and 3-3. Further, the results of the determinations obtained in Test C are shown.

Table 2 Inhibitory effect of the reference compound in the test A Reference compound IC50 (molar concentration )

CS-5141,1 χ 10 ~ ^ö

In Table 2-2, the relative activities are reported relative to the activities of CS-514 in Test A, which are rated as 1.

Table 2-2: Relative activities in the test A

invention Relative activities Structures of the reference compounds: OH NaO ζΟ'Ύ Connection, (1) CS-514 O HO. J 1-5-1 9.6 1-5-2 3.1 1-5-4 3.0 1-5-5 11.8 1-5-6 7.5 1-5-9 5.8 1-5-13 5.1 1-5-14 7.9

CH ₃ = H

Table 3 : Inhibitory effect in Test B-1

Reference compound IC50 (molar concentration) CS-5141.1 χ 10 " ^b

In Table 3-2, the relative activities are shown relative to the activities of CS-514 in Test B-1, which are rated as 1.

Table 3-2 Relative Activities in Test B-1

According to the invention, Connect. Relative activities

1-1-5 204

1-1-6 59

1-1-9 103

1-1-12 29

Table 3-2 (cont.)

1-5-13 149 1-5-1 15

1-5-2 0.8

1-5-4 5.5

1-5-7 31

ΐ-5-8 39

1-5-10 17

1-5-14 14.1

1-5-15 10.6

11-11 187

Further, the inhibitory activities of compounds of the invention as determined in Test B-1 are shown at a concentration of 1.0χ10 "¹ Mol mol / l in Table 3-3.

Table 3-3 ; Inhibitory activities of the present compound χ 10 ~ ⁷ mol / l in Test B-1 at a concentration of 1.0

Invention according to. Connect. Relative activities

1-5-3 36.3

1-5-5 78.2

1-5-6 - 53.3

1-5-9 55.3

1-5-11 * 58.8

1-5-12 47.3

1-5-13 55.5

1-5-16 49.0

1-5-17 36.0

Results of Determination of Inhibitory Activities in Test C

The percentage decrease in counts after oral administration of 0.2 mg / kg of compound 1-5-4, 1-5-5 and 1-5-7 is 53%, 49% and 52%, respectively

2838

measured value of the Kontnilgruppe. The percentage decrease in counts after oral administration of 0.2 mg / kg CS-514 is 39% under the same conditions.

The compounds of the present invention have superior activities over the reference compound CS-514 in Tests A, B and C.

Test D ; acute toxicity

A 0.5 .mu.CMC suspension of a test compound is orally administered to male ICR mice (group of 3 mice). The acute toxicity is determined on the basis of mortality after 7 days. With the compounds 1-5-1, 1-5-2, 1-5-4, 1-5-7, 1-5-10, 1-5-11 ', 1-5-12, 1-5- 14 and 1-5-15 of the present invention, the mortality is 0% even when the compounds are each orally administered in an amount of 1000 mg / kg.

example 1

Ethyl (e) -7- [4- ^t - (4-fluorophenyl) -1 ', 3- ^t- dimethyl-6' - (1 "-methylethyl) -pyrazolo [3,4-b] pyridine-5 ' yl] -3,5-dihydroxy hept-6-enoate (Compound 1-1-1)

This compound is prepared by a synthesis comprising the following reaction steps Example 1-a to Example 1-g.

Example 1-a

Ethyl 4- (4'-fluorophenyl) -1,3-dimethyl-6- (1'-methylethyl) pyrazolo [3,4-b] pyridin-5-ylcarboxylate (Compound U

Synthesis of the dihydro compound

^, 22 g (0.02 mol) of 5-amino-1,3-dimethylpyrazole and 5.3 g (0.02 mol) of ethyl 2- (4'-fluorobenzylidene) -4-methyl-3-oxopentanoate are combined mixed and heated for 1 h at about 130 ⁰ C. Low boiling point substances are distilled off under reduced pressure by means of a rotary evaporator. Then, the reaction mixture is dissolved in chloroform, washed with a sodium carbonate aqueous solution and with water, and dried over anhydrous magnesium sulfate. Chloroform is evaporated and the residual oil is purified by silica gel column chromatography; dihydropyrazolo [3,4-b] pyridine (XI-1) is obtained.

PNMR (CDCl ₃₎ 6 ppm: 0.81 (d, J = 7JZ, 3K), 1.0-1.3 (m, 6H), 1.97 (s, 3H), 2.64 (m _r lH), 3:44 (d, J = 3Hz, lH ), 3.81 (s, 3H), 4.06 (q, J = 7Hz, 2H), 4.48 (d, J = 3Hz, IH), 6.84 (m, 4H)

Oxidation method 1

7.54 g of the dihydro compound obtained in the above step are dissolved in 15% glacetic acid and treated with 2.2 g of chromic anhydride. The mixture is stirred at room temperature (15 to 20 ⁰ C). After the disappearance of the starting materials was determined by thin layer chromatography, 100 ml of water are added. The mixture is extracted with chloroform. The chloroform layer is shaken with a saturated aqueous sodium carbonate solution and water, and then dried over anhydrous magnesium sulfate.

The chloroform is distilled off. The residual oil is purified by silica gel column chromatography (eluent: 1% methanol / chloroform); the desired compound is obtained as white crystals. Fp.60 to 64 ⁰ C; Yield 52% (based on aminopyrazole).

Oxidation method 2

1 g of the dihydro compound obtained in the above step is dissolved in acetone containing a small amount of ethanol. Potassium permanganate (1.5 mol times) is added. The mixture is stirred for one day at room temperature. After detecting complete disappearance of the unreacted dihydro compound by thin layer chromatography, manganese dioxide is removed by filtration. The filtrate is concentrated and the remaining oil is treated in the same manner wio oxidation method 1 to obtain the desired compound

 Yield 60% (based on aminopyrazole).

Example 1-b

4- (4 ^l -fluorophenyl) -5-hydroxymethyl-1,3-dimethyl-6- (i- methyl-ethyl) -pyrazolo [3 _t 4-b1pyridine (compound VI-1)

5.0 g (0.014 mol) of compound VII-1 are dissolved in dry toluene under a nitrogen atmosphere and cooled to ⁰ ° C. in an ice bath. 35 ml of a 16% strength by weight diisobutylaluminum hydride / toluene solution are added dropwise to this solution, and the mixture is stirred at ⁰ ° C. for 2 hours. After complete disappearance of compound VII-1 by thin layer chromatography, a saturated aqueous ammonium chloride solution is obtained at ⁰ ° C to remove the reaction

stop. The reaction mixture is mixed with diethyl ether and the organic layer is separated off. The gelled substance is dissolved by adding an aqueous sodium hydroxide solution and extracted again with ethyl ether. The ethyl ether extracts are combined and dried over anhydrous magnesium sulfate. The extract is separated by filtration and the solvent is distilled off; 3.9 g of pale yellow, desired compound are obtained

Yield: 88%; Mp 174 to 175 ⁰ C

Example 1-c

[4- ( 4'- fluorophenyl) -1,3-dimethyl-6- (1'-methylethyl) pyrazolor3,4-b1pyridin-'5-yl1-carboxaldehyde (Verb.V-1)

4.2 g (19 mmol) of pyridinealachlorochromate, 0.69 g of anhydrous sodium acetate and 3.8 g (12 mmol of compound VI-1) are suspended at room temperature in 50 ml of dry dichloromethane, the reaction solution is stirred for 1 h and then treated with 100 ml of diethyl ether The mixture is stirred thoroughly The reaction mixture is subjected to suction filtration through a celite layer and the extract is evaporated to dryness under reduced pressure The residue is subjected to silica gel column chromatography (eluent: chloroform) to obtain 2.9 g g (yield 7Q%) desired compound a, s hollgelbe substance;? mp 144 to 146 ⁰ C..

Examples 1-d and 1-e

(E) -3- [4 ^I - (4 "-fluorophenyl) -1 ^f, 3 ^l-dimethyl-6 '- (1" -methylethyl) -pyrazolo [3,4-b Jpyridin-5'-yl] - propenaldehyde ( compound IIJ> 1)

Example 1-d

Dissolve 14.5 g (40 mmol) of cis-1-ethoxy-2 - ( 'tri-n-brtylstannyl) ethylene in 50 ml of dry tetrahydrofuran and the solution is cooled under a nitrogen atmosphere to -78 ⁰ C. 26 ml (AO mmol) of a 15% by weight n-butyllithium-n-hexane solution are added dropwise to this solution. The mixture is stirred for 20 minutes and then treated dropwise with a solution of 2.5 g (8 mmol) of compound V-1 dissolved in 20 ml of dry tetrahydrofuran. The reaction mixture is stirred for 1 h at -TB ⁰ C and then treated with 26 ml of saturated ammonium chloride solution to terminate the reaction. The organic layer is extracted with diethyl ether. The ether extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to liquid separation between η-hexane and acetonitrile. The acetonitrile layer is distilled under reduced pressure; Essentially pure compound IV-1 is obtained.

Example 1-e

The compound IV-1 obtained in Example 1-d is dissolved in 70 ml of tetrahydrofuran and 20 ml of water and 3 g of p-toluenesulfonic acid are added thereto. The mixture is stirred for 2 h at room temperature. The reaction solution is carefully neutralized with aqueous sodium hydroxide solution. Then diethyl ether is added and the extraction is continued for a while. The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Then the solvent is

71 283 6 21

distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (eluent / ethyl acetate / n-hexane = 1/9, v / v) to obtain the objective compound as a yellow substance; Quantity 2.2 g (yield 7990), mp 133 to

Example 1-f

Ethyl (E) -7- [4 "- (4" -fluorophenyl) -1 ^l , 3 ^l -dimethyl-6 ^l - (i "-methylethyl) -pyrazolo [3,4-b] pyridine-5 ' yl] -5-hydroxy-3- oxohepto-6-enoate (compound II-1)

1.25 g of 60% sodium hydride are washed with dry petroleum ether, dried under a stream of nitrogen and then suspended in 200 ml of dry tetrahydrofuran. The suspension is cooled under a nitrogen atmosphere to -15 ⁰ C and treated dropwise with 3.9 ml (3OmMoI) of ethyl acetoacetate was added. The mixture is stirred for 15 min. Then, 20 ml (30 mmol) of 15% strength n-butyllithium-n-hexane solution are added dropwise and the mixture is stirred for 30 min. Further, a solution of 2.1 g (6.1 mmol) of compound III-1 dissolved in dry tetrahydrofuran is added and the mixture is stirred for 1 h. 10 ml of a saturated aqueous ammonium chloride solution are added at -15 ⁰ C to the reaction mixture and the mixture is extracted three times with diethyl ether. The ether solution is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated to dryness under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: ethyl acetate / chloroform = 1/9, vol / vol); 2.5 g (yield 89%) of the desired compound are obtained as white substance; Fp.95 to 98 ⁰ C.

Example 1-g ^l

Reduction method 1

Ethyl (E) -7- [4 ^l - (4 "-fluorophenyl) -1 '^' - ^dimethyl-1 ö - (1") - methylethyl) pyrazolo [3, 4-b] pyridin-5'- yl] -3j- 5- dihydro-hept-6-enoate (Compound 1-1-1)

Dissolve 2.32 g (4.96 mmol) of compound II-1 in 20 ml of ethanol under a nitrogen atmosphere and cool the mixture to ⁰ ° C. Add 740 mg (20 mmol) of sodium borohydride and stir the mixture for 1 h. The mixture is carefully neutralized by adding a 10% aqueous hydrochloric acid solution and then extracted three times with diethyl ether. The diethyl ether solution is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated to dryness under reduced pressure. The residual oil is purified by silica gel column chromatography (eluent: ethanol / chloroform = 3/97, v / v); the pure, desired product is obtained as a colorless, viscous, oily substance in an amount of 1.81 g (yield 78%). NMR (δρρπι in CDCl ₃ )

1.28 (t _f J = 8Hz, 3H), 1.32 (d, J = 8Hz, 6H), 1. 4-1.8 (m, IH), 1.92 (s, 3H), 2.2-2.6 (m, 3H), 2.9 -3.8 (m, 2H), 3.42 (Heptalet, J = 8Hz, lH), 4.06 (s, 3H), 4.1-4.6 (m, 4H), 5.1-5.5 (111.1H), 6.4-6.7 (m, IH), 6.9-7.3 (m, 4H)

Reduction method 2

Ethyl (E) -7- [6 ^l -cyclopropyl] -4 ^! (4 "-fluorophenyl) -1-methyl-3'-phenylpyrazolo [3,4-b] pyridin-5- yl- 3, 5- dihydroxy-hept-6-enoate (Compound 1-1- 14)

200 ml of a diethyl ether solution of about 0.15 mole / l zinc borohydride are stirred under a nitrogen atmosphere while the solution at -7O ⁰ C is cooled. A solution of 3.75 g (10 "^ mole 7.12 χ) Compound 11-14 dissolved in 40 ml of dry diethyl ether, is added gradually along the reactor wall. The reaction solution is stirred for another 6 h at -70 ⁰ C. After by thin layer chromatography the substantial removal of the starting material was determined, 40 ml of methanol and then 100 ml of water are added to stop the reaction, the reaction solution is mixed with diethyl ether and dilute acetic acid and the product is extracted with diethyl ether ,

The diethyl ether layer is washed to neutrality with water and further washed with saturated aqueous sodium chloride solution. The diethyl ether layer is dried over anhydrous magnesium sulfate and then the solvent is evaporated by means of an evaporator. The residue is subjected to silica gel column chromatography (eluent: benzene / ethyl acetate); 3.09 g (82.0%) of the desired compound are obtained as a light yellow powder.

Example 2

Sodium (E) -7- [4 ^l - (4-fluorophenyl) -1,3'-dimethyl-6 · (1 "-methylethyl) pyrazolo [3,4-b] pyridine-5 ' yl] -3,5- dihydroxyhept-6-enoate (Compound 1-5-1) ____

Dissolve 200 mg (0.43 mmol) of compound 1-1-1 in 2 ml of ethanol and dropwise add 0.85 ml of a 0.5N aqueous sodium hydroxide solution. The mixture is added for 1 h

74

Room temperature stirred. Ethanol is then distilled off under reduced pressure, 2 ml of water are added and the mixture is extracted with diethyl ether. The aqueous layer is freeze-dried; 180 mg (yield 91%) of hygroscopic, pale yellow powder are obtained; Fp.258 to 264 ⁰ C (Zers.).

In the same manner as in Example 1-a, the compounds VII-2 to VII-18 are prepared. The physical properties of the compounds obtained are shown in the following table.

Table 4 R ³ . ⁴

CO ₂ R ²¹

Connect. R 'R ^z R ³ R ⁴ R ⁵ R ²¹ mp _.: "CC)

VH-2 Me 1-Ph 4-F

W-3 Me 2-Ph 4-F

VI- 4 Ph 1 ^ Me 4-F

W- 5 Me 1-Me 4-F

W- 6 H 1-Ph 4-F

W-7 He 1-t-Bu 4-F

W- 8 H 1-Et 4-F

W-9 c-Pr 1-Me 4-F

W-IO Me 1-Ph 4-F-CH ₂

W-II 4-1-Me 4-F CU -Ph

H i-Pr Et 84-89

H i-Pr Et 90-94

H i-Pr Et oil

H c'-Pr He 121-123

H i-Pr Et 96-98

H i-Pr Et 88-91

H i-Pr Et oil

H i-Pr Et 105-107

H i-Pr Et 84-86

H i-Pr Et 138-141

W-12 c-Pr 1-Ph 4-F H i-Pr Et 156-158

Table 4 (cont.)

VH -13 Me l- (4-4-F Hi-Pr Et 116-118 MeO-Ph)

VK-14 Ph 1-He 4-F H c-Pr Me 141-143 W-15 Me 1-t-Bu 4-F H c-Pr Me 147-148 VK-16 c-Pr 1-t-Bu 4-F H c-Pr Me 115-120 Vn-17 Ph 1-t-Bu 4-F Hc-Pr Me 182-185 Vg-18 Me py ^ tY ^ -FH C-PrHe i ₂ p-i25

PNMR of Ve_rbina.VII-4 (CDCl ₃ ) 5ppm:

0.96 (t, J = 8Hz, 3H), 1.42 (d, J = 7Hz, 6H),

3.27 (Heptalet, J = 7Hz, lH), 4.02 (q, J = 8H, 2H) , 4.18 (s, 3H),

6.6-7.3 (m, 9H) PNMRder Connect. VI1-8 (CDCI3) δρρία:

1.07 {t, J = 8Hz, 3H), 1.42 (d, J = 7Hz, 6H), 1.59 (t, J = 8Hz, 3H),

3.41 (Heptalet, J = 7Hz, IH), 4.20 (q, J = SHz, 2H), 4.70 (q, J = 8Hz, 2H), 7.1-8.0 (m, 5H)

In the same manner as in Example 1-b, Compounds VI-2 to VI-17 are prepared. The physical properties of the compounds obtained are shown in the following table.

Table 5

MQ

Connect. R ¹ R ² R ³

Mp. ( 'C)

VI-2 He 1-Ph 4-F H i-Pr 139-141 VI-3, He 2-Ph 4-F H i ~ Pr 142-144 VI- 4 Ph 1-He 4-F H i-Pr 237-239 VI- 5 He 1-He 4-F H c-Pr 168-170 VI- 6 H 1-Ph 4-F H i-Pr 189-192 VI- 7 He 1-t-Bu 4-F H i-Pr 150-152 VI-S H 1-Et 4-F H i-Pr .149-148 VI- 9 c-Pr 1-He 4-F H i-Pr 224-226 VI-IO He 1-Ph-CH ₂ 4-F H i-Pr 162-164 VI-Il 4- Zi - 1-He Ph 4-F H i-Pr 216-218 VI -12 c-Pr 1-Ph 4-F H i-Pr 196-198 VI-13 He l- (4-HeO-Ph) 4-F H i-Pr 155-157 VI-14 Ph 1-He 4-F H c-Pr 214-215 VT -15 He 1-t-SSU 4-F H c-Pr 135-139 VI -16 c-Pr 1-t Bu 4-F H c-Pr 105-115 VI -17 Ph 1-t-Bu 4-F H c-Pr 204-208

In the same manner as in Example 1-c, the compounds V-2 to V-18 are prepared. The physical

Properties of the compounds thus obtained are listed in the following table. Table 6 R ³

Compound R 'R

Mp CC)

V-2 me 1-Ph 4-F H i-Pr 110-111 V-3 me 2-Ph 4-F H i-Pr 118-120 V- 4 Ph 1, Me 4-F H' i-Pr 163-164 V-5 me 1-Me 4-F H c-Pr 14-9-151 V-6 H 1-Ph 4-F H i-Pr 139-142 V-7 me 1-t-Bu 4-F H i-Pr 104-106 V-8 H 1-Et 4-F H i-Pr 77-80 V-9 c-Pr 1-Me 4-F H i-Pr 99-101 V-IO me 1-Ph-CH ₂ _4-F H i-Pr 110-112 V-Il 4 Zi- 1-Me Ph 4-F H * I-Pr 164-167 V-12 c-Pr 1-Ph 4-F H i-Pr 150-152 V-13 V-14 Me ph MeO-PhJ 1-Me 4-F 4-F H H i-Pr c-Pr 130-132 168-171 V-15 me 1-t-Bu 4-F H c-Pr 94-96 V-16 c-Pr 1-t-Bi 4-F H c-Pr 122-125 V-17 Ph 1-t-Bu 4-F H c-Pr 170-172 VI ₈ me Pyridyl. H c-Pr 180-200

In the same manner as in Examples I-d and I-e, compounds III-2 to III-18 are prepared. The physical properties of the compounds obtained are shown in the following table.

R ³

Table 7 Compound K 'K ² R ³ « ⁴ K ⁵ mp CO

.1-2 Me 1-Ph 4-F Hi-Pr 158-161

1-3 Me 2-Ph 4-F H i-Pr 176-177.5

1-4 Ph 1-He 4-F Hi-Pr 148-150

I - 5 Me 1-Me 4-F H c-Pr 135-137

ΠΙ -6H1-Ph4-FHi-Pr174-176

1-7 Me 1-t-Bu 4-F H i-Pr 170-172

1-8 H 1-Et 4-F H i-Pr 130-133

1-9 c-Pr 1-Me 4-F H i-Pr 127-129

1-10 Me 1-Ph 4-F H i-Pr 147-150 - CH 2

I -11 4-1-He 4-F Hi-Pr 88-90 C jg -Ph

I-12 c-Pr 1-Ph 4-F H i-Pr 178-180

1-13 Me l- (4-4-F Hi-Pr 147-150 MeO-Ph)

ΠΙ-14 Ph 1-Me 4-F H c-Pr <40

1-15 Me l-t.-Bu 4-F H c-Pr 186-190

M -16 c-Pr 1-t-Bu 4-F H c-Pr 192-195

1-17 Ph 1 -t-Bu 4-F Hc-Pr 148-150

K "M yj- 4-F ~" H c-Pr ₁₇₅ '_ ₁₈₅

In the same manner as in Example 1-f, the compounds II-2 to 11-13 are prepared. The physical properties of the compounds obtained are shown in the following table.

P CO ₂ R ¹² Table 8 R \ . R ⁴

Compound R 'R

1 no

R ^;

R ⁴ R ⁵ R ¹² Fp. CC)

e - 2 He 1-Ph 4-F H i-Pr et 93-95 e , q He 2-Ph 4-F H i-Pr et 87-94 e - 4 Ph 1-Me 4-F H i-Pr et oil e - 5 He 1-Me 4-F H c-Pr Et. oil e - 6 H 1-Ph 4-F H i-Pr et 101-104 e - 7 He 1-t-Bu 4-F H i-Pr et 66-69 e - 8th H 1-Et 4-F H i-Pr et 91-94 e - 9 c-Pr 1-Me 4-F H i-Pr et 68-72 e -10 He 1-Ph-CH ₂ 4-F H i-Pr et oil e -11 4- Zi - 1-Me Ph 4-F H i-Pr et 129-132 e -12 c-Pr 1-Ph 4-F H i-Pr et 132-135 e -13 He MeO-Ph) 4-F H i-Pr 'Et 131-133 E E -14 -15 Ph hee 1-Me 1-t Bu 4-F 4-F H H c-Pr c-Pr Et Et Oil oil e -16 c-Pr 1-t-Bu 4-F H c-Pr et 103-107 E E -17 -18 Ph Me 1-t-Bu 5-C2-pyrrylyl ") 4-F 4-F H H c-Pr c-Pr Et Et .. Oil 45-50

PNMR Compound JI-4 (CDCl ₃ ) 8ppm:

1.24 (t, J = 9Hz _f 3H), 1.32 (d, J = 8Hz, 6H0, 2.1-2.5 (m, 2H), 2.6-2.9 (IHrIH), 3.2-3.7 (111.3H), 3.9-4.7 ( m, 3H), 4.11 (s, 3H), 4.9-5.4 (m, 1H), 6.3-7.2 (m, 10H)

PNMR of Compound JI-5 (CDCl3) δρρία: 0.8-1.5 (m, 4H), 1.27 (t, J = 7Hz, 3H), 1.89 (s, 3H), 2.1-2.4 (in, IH), 2.51 (i.e. , J = 6Hz, 2H), 2.6-3.1 (in, IH), 3.40 (s, 2H), 3.94 (s, 3H), 4.17 (q, J = 7Hz, 2H), 4.4-4.8 (m, IH) , 5.3-5.7 (m _f lH), 6.4-6.8 (m, IH) _f 7.0-7.4 (in, 4H)

PNMR connection JI-IO {CDCI3) 8ppm:

1.26 (t, J = 7Hz, 3H), 1.33 (d, J = 7Hz, 6H), 1.92 (s, 3H), 2.2-2.6 (m, 1H), 2.45 (d, J = 6Hz, 2H), 3.41 (s, 2H), 3.43 (Heptal, J = 7Hz, IH), 4.22 (q, J = 7Hz, 2H), 4.4-4.8 (m, lH), 4.8-5.6 (m, IH), 5.65 (s, 2H), 6.4-6.8 (m, IH), 7.0-7.7 (m, 9H)

PNMRder connection. 11-14 _(CDCl3) :. δρρίη

0.9-1.5 (m, 4H), 1.24 (t, J = SHz, 3H), 2.1-2.5 (m, IH), 2.5-2.7 (m, 2H), 3.31 (s, 2H), 4.05 (s, 3H ), 4.12 (q, J = 8Hz, 2H), 4.4-4.8 (m, IH), 5.35 (d, d, J = 17Hz, J = 6Hz, IH), 6.4-7.2 (m, 1OH)

PNMR of Verbind.II ~ 15 _(CDCl3) SPPM: 0.9-1.4 (m, 4H), 1.26 {t, J = SEZzSH), 1.74 (s _r 9H), 1.88 (s, 3H), 2.2-2.4 (m , IH), 2.4-2.6 (111.2H), 3.35 (s, 2H), 4.14 (q, J = 8Hz, 2H), '4.3-4.7 (m, lH), 5.40 (d, d, J = 17Hz , J = 6 Hz, lH)

6.50 (d, J = l7Hz, lH), 6.9-7.4 (m, 4H) PNMR of the compound. 11-16 (CDCl ₃₎ 5 ppm:

0.4-1.4 (m, 8Hz), 1.28 (t, J = 8Hz, 3H), 1.75 (s, 9H), 2.1-2.5 (in, 2H), 2.4-2.6 (m, 2H), 3.43 (s, 2H ), 4.23 (q, J = 8Hz, 2H), 4.4-4.7 (m, IH), 5.52 (d, d, J = l7Hz, J = 6Hz, lH), 6.64 (d, lH, J = 6Hz), 6.9-7.6 (ra, 4H)

PNMR Compound .11-17 (CDCl ₃ ) 6ppm:

0.8-1.5 (m, 4H), 1.20 (t, J = 8Hz, 3H), 1.80 (s, 9H), 2.0 ~ 2.7 (m, 1H), 2.3-2.5 (m, 2H), 3.30 (s, 2H ), 4.10 (q, J = 8Hz, 2H), 4.3-4.7 (m, lH), 5.35 (d, d, J = l7Hz, J = 6Hz, lH), 6.3-7..3 (m, 10E)

In the same manner as in Example 1-g, the compounds 1-1-2 to 1-1-18 are prepared. The physical properties of the compounds obtained are in. compiled the following table.

82

Table 9

OH CO ₂ R ¹²

Compound R ¹ R

R ⁴ R ⁵ R ¹² Fp.CC)

I -1-2 me 1-Ph 4 F H i-Pr e t oil I -1-3 me 2-Ph 4 F H i-Pr e t oil I -1-4 Ph -1-Me 4 F H i-Pr e t oil I -1-5 me 1'Me 4 F H C-Pr ' e t oil I -1-6 H 1-Ph 4 F H i-Pr e t oil I -1-7 me 1-t-Bu 4 F H i-Pr e t oil I -1-8 H 1-Et 4 F H i-Pr e t 58-63 I -1-9 c-Pr 1-Me 4 F H i-Pr e t 77-83 I -1-10 me 1-Ph-CH ₂ 4 F H i-Pr e t oil I -1-11 4- Zl -Ph 1-Me 4 F ' H i-Pr e t 116-120 I -1-12 c-Pr 1-Ph 4 F H i-Pr e t 99-102 I -1-13 me MeO-Ph) 4 F H i-Pr e t 149-151

I -1-14 Ph 1-Me 4-F

I -1-15 Me 1-t-Bu 4-F

I -1-16 c-Pr 1 -t-Bu 4-F

I -1-17 Ph 1 -t-Bu 4-F

I -1-

me

PvridvP

4-F

H c-Pr Et 45-50

H c-Pr Et 144-145

! ί c-Pr Et 159-160

H c-Pr Et 35-40

H c-Pr Et 35-38

PNMRder connection.1-1-2 (CDCl ₃ ) 6ppm:

1.29 (t, J = 8Hz, 3H), l, 36 (d, J = 8Hz, 6H), 1.5-1 1.98 (ε;, 3Η), 2.2-2.7 (01.3H), 2.9-3.7 (m, 2H), 3.47 (Heptalet, J = 8Hz, IH), 3.8-4.6 (m, 2H), 4. 20 (q, J = 8Hz, 2H), 5.1-5.6 (IUzIH), 6.3-6.7 (• 6.9- 7.7 (in, 7H), 8.3-8.6 (in, 2H)

PNMR Compound 1-3 (CDCl ₃ ) 8ppm:

II-1.5 (m, 9H), 1.6-1.7 (m, 1H), 1.9-2.0 (m, 3H), 2.3-2.5 (m, 2H), 2.8-3.2 (m, 1H), 3.3-3.7 (m , 3H), 3.8-4.5 (m, 4H), 5.2-5.6 (m, 1H), 6.4-6.7 (m, 1H), 7.0-7.6 (m, 7H), 8.3-8.5 (m, 2H)

PNMRder Connect. 1-1-4 _(CDCl3) δρρπι:

1.25 (t, J = 8Hz, 3H), 1.33 (d, J = 8Hz, 6H), 1.7-2.0 (m, IH), 2.2-2.6 (m, 3H), 2.9-3.8 (m, 3H), 3.8 -4.6 (m, 2H), 4.10 (q, J = 8Hz, 2H), 4.12 (s, 3H), 4.9-5.4 (m, IH), 6.3-7.2 (m, 10H)

PNMR of the connection. 1-1-5 (CDCl ₃ ) 6ppm:

0.8-ll (m, 4H), 1.28 (t, J = 7Hz, 3H), 1.4-1.8 (m, 2H), 1.89 (s, 3H), 2.1-2.6 (m, 4H), 3.0-3.8 (m , 2H), 3.98 (S, 3H), 4.18 (q, J = 7Hz, 2H), 4.3-4.6 (m, lH), 5.3-5.7 (ra, IH), 6.4-6.8 (m, lH), 6.9 -7.3 (m, 4H)

PNMR of the connection. 1-1-6 _(CDCl3) öppm:

1.29 (fc, J = 7Hz, 3H), 1.37 (d, J = 7Hz, 6H), 1.4-1.9 (m, 2H), 2.2-4.7 (m, 2H), 3.0-3.9 (m, 3H), 3.9 -4.7 (m, 2H), 4.19 (q, J = 7Hz, 2H), 5.1-5.5 (m, IH), 6.6-6.9 (m, IH), 7.0-8.6 (ra, 10H)

84 2 838

PNMR the connection '. 11-1-7 (CDCl ₃₎ 6 ppm:

1.28 (t, J = 7Hz, 3H), 1.32 (d, J «7Hz, 6H), 1.4-1.8 (m, 2H), 1.84 (s, 9H), 1.89 (3,3H), 2.3-2.6 (in , 3H), 3.1-3.7 (m, IH), 3.41 (Heptalene, J = 7Hz, lH), 3.9-4.7 (m, 2H), 4.17 (q, J = 7Hz, 2H), 5.1-5.5 (ra, IH), 6.4-6.7 (m, IH), '6.9-7.3 (in, 4H)

PNMRder connection. 1-1-10 _(CDCl3) 5 ppm:

1.29 (t, J = 7Hz, 3H), 1.33 (d, J = 7Hz, 6H), 1.4-1.9 (m, 2H), 1.90 (s, 3H), 2.2-2.6 (m, 3H), 3.1-3 , 7 (πι, 1Η), 3.43 (heptalet, J = 7Hz, IH), 3.8-4.5 (m, 2H), 4.19 (q, J = 7Hz, 2H), 5.1-5.5 (m, IH), 5.62 ( s, 2H), 7.3-7.7 (nw IH), 6.9-7.6 (in, 9H)

PNMR Compound £ -1-14 (CDCl ₃ ) 8ppm:

O.9-1.3 (ra, 4H), 1.4-1.8 (m, 2H), 1.28 (t, J = 8Hz, 3H), 2.3-2.5 (m, 3H), 4.1-4.2 (m, lH), 4.3 -4.5 (m, lH), 4.18 (q, J = 8Hz, 2H), 4.13 (s, 3H), 5.45 (d, d, J = 17Hz, J = 6Hz, IH), 6.6-7.3 (m, lOH )

PNMRder connection. 1-1-15 _(CDCl3) δρρπι:

0.9-1.4 (m, 4H), 1.29 (t, J = 8Hz, 3H), 1.4-1.8 (m, 2H), 1.78 (s, 9H), 1.87 (s, 3H), 2.3-2.5 (m, lH ), 2.4-2.5 (m, 2H), 4.0-4.1 (m, 1H), 4.18 (q, J = 8Hz, 2H), 4.3-4.4 (m, 1H), 5.50 (d, d, J = 17Hz, J = 6Hz, lH), 6.55 (d, J = l7Hz, lH), 7.0-7.3 (m, 4H)

PNMR Compound J 1-1-16 (CDCl ₃ ) 8ppm:

0.4-0.9 (ra _f 4H), 0.9-1.5 (m, 6H), 1.29 (t, J = 8Hz, 3H), 1.74 (s, 9H), 2.2-2.5 (m, 2H), 2.4-2.5 (m , 2H), 3.9-4.5 (m, 2H), 4.19 (q, J = 8Hz, 2H) _f • 5.50 (d, d, J = ITHZzJ = OHz, IH), 6.58 (d, J = l7Hz, lH) , 6.9-7.4 (111.4H)

PNMR of the compound i 1-1-17 (CDCl ₃ ) δρρπι:

O.9-1.5 (m, 6H), 1.28 (t, J = 8Hz, 3H), 1.86 (s, 9H), 2.2-2.6 (m, 1H), 2.3-2.5 (m, 2H), 3.9-4.5 (m, 2H), 4.18 (q, J = 8Hz, 2H), 5.45 (d, d, J = 17Hz, J = SHz, IH), 6.63 (d, J = 17Hz, lH), 6.8-7.3 (m , 9 H)

In the same manner as in Example 2, compounds 1-5-2 to 1-5-18 are prepared. The physical properties of the compounds obtained are shown in the following table.

86

Table 10

CO ₂ R

-5-2 C -5-12 R ^z R ^{3 N} R ⁵ R ⁵ • c-Pr R '* ** N / A Mp CC) -5-3 R ¹ 4-F R ⁴ i-Pr N / A 271-279 (Zers.) 263-272 connection -5-13 He 4-F H i-Pr i-Pr N / A N / A (Dec.) I -5-4 He H 264-275 I -5-14 4-F i-Pr " i-Pr N / A (Dec.) -5-5 Ph H 230-237 I -5-15 4-F i-Pr N / A (Dec.) -5-6 He H i-Pr 247-249 I -5-16 4-F N / A (Dec.) -5-7 H H i-Pr 249-252 I -5-17 4-F N / A (Dec.) -5-8. He H i-Pr - I -5-9 - "5-18 4-F N / A 215-220 H 4-F H i-Pr N / A (Dec.) I -5-10 c-Pr H 240-247 I 4-F - i-Pr N / A (Dec.) -5-11 He H 289-295 I 4-F c-Pr N / A (Dec.) 4 H 207-214 I i -Ph 4-F c-Pr N / A (Dec.) c-Pr H 220-226 I 4-F c-Pr N / A (Dec.) He H . 240-250 I 4-F c-Pr N / A (Dec.) Ph H 225-230 I 4 ^ F c-Pr N / A (Dec.) He H 220-221 I 4-F N / A (Dec.) c-Pr H 210-215 I 4-F (Dec.) Ph H 160-175 (Zers.) I 4-F Me j H I - ^ ^ fT R ² 1-Ph 2-Ph 1-He 1-He 1-Ph 1-t-Bu 1-Et r-He 1-Ph -CH ₂ 1-He 1-Ph l- (4- Heo-Ph) 1-He 1-t-Bu 1-t-Bu 1-t-Bu 1- (2-pyridyl)

PNMRder connection. 1-5-8 _(CDCl3) δρρπι:

1.0-1.7 (m, 2H), 1.29 (d, J = 7Hz, 6H), 1.47 (t, J = 7Hz, 3H), 1.7-2.3 (m, 3H), 3.1-3.3 (m, IH), 3.3 -3.9 (m, IH), 3.53 (Heptalene, J = 7Hz, IH), 4.0-4.3 (m, IH), 4.49 (q, J = 7Hz, 2H), 5.2-5.5 (m _f IH), 6.4- 6.7 (m, IH), 7.0-7.7 (111.5H)

PNMRder connection. 1-5-14 (CDCl ₃ ) 8ppm:

0.9-1.3 (m, 4H), 1.3-1.8 (ra, 2H), 1.9-2.0 (m, 1H), 2.4-2.6 (ra, 2H), 3.5-3.7 (m, 1H), 4.04 (s, 3H ), 4.1-4.2 (m, IH), 5.51 (d, d, J = 17Hz, J = 6Hz, lH), 6.44 (d, J = 17Hz, lH), 6.8-7.2 (m, 9H)

PNMRder connection. 1-5-15 (CDCl ₃ ) 8ppm:

1.0-1.2 (m, 4H), 1.3-1.8 (m, 2H), 1.71 (s, 9H), 1.77 (s, 3H), l-.9-2.1 (m, lH) _# 2.4-2.5 (m, 2H), 3.5-3.6 (m, IH), 4.1-4.2 (m, IH), 5.52 (d, d, J = l7Hz, J = 6Hz, lH), 6.38 (d, J = l7Hz, lH), 7.1 -7.3 (m, 4H)

PNMRder connection. 1-5-I6 (CDCl ₃₎ 6 ppm:

0.4-0.7 (m, 4H), 0.9-1.2 (m, 4H), 1 ^ 3-1.7 (m, 2E), 1.68 (s, 9H), 1.7-1.8 (m, IH), 1.9-2.0 (m , IH), 2.4-2.5 (m, 2H), 3.5-3.6 (m, IH), 4.1-4.2 (m, IH), 5.52 (d, d, J = l7Hz, J = 6Hz, lH), 6.40 ( d, J = 17Hz, 1H), 7.2-7.4 (m, 4H)

PNMRder connection. 1-5-17 (CDCl ₃ ) öppm:

1.0-1.2 (m, 4H), 1.3-1.8 (m, 2H), 1.80 (s, 9H), 1.9-2.1 (m, 1H), 2.5-2.6 (m, 2H), 3.5-3.6 (m, lH ), 4.1-4.2 (m, lH), 5.51 (d, d, J = 17Hz, J = 6Hz, lH), 6.42 (d, J = 17Hz, lH), 6.8-7.2 (m, 9H)

Example 3

(E) -7- [4 ^l - (4 "-fluorophenyl) -1 ^l , 3 ^l -dimethyl-6 '- (1" -methylethyl) -pyrazole "[3,4-b] pyridin-5'-yl ] -3,5-dihydroxy hept-6-enoic acid (Compound 1-2-1)

Dissolve 0.25 g (0.53 mmol) of compound 1-1-1 in 3 ml of ethanol and dropwise add 1.06 ml of aqueous 0.5N sodium hydroxide solution. Ethanol is distilled off under reduced pressure and then 3 ml of distilled water are added. The solution is washed with diethyl ether. The aqueous layer is carefully neutralized with 1% hydrochloric acid and extracted with diethyl ether. The ether layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure; The desired compound is obtained in an amount of 0.21 g (yield 90 ^).

PNMR (DMS0-d6) 5ppm: 1.29 (d, J = 7Hz, 6H), 1.83 (s, 3H), 2.1-2.3 (m, 2H), 2.4-2.6 (m, lH), 3.0-3.6 (m, 4H), 3.96 (s, 3H), 4.3-4.8 (m _/ 2H), 5.2-5.6 (m, IH), 6.3-6.6 (m, 1H), 7.2-7.4 (m, 4H), 11.5-12.0 ( bs, lH)

Example 4

(E) -trans-6- (2 '- [4 ^II - (90 ^I "-fluorophenyl) -1", 3 "-dimethyl-6" - (1 η · -methylethyl) -pyrazolo [3,4-b ] pyridin-5 "-yl] -ethenyl) -4-hydroxy-3", 4,5,6-tetrahydro-2H-pyran-2-one (Compound 1-3-1) _:

Dissolve 130 mg (0.29 mmol) of compound 1-2-1 in 6 ml dichloromethane, and is 125 mg (0.29 mmol) of N-cyclohexyl-N ^l - (2'-methylmorpholinoethyl) carbodiimide p-toluenesulfonate , The mixture is stirred for 2 h at room temperature.

stirred and then subjected to distillation under reduced pressure to remove the solvent to dryness. The residual oil is purified by silica gel thin-layer chromatography (eluent: hexane / ethyl acetate = 9/1, v / v); the pure, desired compound is obtained as a colorless, viscous, oily substance in an amount of 48 mg (yield 39%). P-NMR _(CDCl3) öppm:

1.33 (d, J = 6, 8Hz, 6H), 1.4-1.5 (m, IH), 1.6-1.7 (m, 2H), 1.93 (s, 3H), 2.5-2.6 (m, IH), 2.68 (dd , J = 18Hz, J = 5Hz, lH), 3.39 (Heptal, J = 6.8Hz, lH), 4.07is, 3H), 4.1-4.2 (m, lH), 5.1-5.2 (ai, IH),

5.31 (dd, J = 16Hz, J = 6Hz, lH), 6.61 (dd, J = 16Hz, J = 1.5Hz, lH), 7.1-7.3 (m, 4H)

Example 5

6-Cyclopropyl-4- (4'-fluorophenyl) -S-hydroxymethyl-1-methyl-1- (2'-pyridyl) pyrazolo [3,4-b] pyridine (Compound VI-18) (Steps P.S. and T)

Dissolve 5.04 g (1.25 x 10 ^"2 mole) of compound VII-18 in 50 ml of ethylene glycol and 15 ml (1.5 x 10 ^-2 mole) of a 1 mol / l aqueous sodium hydroxide to. The reaction solution is stirred for 3 days at 22O ⁰ C. After the disappearance of starting material was confirmed by thin layer chromatography, the reaction solution is cooled to room temperature. to adjust the pH to 2 is added chloroform, "ine aqueous sodium chloride solution and dilute hydrochloric acid to the product is isolated. The chloroform layer is washed with water and dried over anhydrous magnesium sulfate.

is distilled off to give colorless, powdery crystals, which are washed thoroughly with n-hexane; 4.60 g (yield 94.8 #) of compound XIII-18 are obtained; Mp. 235-245 ⁰ C.

4.24 g (1.09 x 10 ^"2 mole) of Compound XIII-18 was suspended in 90 ml of dry benzene. 6.92 g (5.45 x 10" mol) of oxalyl dichloride are added and the mixture is heated at 60 ⁰ C stirred. 5 hours later, add 3 grams of additional oxalyl dichloride and continue heating and stirring for a further 4 hours. After confirming the disappearance of the starting material by thin layer chromatography, the solvent is removed by means of an evaporator to give compound XIV-18 as a light yellow powder. The resulting compound XIV-18 is dissolved in 90 ml of dry diethyl ether without further purification. Are added to 0.78 g (2.06 χ 10 ^-2 mol) of lithium aluminum hydride and the mixture is stirred for 5 h at room temperature. After confirming disappearance of the starting material by thin layer chromatography, chloroform, ice and aqueous ammonium chloride solution are added to terminate the reaction. The product is extracted with chloroform. The chloroform layer is washed with dilute aqueous sodium hydroxide solution and with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Subsequently, the solvent is evaporated. The resulting residue is purified by silica gel column chromatography (eluent: benzene / ethyl acetate); 3.27 g (yield 80.2%, based on compound XIII-18) of desired compound VI-18 are obtained as a light yellow powder; Fp.75 to 82 ⁰ C.

Formulation Example 1 Tablets

Connection 1-5-1 1.0 g lactose 5.0 g crystalline cellulose powder 8.0 g corn starch 3.0 g Hydroxypropyl cellulose 1.0 g CMC-Ca 1.5 g magnesium stearate 0.5 R a total of 20.0 g

The above components are mixed together in the usual manner and then tableted to prepare 100 tablets, each containing 10 mg of active ingredient.

Formulation Example 2 1.0 g capsules 3.5 g Connection 1-5-1 10.0 g lactose 0.5K crystalline cellulose powder 15.0 g magnesium stearate a total of

The above components are mixed together in the usual way and then packed in No. 4 gelatin capsules. This gives 100 capsules each containing 10 mg of active ingredient.

Formulation Example 3 1 00 G soft capsules 3 , 89 G Connection 1-5-1 15 00 G PEG (polyethylene glycol) 400 0 , 01 G saturated fatty acid triglyceride 0 10 peppermint oil 20 00 G Polysorbate 30 a total of

The above components are mixed together and packed in No. 3 soft gelatin capsules by a usual method. This gives 100 soft capsules, each containing 10 mg of active ingredient.

Formulation Example 4 Ointment

Compound 1-5-1 1.0 g (10.0 g)

liquid paraffin 10.0 g (10.0 g)

Cetanol 20.0 g (20.0 g)

white Vaseline 68.4 g (59.4 g)

Ethyl paraben 0.1 g (0.1 g)

1-menthol 0.5 E (0.5 g)

total - 100.0 g

The above components are mixed together by a conventional method to prepare an ointment.

Formulation Example 5 1.0 g suppository 46.9 g Connection 1-5-1 52.0 g Witepsol H15 ⁺ 0.1β Witepsol W35 ⁺ Polysorbate 80

total 100.0 g

: Trademark for triglyceride compounds

The above components are melt blended by a conventional method and poured into suppository containers. Then it is cooled to solidify. This gives 100 suppositories of 1 g, each containing 10 mg of active ingredient.

Formulation Example 6 Formulation for Injection Compound 1-5-1 1 mg

distilled water for an injection formulation 5 ml

The formulation is prepared by dissolving the compound in the distilled water as needed.

Formulation Example 7 Granules

Compound 1-5-1 1.0g

Lactose 6.0 g

crystalline cellulose powder 6.5 g

Cornstarch 5.0 g

Hydroxypropyl cellulose 1.0 g

Magnesium stearate _ 0.5 g

a total of 20.0 g

The above components are granulated and packaged by a usual method. 100 packages are obtained, each containing 200 mg of granules, so that each package contains 10 mg of active ingredient.

Claims (32)

claims 1 ', 3 ^l -dimethyl-6' - (1 »-methylethyl) -pyrazolo [3,4-b] pyridine-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a Cj _, - alkyl ester of the carboxylic acid produces. 1? and R is an alkyl moiety of a chemically or physiologically hydrolyzable alkyl _ester , for example C _{1 -Zf-} alkyl, a compound of the following formula (III) (U) ,1 R ² , R and wherein R ¹ , R ^fc , R ⁷ , R " ¹ " and R 1 are as defined above, reacted with a double anion of the R-ester of acetoacetic acid (wherein R is as defined above) and, optionally, the compound of formula Subjecting II to a reduction reaction; or (B) for the preparation of a compound of the formula .0R ²⁶ (XXII) wherein R ¹ represents hydrogen, C ^ g alkyl, C _1-6 cycloalkyl C ^ y, C ₂ _ ₆ alkenyl α- or ß-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3 Thienyl, 2- or 3-furyl, fluorine, chlorine, bromine, [wherein R ⁶ , R 'and R are independently hydrogen, C ₁ -Q alkyl, C ₁ p -alkoxy, C ₁ , -alkylthio, chloro, bromo, fluoro, -NR ^ R ^IU (where R ^ and R ^{IU are} independently C ₁ , -alkyl), chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, phenoxy, 100 Benzyloxy, trimethylsilyloxy, diphenyl-t-butylsilyloxy "or -O (CH ₂ ) _k 0R ¹⁸ (wherein R ^{18 is} C _1-3 -alkyl and k is 1, 2 or 3); and when R ^{8 is} hydrogen and R and R 'are ortho to each other, they may together form -OC (R 1) (R ²⁰ ) O- (wherein R 1 and R ° are independently hydrogen or stand); or if R ⁷ and R ^{8 are the} same Are hydrogen, R for Z 5 (wherein R ⁵ is hydrogen, C ^ alkyl, C ₁ alkoxy, trifluoromethyl, chlorine, bromine or fluorine)], phenyl-C _2- 3-alkenyl, the phenyl group is unsubstituted or substituted by C ^^ - Alkyl, C ₁ , alkoxy, fluorine, chlorine or bromine, or C ₁ , alkyl substituted by a member selected from the group C ₁ , alkoxy, naphthyl and R ⁶ R ⁷ C. rf O (wherein R, R 'and R are as defined above) and by 0, 1 or 2 members selected from the group consisting of C _1-8 alkyl; R is bonded to the nitrogen atom in the 1- or 2-position of the pyrazolopyridine ring and is hydrogen, C _1-8 alkyl, C ₁ --Alkyl substituted 101 with 1 to 3 fluorine, C ^ y-cycloalkyl, α- or ß-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl or R ⁶ R ⁷ (wherein R, R 'and R are as defined above), or C 1-8 alkyl substituted by a member of the group consisting of C _1- J -alkoxy, naphthyl and R ⁴ R ⁷ · (kl fl (wherein R, R 'and R are as defined above) and by 0, "is 1 or 2 members selected from the group consisting of C ^ _-8 alkyl; R ^ and R are independently hydrogen, C _1-8 alkyl, C ^ _y-cycloalkyl, C _1- ^ -alkoxy, n-butoxy. i-butoxy, sec-butoxy, R ² % N- (where R 1 and R ^{2 are} independently "C 1-10 -alkyl"), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, trimethylsilyloxy, diphenyl-t-butylsilyloxy or -O (CH ₂ J ₁ OR ¹⁵ (wherein R ¹⁵ C.,, -alkyl and 1 is 1, 2 or 3); or, when R- 'and R are ortho to each other, they may together -CH = CH-CH = CH- or methylenedioxy; 102 R ^ represents hydrogen, chlorine, bromine, Cj, alkoxy, R ²³ R ²⁴ N- (wherein R ²³ and R ²⁴ Cj ^ alkyl), C _1-6 alkyl, C ₂ _6-alkenyl, C ^ cycloalkyl , C ^ alkenyl, {[wherein R is as defined above) or C 1-6 alkyl substituted by a member selected from the group consisting of (wherein R, R 1 and R ^{8 are} as defined above) and by 0, 1 or 2 members selected from the group consisting of C 1-8 alkyl; and R represents a protective group for hydroxyl, a compound of the following formula (XVI) iÖIO CH ₂ P ⁺ Ph ₃ HaT (XVI) wherein R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined in formula XXII and Hal is chlorine, bromine or iodine, reacted with a strong base to form an ylide compound and the ylide with a Compound of the following formula iXXI) 103 28382t H (O) C (XXI) , 26 where R is as defined above i .., t; or (C) for the preparation of a compound of the formula CO ₂ R I Z 1 fi 17 - (CH ₉ ) ,, - form; R and R 'are independently hydrogen 1
where R is hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy, C-, - Cyanoalkyl, C ₂ _g-alkenyl, cC - or ß-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-l'uryl, fluorine, chlorine, bromine, , 6 1 A method for the preparation of mevalonolotonia with a pyrazolopyridine ring of the formula R- (D, 2 6 (XVIII) wherein R ¹ , R ² , R ⁵ , R ⁴ and R ^{5 are} as defined for formula XVI, R stands for a hydroxyl-protecting group 12 and R represents an alkyl moiety of a chemically or physiologically hydrolyzable alkyl ester, for example C 1-6 alkyl, which reacts the ylide compound formed by reacting the compound of formula (XVI) with a strong base with a compound of the following formula (XVII) H (O) CCH (OR ²⁶ ) 3. The method according to claim 2, characterized in that in the formula IR is hydrogen, C _1-8 alkyl, C ^ g-alkoxy, C ^^ - cycloalkyl, Cg_g-alkenyl, α- or ß-naphthyl, 2- , 3- or 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, / ty Q (wherein R, R 'and R are as defined above) or Cj ^ alkyl substituted by a member of the group consisting of C ₁ , alkoxy, naphthyl and (wherein R, R ^ and R ^{8 are} as defined above) and by 0, 1 or 2 members of the group consisting ρ
from C, Q-alkyl; R is attached to the nitrogen atom in the 1- or 2-position of the pyrazolopyridine ring and is C,] _Q-alkyl, C ₁ , -alkyl substituted by 1 to 3 fluoro, C ₁ -C 6 -cycloalkyl, α- or ß-naphthyl, 2-, 3- or 4-pyridyl or (wherein R, R 'and R are as defined above) or C ₁ , alkyl substituted by a member of the group consisting of C ₁ , alkoxy, hydroxy, naphthyl and (wherein R, R 'and R are as defined above), and by 0, 1 or 2 members of the group consisting of C _1-8 -AlkJrI; if R is hydrogen, R? Hydrogen, 4-methyl, 4-chloro or 4-fluoro; or R * and R together represent 3,5-dimethyl or 3-methyl-4-fluoro; and Y is -CH ₂ -CH ₂ - or (E) -CH = CH-. 4. The method according to claim 2, characterized in that in the formula IR ^{1 is} hydrogen, C _1-8 alkyl, C, y-cycloalkyl, C _2- g alkenyl or (wherein R, R ^ and R ^{8 are} as defined above); ρ
if R is attached to the nitrogen in the 1-position of the pyrazole lopyridine rings, R is C _1-8 -alkyl, C ₁ , - Alkyl substituted by 1 to 3 fluoro, C ^ y kyl, α- or ß-naphthyl, 2-, 3- or 4-pyridyl or -W- \ ^ s (wherein R, R ^ and R ^{8 are} as defined above or C _{1 is} alkyl substituted by a member of Group consisting of C ^, alkoxy, hydroxy, naphthyl and (wherein R, R 'and R are as defined above), and by 0, 1 or 2 members of the group, consisting of C ^ _-8- alkyl; or, when R is attached to the nitrogen at the 2-position of the pyrazolopyridine ring, R is α- or β-naphthyl or (wherein R, R 'and R are as defined above); if R is hydrogen, V? Hydrogen, 4-chloro or 4-fluoro; or R and R ^ together represent 3-methyl-4-fluoro; R ^{5 is} ethyl, n-propyl, isopropyl or cyclopropyl; and X is (E) -CH = CH-. 5. The method according to claim 2, characterized in that in the formula I R for 109 Is hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, cyclopropyl, cyclohexyl, phenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-tolyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2 , 3- or 4-chloromethylphenyl, 3- or 4-ethoxyphenyl, 4- (2-methylbutyl) -phenyl, 4-n-heptylphenyl, 4-n-octylphenyl, 4-n-pentylphenyl, 4-n-hexylphenyl, 4-n-propylphenyl, 4-n-butylphenyl, 4-t-butylphenyl, 4-n-butoxyphenyl, 4-n-pentyloxyphenyl, 4-n-hexyloxyphenyl, 4-n-heptyloxyphenyl, 4-n-octyloxyphenyl, 4- Phenoxyphenyl, 4-biphenyl, 4-trichloromethoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2,3-difluorophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2,4- Dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl , 3,4-dimethylphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2,4 -Dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-diynethoxyphenyl, 3,5-bis (trifluoromethyl) phenyl, 3,4-methylenedioxyphenyl, 2,4,6-trimethoxyphenyl, 3,4,5-trimethylphenyl or 2 4,6-triisopropylphenyl; R is attached to the nitrogen in the 1-position of the pyrazolopyridine ring and is methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, 2,2,2- Trifluoroethyl, 2-hydroxyethyl, cyclohexyl, benzyl, 2-chlorobenzyl, 2-hydroxybenzyl, 3-trifluoromethylbenzyl, 2-phenylethyl, phenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2- , 3- or 4-fluorophenyl, 2-, 3- or 4-tolyl, 2-, 3- or 4-trifluoromethylphenyl, 3- or 4-methoxyphenyl, 2-hydroxy- phenyl, 4-isopropylphenyl, 4-t-butylphenyl, 4-trifluoromethoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5- Dichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4-trichlorophenyl, 2,4-difluorophenyl, 3,5-bis (trifluoromethyl) -phenyl, 3-chloro-4-tolyl, 3-chloro-6 tolyl, 4-chloro-2-tolyl, 2-chloro-6-tolyl, 2-chloro-6-fluorophenyl, .2-chloro-5-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 4-bromo-3- chlorophenyl, 2-chloro-4-trifluoromethylphenyl, 3-fluoro-6-tolyl, a-naphthyl, 2-pyridyl, 3-methyl-5-trifluoromethyl-2-pyridyl, 4-pyridyl or 2,6-dichloro-4- pyridyl stands; R ^ is hydrogen; R is 4-chloro or 4-fluoro; R 1 represents isopropyl or cyclopropyl; and Y is (E) -CH = CH-. 6. The method according to claim 1, characterized in that (E) -3,5-Dlhydroxy-7- [4 ^l - (4 "-fluorophenyl) - 6 7 8
wherein R, R 'and R are independently hydrogen, C, _Q alkyl, C ₁ "alkoxy, C, alkylthio, chloro, bromo, fluoro, -NR ^ R (wherein R ^ and R ^ are independently C _1-3 Alkyl), chloromethyl, tri-chloromethyl, trifluoromethyl, trifluoromethoxy, trichloromethoxy, difluoromethoxy, phenoxy, in Benzyloxy, hydroxy, trimethylsilyloxy, diphenyl-t- 18 butylsilyloxy, hydroxymethyl or -O (CH ₂ ) _k 0R (where R ^{10 is} hydrogen or C ₁ , -alkyl and k is 1, 2 or 3), and if R ^{8 is} hydrogen and R and R ' in ortho position to each other, they can together form -OC (R ^) (R) 0- 1Q 20 (wherein R '* and R are independently hydrogen or 7. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-yT ^ ^1- cyclopropyl-4 '- (4 "-fluorophenyl) -1 ·, 3'-dimethylpyrazolo [3,4- b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ -alkyl ester of the carboxylic acid. I! 111 7 8 C ₁ , alkyl); or if R 'and R are simultaneously hydrogen, R for (wherein R ^ is hydrogen, C ₁ -Zf-alkyl, C ₁ , alkoxy, trifluoromethyl, chlorine, bromine or fluorine)], phenyl-C ₂ τ-alkenyl, the phenyl group is unsubstituted or substituted with Cj ^ alkyl , C ₁ , alkoxy, fluoro, chloro or bromo, or C ₁ , alkyl substituted by a member selected from the group C ₁ , alkoxy, naphthyl and R ⁶ R ⁷ f \ 7 8 (wherein R, R 'and R are as defined above) and by 0, 1 or 2 members selected from the group consisting of C _1-8 alkyl; R is bonded to the nitrogen atom at the 1 or Z position of the pyrazolopyridine ring and is hydrogen, C _1-8 alkyl, C _1- alkyl substituted, with 1 to 3 fluorine, Cj ^ -cycloalkyl, α- or ß-naphthyl, 2-, 3- or 4-pyridyl, Z- or 3-thienyl, 2- or 3-furyl or R ⁶ R ⁷ C o ο (wherein R ₁ R 'and R are as defined above), or Cj, alkyl substituted by a member of the group consisting of C ₁ , alkoxy, hydroxy, naphthyl and B ⁶ B ⁷ · fi 7 ft (wherein R, R 'and R are as defined above), and by 0, 1 or 2 members of the group consisting of C 1-6 alkyl; R? and R is independently hydrogen, C _1-8 alkyl, C, y-cycloalkyl, C ₁ alkoxy, n-butoxy. i-butoxy, sec. -Butoxy, R ² ^ R N- (wherein R ² ^ and R ^{2 are} independently hydrogen or C ₁ , alkyl), trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoro, chloro, bromo, phenyl, phenoxy, benzyloxy, hydroxy, trimethylsilyloxy , Diphenyl-t-butylsilyloxy, hydroxymethyl or -O (CH ₂ J ₁ OR ¹ ^ (wherein R ¹ ^ is hydrogen or C ₁ , -alkyl and 1 is 1, 2 or 3), or if R 1 and R are ortho to each other, they may together form -CH = CH-CH = CH- or methylenedioxy; Y is -CH ₂ -, -CH ₂ CH ₂ -, -CH = CH-, -CH ₂ -CH = CH-, -CH = CH-CH ₂ -, -C (CH ₃ ) = CH- or -CH = C (CH ₃ ); Z is -Q-CH ₂ WCH ₂ -CO ₂ R ¹² , or CO ₂ R ¹² [wherein Q is -C (O) -, -C (OR ¹³ ) ₂ - or -CH (OH) -; W is -C (O) -, -C (OR ¹³ ) ₂ - or -C (R ¹¹ ) (OH) -; R is hydrogen or C ₁ , alkyl; R ¹² 1U- ™Λ U Represents hydrogen or R (wherein R represents the alkyl moiety of chemically or physiologically hydrolyzable alkyl ester or M (wherein M is NH ^, sodium, potassium, 1/2 calcium or a hydrogen addition product to nitrogen of lower alkylamine, di-lower alkylamine or "tri-lower alkylamine stands)); A-X two R ^J is independently primary or secondary .C ₁ er are alkyl; or two R- ⁷ together - (CH _O ) _O - or 8. The method according to claim 1, characterized in that one comprises (E) -3,5-dihydroxy-7- [i ^l- t-butyl-4 ^l - (4 "-fluorophenyl) -3'-methyl-6 · - (1 "-methylethyl) pyrazolo [3" 4-b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ alkyl ester of the carboxylic acid. 9. The method according to claim 1, characterized in that one comprises (E) -3,5-dihydroxy-7- [i'-t-butyl-ö'-cyclopropyl-4 · - (4 "-f luorphenyl) -3 ' -methylpyrazolo [3,4-b] pyridine-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ , - Alkyl ester of the carboxylic acid produces. • _{9 (} - _Λ9 (XVII) CH ₂ CH (OR ^) CH ₂ CO ₂ R '* wherein R and R are as defined above; or (D) for the preparation of a compound of the formula IR ^24th (XX) 104 where R ¹ , R ² , B? , R and R ^ as in the above formula (XVI), R ^{26 is} a hydroxyl-protecting 10. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [i 'benzyl] ¹ - (4 "-fluorophenyl) -3'-methyl-6' - (1" -methylethyl) pyrazolo [3,4-b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C _{1 -} , Alkyl ester of the carboxylic acid produces. 11. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [i'-benzyl-ö'-cyclopropyl-4 '- (4 "-fluorophenyl) -3'-methylpyrazolo [ 3,4-b] -pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ _z-alkyl ester of the carboxylic acid manufactures. 112 12. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [4 ^l - (4-fluorophenyl) -1 "- (4" -methoxyphenyl) -3 ^l -methyl- 6 '- (1 "-methylethyl) pyrazolo [3' 4-b] pyridine-5 ^t -yl] hept-6 ~ enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ^, alkyl ester of the carboxylic acid produces. 12
R is an alkyl moiety of chemically or physiologically hydrolyzable acetal, for example Cj ^ alkyl, a reacted by reaction of a compound of formula (XVI) with a strong base Ylid compound with a compound of the following formula (XIX) , (XIX) H (O) C " ρ / Γ -4 p wherein R and R are as defined above; or (E) for the preparation of a compound of the formula R ^; (I - I) wherein Y has the meaning given below for the formula IJ, 1-6 or XV and R ¹ , R ² , R ³ , R, R ⁵ and R ^{12 are} as defined for formula I, a compound of formula CO ₂ R '* Π ((U-CH (OH) -: WC (O) -; Y-CH = CH-) I -6 (QC (O) -; W-CH (OH) -; Y-CH = CH-) XV (Q-CH (OH) -; WC (O) -; Y-CHfCHt-) R ² , R ³ , R ⁵ and R ¹² as defined above where R ¹ ,
are, reduced \ and optionally, subjecting the products obtained in the above process alternatives (A), (B), (C), (D) and (E) to a reaction to remove scavengers and / or to convert them into a physiologically acceptable salt. Process according to Claim 1, characterized in that a compound is prepared in which, in the formula I, if R is hydrogen, R 1 is hydrogen, 3-fluoro, 3-chloro, 3-methyl, 4-methyl, 4-chloro or 4-fluoro; or R and R together represent 3-methyl-4-chloro, 3t5-dichloro, 3,5-difluoro, 3,5-dimethyl or 3-methyl-4-fluoro; R is primary or secondary C _1-6 alkyl or C, _ ₆ cycloalkyl; Y is -CH ₂ -CH ₂ - or -CH = CH-; and Z for R ¹¹ 106 -CH (OH) CH ₂ CH (OH) CH ₂ COgR ¹² , -CK (OH) CHgC (O) CHgCOgR ¹² or -CH (OH) CHgC (OR ¹³ JgCHgCO ₉ R ¹²⁾ (wherein R ¹ ^ and ¹³ C. as defined above. 13. The method according to claim 1, characterized in that one comprises (E) -3,5-dihydroxy-7- [6'-cyclopropyl-4 '- (4 "-fluorophenyl) -1' - (4" -methoxyphenyl) - 3-methylpyrazolo [3,4-b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a Cj, Alkyl ester of the carboxylic acid produces. 14. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [3'-cyclopropyl-4 ^l - (4 "-fluorophenyl) -1! -Methyl-6 · - (1 "-methylethyl) pyrazolo [3,4-b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a Ci -z-alkyl esters of carboxylic acid produces. 15. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [3 ^f , 6'-dicyclopropyl-4 '- (4 "-fluorophenyl) -1'-methylpyrazolo [3, 4-b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy 'at the 5-position, or a sodium salt or a C ₁ , alkyl ester of the carboxylic acid. 16. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [4 ^f - (4 "-fluorophenyl]> - 1 'methyl-6 · - (1" -methylethyl) 3'-phenylpyrazolo [3 ', 4-b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C; ₁ , alkyl ester of the carboxylic acid produces. ^ 16 17 or Cj, -alkyl; or R and R 'together form - (CH ₂ ) O- or - (CH ₉ ), -]]; R- ³ for hydrogen. Chlorine, bromine, hydroxy, C ^ _- alkoxy, R ^ R N (wherein R ^ and R are independently hydrogen or C ₁ alkyl), C | _ _Q alkyl, C ^ _g-2 alkenyl, C ₇ cycloalkyl, Cc ₇ -Cycloalkenvi, trifluoromethyl or _R2S 98 (wherein R ^{5 is} as defined above) or C ₁ , alkyl substituted by a member of the group consisting of (wherein R ⁶ , R ⁷ and R ^{8 are} as defined above) and by 0, 1 or 2 members selected from the group consisting of C ₁ , -alkyl, characterized in that (A) - for the preparation of a compound of formula CO ₂ R ¹² (H) where R ¹ , R ² , R ⁵ , R and R ^{5 are} as defined above for formula I 17. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [6'-cyclopropyl-4 ^f - (4 "-fluorophenyl) -1 · methyl-3'-phenylpyrazolo [ 3,4-b] pyridine-5 ^! -Yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ , alkyl ester of the carboxylic acid manufactures. 18. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [3 ^f - (4 »-chlorophenyl) -4 '- (4 ¹ ^ fluorophenyl) -1'-methyl- 6 '- (1 "-methylethyl) pyrazolo [3,4-b] pyridine-5 ^! -Yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ , alkyl ester of the carboxylic acid produces. 19. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [3 '- (4 "-chlorophenyl) -6 · cyclopropyl-4 · - (4" -fluorophenyl) - 1'-methylpyrazolo [3,4-b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ , alkyl ester of the carboxylic acid produces. 20. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [i ^l -ethyl-4 ^l - (4 "-fluorophenyl) -6 '- (1" -methylethyl) - pyrazolo [3,4-b] pyrldin-5 · yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ , -alkyl ester of Carboxylic acid produces. 21. The method according to claim 1, characterized in that one comprises (E) -3,5-Dihydroy.y-7- [6'-cyclopropyl-1 · ethyl-4 '- (4 "-f luorphenyl) -pyrazolo [ 3,4-b] pyridine-5 ^! -Yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ , alkyl ester of the carboxylic acid , 22. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [4 ^f - (4 »-fluorophenyl) -6 '- (1» -methylethyl) -1'-phenylpyrazolo [ 3,4-b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ , alkyl ester of the carboxylic acid , 23. The method according to claim 1, characterized in that one comprises (E) -3,5-dihydroxy-7- [6 ^t -cyclopropyl-4 ^l - (4 "-fluorophenyl) -1'-phenylpyrazolo [3,4-b ] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy 'at the 5-position, or a sodium salt or a C ₁ , alkyl ester of the carboxylic acid. 24. The method according to claim 1, characterized in that one comprises (E) -3,5-dihydroxy-7- [4 '- (4 "-fluorophenyl) -3' methyl-6 · - (1" -methyleth! L) -I ¹ -phenylpyrazolo [3,4-b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or produces a C ₁ , -alkyl ester of the carboxylic acid. 25. The method according to claim 1, characterized in that (E ^^ - dihydroxy ^ -Cö'-cyclopropyl ^ ¹ - (4 "-fluorophenyl) -3'-methyl-1 · -phenylpyrazolo [3,4-b ] -pyrid: Ln-5'-yl] -hept-6-enoic acid, a lacto.i formed by the condensation of the carboxylic acid with hydroxy rn at the 5-position, or a sodium salt or a C ₁ , alkyl ester of the carboxylic acid , 26. The method according to claim 1, characterized in that one comprises (E) -3,5-dihydroxy-7- [3'-cyclopropyl-4 '- (4 "-fluorophenyl) -6 ^L - (1" -methylethyl) - 1'-phenylpyrazolo [3,4-b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ , -Arylester the carboxylic acid produces. 27. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7- [3 ^! ', o'-dicyclopropyl-4' - (4 "-fluorophenyl) -1-phenylpyrazolo [3,4-b] pyridoxn-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ , alkyl ester of the carboxylic acid. 28. The method according to claim I ^, characterized in that (E) -3,5-dihydroxy-7-i.1 '-t-butyl-3 »-cyclopropyl-4 ^f - (4" -fluorophenyl) -6' - (1 "-methvlethyl) pyrazolo [3" 4-b] pyridin-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a Sodium salt or a C ₁ , alkyl ester of the carboxylic acid produces. 29. The method according to claim 1, characterized in that one comprises (E) -2,5-dihydroxy-7- [1'-t-butyl-3 ¹ , 6 "-dicyclopropyl-4 '- (4" -f luorphenyl) pyrazolo Io [3,4-b] pyridine-5 ^! -yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid hydroxy at the 5-position, or a sodium salt or a C., Alkyl ester of the carboxylic acid produces. 30. The method according to claim 1, characterized in that one comprises (E) -3,5-dihydroxy-7- [1 "-t-butyl ~ 4 '- (4» - fluorophenyl) -6 · - (1'-methylethyl ) -3'-phenylpyrazolo [3,4-b] pyridine-5- ^f ] -yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ^ _, - Alky! Ester of the carboxylic acid produces. 31. The method according to claim 1, characterized in that (E) -3,5-dihydroxy-7 ~ [i'-t-butyl-6'-cyclopropyl-4 '- (4 "-fluorophenyl) -3'- phenylpyrazolo [3,4-b] pyridine-5'-yl] -hept-6-enoic acid, a lactone formed by the condensation of the carboxylic acid with hydroxy at the 5-position, or a sodium salt or a C ₁ , Alkyl ester of the carboxylic acid produces. Use of a compound of the formula (I) defined in claim 1, characterized in that it is used for the preparation of either A) 'an anti-Hyperlipidä'sjie agent or B) an anti-hyperlipoprotemic agent or 0) of an anti-atherosclerosis agent is used.