LT3810B - New benzimidazole derivatives, a process for production thereof and a pharmaceuticalcomposition containing the same - Google Patents

Description

It is an object of the present invention to provide novel compounds and therapeutically acceptable salts thereof which inhibit exogenously or endogenously stimulated gastric acid secretion and to use them in the prophylaxis and treatment of gastrointestinal ulcers.

The invention relates to the use of the compounds described herein, in particular therapeutically acceptable salts thereof, for inhibiting gastric acid secretion in mammals and humans. In a broader sense, the compounds of the invention may be used for the prophylaxis and treatment of gastrointestinal inflammation, gastric acidity-related mammalian and human diseases such as gastritis, gastric ulcer, duodenal ulcer and esophageal varices. In addition, the compounds may be used in the treatment of other gastrointestinal disorders where antisecretory effects are desired, such as in patients with gastrinoma or acute gastrointestinal bleeding. They can also be used to treat patients intensively before or during the postoperative period to prevent acid extraction and ulceration. The invention also relates to pharmaceutical compositions containing as active ingredient at least one compound of the invention or a therapeutically acceptable salt thereof. The invention further relates to methods for preparing such novel compounds, novel intermediates for the preparation of these compounds, and the use of the active compounds in the preparation of pharmaceutical compositions for the aforementioned medical purposes.

Benzimidazole derivatives for the inhibition of gastric acid secretion are described in a number of patents including GB 1,500,043, GB 1,525,958, US 4,182,766, EP 0 005 129 and BE 890 024. Benzimidazole derivatives proposed for the treatment of some gastrointestinal inflammations forms for the treatment and prophylaxis of the forms described in EP-A-0 045 200.

N-Substituted-2- (pyridylalkylsulfinyl) benzimidazoles are described in EP-A-0 176 308.

In some cases, it is essential that the compound is highly soluble in water, for example by intravenous or intramuscular injection, when the dose should be dissolved in a small amount of water. This, of course, requires good water solubility. However, this property often gives the compound an advantage in other situations, such as oral formulations.

The compounds described above have a low solubility in water, which prevents the production of the concentrated aqueous solutions required for intravenous and intramuscular injection. Fig. The compounds disclosed in European Patent Publication No. 0176308, which describes N-substituted benzimidazole derivatives, have low water solubility and are not suitable for the above-mentioned uses.

Compounds of formula I have been found to be potent inhibitors of gastric acid secretion in mammals and humans, and that said compounds I exhibit an incredibly high solubility in water compared to prior art compounds.

The compounds of the present invention wherein X is SO exhibit a higher chemical stability in aqueous solutions at pH where optimal stability is obtained as compared to the corresponding N-l unsubstituted compounds at the same pH. Some of the compounds of the invention exhibit exceptionally high chemical stability in solutions. Therefore, the compounds of formula I are particularly suitable for parenteral administration, particularly intravenous and intramuscular administration. The high solubility and chemical stability make the compounds of the invention suitable and suitable for their delivery routes such as oral or rectal administration.

The present invention provides compounds of formula I:

and their physiologically acceptable salts, wherein

X is -S- or -SO-;

R ¹ , R ² , R ³ and R ⁴ are the same or different and are (a) H (b) alkyl having 1-8, especially 1-6 carbon atoms (c) Alkoxy having 1-8, especially 1-6 carbon atoms (d) alkoxyalkyl having 1-3 carbon atoms in each alkyl group (e) alkoxyalkoxy having 1-3 carbon atoms in each alkyl group (f) halogen (g) -cn (h) -cf ₃ (i) ) -NO ₂ (j) -COR ¹⁰ (k) alkylthio having 1-6 carbon atoms in the alkyl moiety (l) alkylsulfinyl having 1-7 carbon atoms in the alkyl moiety (m) arylthio, -sulfinyl, -sulfonyl, - sulfonyloxy, oxysulfonyl, -sulfonamide or -aminosulfonyl, wherein each aryl group may be substituted with 1 to 3 substituents, the same or different, halogen, CF ₃ , (1-5C) alkyl or (1-5C) alkoxy, optionally (n ) arylalkyl or arylalkoxy having 1-6 carbon atoms in the alkyl and alkoxy moiety, where the aryl moiety may be substituted with 1-3 substituents, the same or different, optionally halogen, CF ₃ , (1-5C) alkyl and {1- 5C) -alkoxy (o) aryl or aryloxy wherein each aryl group may be substituted with 1 to 3 substituents, the same or different, optionally halogen, CF ₃ , (1-5C) alkyl and (1-5C) alkoxy (p) ) haloalkoxy having from 1 to 6 carbon atoms and from 1 to 11, in particular from 1 to 6 halogen atoms (q) hydroxyalkyl having from 1 to 6 carbon atoms (r) R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together with the adjacent carbon atoms in the benzimidazole ring form one or more 5-, 6- or 7-membered rings, each of which may be saturated or unsaturated, and may have 0-3 heteroatoms, optionally N, S or O, wherein each ring may be substituted with 1-10, preferably 1-6 or 1-4, optionally alkyl groups with 1-3 carbon atoms and halogen, or two or four of said substituents together

O

II one or two oxo groups (-C-), where when R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together with the adjacent carbon atoms of the benzimidazole ring form two rings, the rings may be fused to each other;

0 0 0 0 0 0

II e · II p II ii p H Ii H ,. e _{D is} -OCR ⁵ , -OP- (O) s R ^e , -OP-OP- (O) s R ^e , or -OP-OPOP- (O) _s ~ R ^e ;

0H 0H 0H 0H 0H 0H „5

R is (a) - (0) _t

A - N

where the substituent on the phenyl group is in the meta position, or para (d) - (0) _t -

E - C ll 0

B - N <l ₀ \ _R b (R ^q ) " ^R where the substituent on the phenyl group is in the meta or position, para (e) - (Q) _¥ A - OC n 0

B - N <

17?

(R ^q ) " ^R (f) - (0L - AI ·

C - H - (CH ₂ ) _m - Ν <ζ (g) - (0) ₊ - A - C t II / ^{! CH} 2> p \ _d N N - R ^{a X} (CH 2) q / ^X (R ^q ) v (h) - (CH,), -CHCOOH or - CH - (CH,) COOH ά UI [1 U

NH ₂ NH ₂ (i) mono- or dicarboxy-substituted 2-, 3- or 4-pyridinyl, mono- or dicarboxy-substituted 2-, 3- or 4-pyridinyloxy

(b) alkyl having 1-8, especially 1-6 carbon atoms (c) alkoxy having 1-8, especially 1-6 carbon atoms (d) halogen

R ⁸ is (a) H (b) alkyl having 1-8, especially 1-6 carbon atoms (c) alkoxy having 1-8, especially 1-6 carbon atoms (d) halo (e) arylalkyl having alkyl of 1 to 4 carbon atoms

R ⁷ is (a) H (b) alkyl having 1 to 7 carbon atoms (c) alkoxy having 1 to 7 carbon atoms (d) alkoxyalkyl having 1 to 3 carbon atoms in each alkyl moiety (e) alkoxy having 1 to 7 carbon atoms -3 carbon atoms in each alkyl moiety (f) aryloxy, where the aryl group may be substituted with 1 or 2 substituents, the same or different, halogen, CF ₃ , (1-3C) alkyl or (1-3C) alkoxy, optionally (g) ) arylalkyl or arylalkoxy having from 1 to 7 carbon atoms in the alkyl and alkoxy moiety, respectively, where the aryl moiety may be substituted with 1 or 2 substituents, the same or different, optionally halogen, CF ₃ , (1-3C) alkyl or (1) -3C) alkoxy (h) alkenyloxy having 1-7 carbon atoms in the alkenyl moiety (i) alkynyloxy having 1-7 carbon atoms in the alkynyl moiety (j) alkylthio having 1-7, preferably 1-3 carbon atoms in the alkyl moiety (k) ) an arylthio or arylalkylthio group having 1-3, preferably 1, carbon atoms in the alkyl moiety wherein (l) a dialkylamino group having 1 to 7 carbon atoms, preferably 13 carbon atoms in each alkyl moiety (m) morpholine (n) piperidine (o) N-methylpiperazine (p) pyrrolidine (q) floroalkoxy having 2 to 5 carbon atoms and 1 to 5 carbon atoms; 9 atoms of flora

6 7 7 8 or R and R or R and R together with adjacent pyridine ring atoms form a 5- or 6-membered saturated or unsaturated ring which may contain oxygen, sulfur or partially an alkylated nitrogen atom; R ⁹ is present (a) hydrogen (b) alkyl having from 1 to 4 carbon atoms; '10 R is (a) alkyl having 1 to 6 carbon atoms (b) an alkoxy group containing from 1 to 6 carbon atoms

(c) aryl;

A is (a) straight or branched (1-8C) alkylene

(b) (3-7C) cycloalkylene (c) (4-9C) alkylene having a cycloalkylene group; B is (a) - (CH ₂ ) _m - (b) -CH-; L · E is (a) -O- or (b) -NH-;

Z

Z _x is (a) -CH 10 (b) -N-;

Z ₂ is (a) -CH ₂ (b) -NR ^d (R ^q ) _v (c) -S (d) -O-;

R ^a , R ^b , R ^c and R ^q are the same or different, optionally from (a) H (b) (1-6C) alkyl;

R ^e is (a) H (b) (1-6C) alkyl (c) aryl (O-3C) alkyl, wherein the aryl group is optionally substituted with 1-3 substituents, the same or different - halogen, CF ₃ , NO ₂ , (1-5C) alkyl and (1-5C) alkoxy;

R ^f is an amino acid side chain;

m

P q

r s

is hello number 0, 1, 2, 3, 4, 5, θ, 7 or is hello number 1, 2, 3 or 4; is hello number 1, 2, 3 or 4; is hello number 0, 1, 2, 3, 4, 5, 6, 7, 8; is hello number 0 or 11;

t is an integer 0 or 1;

u is an integer of 1 or 2;

v is an integer 0 or 1;

and wherein group D, when having one or two carboxylic groups or a phosphorus-containing group, is usually in the form of mono-, di-, tri- or tetra-ionic salts having a physiologically acceptable cation, or when it contains an amino group, can be ammonium salts (v = l; nitrogen has a positive charge) with a physiologically acceptable anion in the form, or a free amino form (v = O). In the case where R ⁵ is a side chain of aspartic acid (u = 1) or glutamic acid (u = 2) as h), R ⁵ may also be zwitterionic, provided that (1) A is (3-7C) cycloalkylene or (4-9C) alkylene having a cycloalkylene group, when the following conditions are met:.

(a) R is (O) _t - A - Nf (b) R ^a is H, (1-3C) alkyl (c) R ^b is H, (1-3C) alkyl (d) v is 0, or R ^q is H and v is 1 (2) One or both of R ⁶ and R ⁷ are halogen when R ⁷ is dialkylamine, morpholine, piperidine, N-methylpiperazine or pyrrolidine.

It is understood that the terms alkyl and alkoxy include straight, branched and cyclic structures, including cycloalkylalkyl and cycloalkylalkoxy, respectively.

The number of carbon atoms in a given radical is either specified or specifically indicated, or in abbreviated form, in the form of (1-3C) alkyl.

The sulfoxides of the invention have an asymmetric sulfur atom, i.e. these compounds exist as two optical isomers (enantiomers), or when they have one or more asymmetric carbon atoms, the compounds have two or more diastereomeric forms, each of which exists in two enantiomeric forms.

Both pure enantiomers and racemic mixtures (50% of each enantiomer) or simple mixtures thereof are also within the scope of the present invention, i.e. the invention encompasses all possible diastereomeric forms (pure enantiomers or racemic mixtures).

The compounds of the invention having a sulfide structure (X = S) may be asymmetric due to the presence of one or more asymmetric carbon atoms as described above. The various possible diastereomeric forms, as well as the pure enantiomers and racemic mixtures, are an object of the present invention.

Preferred groups of compounds of formula I are:

Compounds wherein X is -SO-.

Compounds wherein X is -S-.

Compounds wherein R ¹ , R ² , R ³ and R ⁴ are the same or different, optionally hydrogen, (1-4C) alLT 3810B, (5-6C) -cycloalkyl, (1-4C) alkoxy, (1-2C) alkoxy (1-2C) alkyl, (1-2C) alkoxy (1-2C) alkoxy, halogen, CF ₃ , (2-4C) alkanoyl, arylcarbonyl, (1-2C) alkoxycarbonyl, aryl (1) -3C) alkoxy, aryl, halogen (1-4C) alkoxy, hydroxy (1-4C) alkyl, (2-4C) alkanoyl (1-3C) alkyl, or wherein R and R together with the ring carbon atoms form or a 6-membered saturated, oxygen or carbocyclic ring, optionally substituted with 1 to 6 substituents, the same or different - optionally halogen, (1-2C) alkyl or wherein two of the substituents together form an oxo group.

Compounds wherein R ¹ , R ² , R ³ and R ⁴ are the same or different - optionally halogen, (1-4C) alkyl, (1-4C) alkoxy, (1-2C) alkoxy (1-2C) alkyl, fluoro, CF ₃ , (2-4C) alkanoyl, (1-2C) -alkoxycarbonyl, fluoro (1-4C) alkoxy, hydroxy (1-4C) alkyl, or wherein R ² and R ³ form a -OCH ₂ group _. O, -OCF ₂ O, -OCF ₂ -CHFO- or -C (CH ₃ ) ₂ COC (CH ₃ ) ₂ -.

Compounds wherein R ¹ , R ² , R ³ and R ⁴ are the same or different - optionally hydrogen, methyl, ethyl, isopropyl, t-butyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, fluorine, trifluoromethoxy, tetrafloroethoxy, hydroxymethyl, or wherein R ² and R ³ form a group -OCF ₂ O-, -C (CH ₃ ) ₂ COC (CH ₃ ) _2, or -OCH ₂ O-.

Compounds wherein R ¹ , R ² , R ³ and R ⁴ are the same or different - optionally hydrogen, t-butyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, fluorine, trifluoromethoxy, tetrafloroethoxy, hydroxymethyl or hydroxyethyl.

Compounds wherein R ¹ and R ⁴ are hydrogen, R ² and R ³ optionally t-butyl, methoxy, methoxymethyl, fluorine, trifluoromethoxy, hydroxymethyl and hydroxyethyl.

Compounds wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen, alkyl of 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms.

1.4 .2.3

Compounds wherein R and R are H and R and R are alkoxy groups having from 1 to 3 carbon atoms.

12 ^ 4

Compounds wherein R, R, R and R are hydrogen.

4

11. Compounds wherein R and R are alkoxy,

containing 1-3 2 carbon atoms, and R and R ³ is H or hydroxyalkyl containing 1-3 carbon atoms. 12th Compounds, wherein R ¹ , R ³ and R ⁴ is H and R ² is and ₃ . 13th Compounds, 1 · T-J rJ · T-d wherein R, R and R is H and R ³ is

OCH ₃ .

Compounds wherein R ⁷ is hydrogen, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms.

Compounds wherein R ⁷ is substituted aryloxy or arylalkoxy.

y

Compounds wherein R is an alkoxy group having 16 carbon atoms.

Compounds wherein R ⁹ is H or CH ₃ , especially H.

18. Preferred substituents at the 2-position of the benzimidazole ring are those wherein R ⁹ is H and D listed in Table 1 below.

O

I '5

19. Compounds wherein D is -OCR.

o O ii it <

Compounds in which D is -OC-A-C-N, especially salts thereof with acids.

NR ^c

0 / -λ

II II / \

Compounds wherein D is -OCCH ^ CH ^ C-N ^ _ ^ N-CH ^ or ii ii

-OCCH ^ CH ^ CH ^ C-N ^ ^ N-CHg, in particular their salts with acids.

22. Compounds in which D is especially its alkali salts.

g

-OP- (O) _s R ^€

OH

23. Compounds in which D is especially its alkali salts.

0

II II _Vol

-OP-OP- (O) _s R ^e

0H 0H

Compounds containing D in particular their alkali salts.

II

-OP-O-P-O-P- (O) R 'I I I s

0H 0H 0H

25. Compounds in which D contains in particular their alkali salts.

II

II • OP-O-P-OR i i 0H 0H

Compounds in which D is especially its alkali salts.

¹¹ e-OP-OR '

I

0H

27. Compounds in which D is especially its alkali salts.

K _e -OP-R ^e

I

0H li

Compounds in which D is -OP-OH, in particular their alkaline salts. OH

II

Compounds wherein D is -OP-OCH ^, in particular their alkali salts. OH

Compounds containing D in particular their alkali salts.

- ° p ° ^c 2h ₅

0H

31. Compounds, Group.

wherein R ^e is optionally substituted aryl

32. Preferred benzimidazole structures are: unsubstituted and substituted with 5-methoxy and 6-methoxy.

33. Preferred pyridine moieties are: 3,5-dimethyl-4-methoxy, 3-methyl-4-methoxy, 5-ethyl-4-methoxy, 4-methoxy, 4-ethoxy, 4-isopropoxy, 3,5-dimethyl, 3,4-dimethyl, 4,5-dimethyl, 3-methyl-4- (2,2,2-trifluoro) ethoxy,

3,4-dimethoxy, 4,5-dimethoxy, 3-methyl-4-ethylthio,

3-methyl-4,5-dimethoxy, 3,4,5-trimethyl, 3-ethyl-4-methoxy, 3-n-propyl-4-methoxy, 3-isopropyl-4-methoxy,

3-t-Butyl-4-methoxy-substituted pyridine.

34. Particularly suitable pyridine moieties are substituted

3,5-dimethyl-4-methoxy, 3-methyl-4-methoxy, 3-ethyl-4-methoxy, 3-isopropyl-4-methoxy, 4-methoxy, 4-ethoxy and 4-isopropoxy, especially In the 3,5-dimethyl-4-methoxy group, pyridine.

35. Additional suitable compounds are obtained by combining the stated most appropriate values with some or all of n

X and r'-R ¹⁰ as defined in groups 1-34 above.

36. The preferred pyridinylmethylsulfinylbenzimidazole moieties are och ₃

8th

37. Preferred R and R radicals are H, CH ₃ , C ₂ H ₅ , nC ₃ H ₇ , iC ₃ H ₇ and tC ₄ H ₉ .

38. Preferred compounds of the invention are

39. Other suitable compounds of the invention are

The following are illustrative examples of the various radicals in formula I. They apply to different radicals, depending on the number of carbon atoms assigned to each radical.

The alkyl group in the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R% R ^b , R ^c , R ^d , R ^e and R ^q is illustrated methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclopentylethyl and cyclohexylmethyl. Lower alkyl groups having 1 to 4 carbon atoms are particularly suitable.

The alkoxy group in the definitions R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ and R ¹⁰ illustrates methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy, s-butoxy, t- butoxy, n-pentoxy, i-pentoxy, n-hexoxy, cyclopropoxy, cyclopentoxy, cyclohexoxy, cyclopropylmethoxy, cyclopentylmethoxy, cyclopentylethoxy and cyclohexylmethoxy. Lower alkoxy groups are most preferred, especially having 1-4 carbon atoms, of which 1-3 carbon atoms are preferred, i.e. methoxy, ethoxy, n-propoxy or isopropoxy.

Halogen in the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁸ is chlorine, bromine, fluorine and iodine, preferably chlorine, bromine and fluorine.

¹ 2 3 4 7

In the radicals R, R, R, R and R denoting alkylthio or alkylsulfinyl, lower alkyls are preferred as alkyl, most preferably having 1-4 carbon atoms, e.g. methylthio, methylsulfinyl, ethylthio, ethylsulfinyl, isopropylthio, n-butylsulfinyl or an isobutylthio group.

A preferred aryl group in the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ¹⁰ and R ^e is a group of up to 10 carbon atoms, in particular groups of up to 6 carbon atoms, such as phenyl.

^{In the} radicals R ¹ , R ² , R ³ , R ⁴ and R ⁷ defining aryloxy or arylthio, most preferred aryl is up to 10 carbon atoms, preferably up to 6, e.g., phenoxy or phenylthio.

Most preferred arylalkyl, arylalkoxy and arylalkylthio groups in R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ and

R ^e has up to 10 carbon atoms in the aryl group. Of particular interest are groups having 6 carbon atoms in the aryl and 1 to 3 carbon atoms in the alkyl or alkoxy group, respectively, such as phenylmethyl, phenylethyl, phenylmethoxy, phenylethoxy, phenylpropyl, phenylisopropoxy, phenylmethylthio and phenylethylthio.

The beveled group (4-9C) alkylene having the cycloalkylene group in Part A is

-ch ₂

-ch ₂ ch ₂

R ¹ , R ² , R ³ , R ⁴ and R ⁷ representing an alkoxyalkyl or alkoxyalkoxy group are illustrated by methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxyethyl, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy and propoxyethoxy.

Most preferably R ⁷ denoting alkenyloxy or alkynyloxy has from 2 to 7 carbon atoms, preferably from 3 to 4 carbon atoms, e.g., allyloxy, propargyloxy, 2-butenyloxy and 2-butynyloxy.

_v _ i. 2 2 '. 3 3

The ring structures formed by R and R, R and R, R and R ⁴ are illustrated by -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ C (CH ₃ ) ₂ CH ₂ -. , - (CH _{2) 5} -, -CH = CH-CH = CH-, -CH ₂ Coch ₂ -, -OCH ₂ -, -OCH ₂ CH ₂ O-, -OCH ₂ CH ₂ CH ₂ O-, - och ₂ ch ₂ -, -ch ₂ ch ₂ nh-, -ch = ch-ch = n ~, -coch ₂ co-, -sch ₂ ch ₂ -, -sch ₂ s-, -SCH ₂ CH ₂ S-. , -C (CH ₃ ) ₂ -COc (ch ₃ ) ₂ -, ocf ₂ o-, -ocf ₂ chfo-, -ocf ₂ cf ₂ o-.

7 7 8

Most preferred R and R or R and R denoting a 5- or 6-membered saturated or unsaturated ring is a saturated carbocyclic ring or a saturated ring containing oxygen or sulfur at the 4-pyridine position, e.g., -CH ₂ CH ₂ CH ₂ -, - CH ₂ CH ₂ CH ₂ CH ₂ -, -O-CH ₂ CH ₂ -, -O-CH ₂ CH ₂ CH ₂ -, -SCH ₂ CH ₂ - or -SCH ₂ CH ₂ CH ₂ -.

3 4

Most preferred R, R, R and R for haloalkoxy are lower haloalkoxy radicals. Most preferred are lower fluoroalkoxy or fluorochloroalkoxy groups, e.g., OCF ₃ , OCHF ₂ , OCF ₂ CHF ₂ , OCF ₂ CF ₃ , ocf ₂ ci, och ₂ cf ₃ .

R ⁷ denoting a f luoral moiety is illustrated in OCH ₂ CF ₃ , OCH ₂ CF ₂ CF ₃ and OCH ₂ CF ₂ CHF ₂ .

3 4

R, R, R and R representing a hydroxyalkyl group are illustrated by CH ₂ OH, CH ₂ CH ₂ OH, CH ₂ CH ₂ CH ₂ OH and (CH ₂ ) ₄ OH.

Most preferred R ⁷ for dialkylamino is (CH ₃ ) ₂ or -N (C ₂ H ₅ ) ₂ .

R ^f , which represents the amino acid side chain, is represented in Figs. , CH ₃ of alanine or COOH of glutamic acid (CH ₂ ) ₂ .

Both the pure enantiomers and the racemic mixtures of the compounds of formula I having an asymmetric center are also an object of the present invention.

Further examples illustrating the radical structure of Formula I are given in the following Examples and in the lists of specific compounds.

It is conceivable that compounds of Formula I are metabolized before they are effective. Such metabolism may occur at the N-position of the 1-position of the benzimidazole ring. Moreover, it is believed that the antisecretory activity of the compounds of the invention wherein X is S occurs after their metabolism to compounds wherein X is SO.

A compound of formula I wherein D is R ⁵ COO can be obtained

A. In reaction with a compound of formula II

II wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and X are the same as in formula I, with a compound of formula III

R ^{5 is} COOH m or an activated derivative thereof wherein R ⁵ is as defined in formula I.

The reaction of a compound of formula II with a compound of formula III is carried out directly in the presence of dicyclohexylcarbodiimide and, if necessary, N, N-dimethylaminopyridine (DMAP), or with an activated form of compound III such as acid anhydride or mixed anhydride.

Preferred solvents are hydrocarbons such as toluene and benzene, or halogenated hydrocarbons such as methylene chloride and chloroform, or polar solvents such as acetone, dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF). and pyridine.

The reaction of compounds II and III can be carried out at temperatures from -15 ° C to the reflux temperature of the reaction mixture.

B. Compounds of formula I wherein R is H in the reaction of a compound of formula IV

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ and X are the same as in formula I and Z is halogen such as Cl, Br or J, or a functionally equivalent group, with with a compound of formula V, VI, VII, VIII, IX, X, XI, XII or XIII:

R ⁵ -CO ₂ M o

RPO-P- (O) .R ^e i ^s OM

VII

VI o

II

MO-P-OM

I 'CM

VIII ooo

II II H -p

MO-POPOP- (O) -R ^{e 1} i I ^s

0M OM. 0M

0 0 II II H-e RP0 į5- _{0M. MO} -POP- (O) _s -R

0M 0M OM

JX

0 II H

MO-P-O-P-OM l ι 0M 0M o o o

II II u

ΜΟ-Ρ-Ο-Ρ-Ο-Ρ-ΟΜ 1 I I

0M OM OM

XI XII XIII θ

wherein s, R and R are as defined in formula I, R ^p is an appropriate protecting group such as cyanoethyl, benzyl or p-nitrophenyl, M is the opposite ion such as Na ⁺ , K ⁺ , Ag ⁺ or trialkylammonium. If a protecting group is used, it is removed after the reaction (see E).

C. By oxidizing a compound of formula I

wherein X is S and R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and D have the meanings given above to give a compound of the same Formula I wherein X is SO. The oxidation may be carried out using an oxidizing agent, optionally from the group: nitric acid, hydrogen peroxide, acid acids, esters, ozone, nitric tetraoxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, t-butyl hypochlorite, diazabicyclo- [2.2.1. , 2] -octane-bromine complex, sodium periodate, selenium dioxide, manganese dioxide, chromic acid, cerium ammonium nitrate, bromine, chlorine and sulfuryl chloride. Typically, the oxidation occurs in a solvent containing a certain excess of the oxidizing agent relative to the product being oxidized.

The oxidation may also be carried out enzymatically using an oxidative enzyme or microbiologically using the appropriate microorganism.

D. In reaction with a compound of formula IIA

IIA wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ and X are the same as in formula I and Ma is either a metal cation such as Na ⁺ , K ⁺ , Li ⁺ or Ag ⁺ , or a quaternary ammonium ion such as tetrabutylammonium, with a compound of formula

D-CH-Y XII wherein D and R are the same as in formula I and Y is a halogen such as Cl, Br or J, or a functionally equivalent group.

The reaction of the compound of formula IIA with the compound of formula XII is preferably carried out in an inert gas environment in anhydrous medium. Preferred solvents are hydrocarbons such as toluene and benzene and halogenated hydrocarbons such as methylene chloride and chloroform.

The reaction of compounds of formula IIA and XII can be carried out at a temperature ranging from room temperature to the reflux temperature of the reaction mixture.

E. The protecting group D is replaced by well known methods. Yes, for example, phosphates can be protected as dibenzyl or diphenyl esters which are destroyed by alkaline hydrolysis. The dibenzyl esters can also be cleaved with sodium iodide in acetone. The protecting cyanoethyl group can be removed by treatment with alkali, e.g., NaOH.

Depending on the reaction conditions and starting materials, the final products of formula I are obtained in either neutral or salt form. Both neutral end products and their salts are an object of the present invention. DrusLT 3810 B can be obtained in the form of half, mono, one and a half polyhydrates.

Amino acid salts of acids can be converted into the free base in a manner known per se by using basic agents such as alkali or ion exchange. The resulting free bases can then be converted again into salts with organic or inorganic acids. The salts used are usually the acids which form the corresponding therapeutically acceptable salts. Examples of such acids include halogen acids, sulfuric acid, phosphoric, nitric, perchloric acids; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleinic, pyruvic, phenylacetic, benzoic, p-aminobenzoic, hydroxybenzoic, salicylic or p-aminosalicylic acids, methanesulfo, ethanesulfo, hydroxyethanesulfo, ethylenesulfo, halobenzenesulfo, toluenesulfo, naphthylsulfonic or aminobenzenesulfonic acids, methionine, tryptophan, lysine or arginine.

Salts of carboxylic or phosphoric acids with bases may be converted in an appropriate manner into the acid form and the latter in turn into the therapeutically acceptable salts such as the sodium or potassium salts.

The resulting racemates are separated by known methods, e.g., by recrystallization from an optically active solvent.

In the case of diastereomeric mixtures (racemate mixtures), they can be separated into stereoisomerically (diastereomerically) pure racemates by chromatography or fractional crystallization.

Some of the starting materials used in Methods A-E are new, but may be obtained by known methods.

The starting materials of Formula II are prepared by reacting the corresponding benzimidazole with the aldehyde R ⁹ CHO in the N-position.

The starting materials of formula IV are novel and form part of the present invention. Compounds of formula IV wherein Z is chlorine are prepared by reacting a compound of formula II with a chlorinating agent such as SOCl ₂ in the presence of a base such as triethylamine in a suitable solvent such as methylene chloride, toluene, acetonitrile, tetrahydrofuran or mixtures thereof. Compounds of formula IV wherein Z is Br or J are obtained by analogous methods using the appropriate reagents containing bromine (BBr ₃ ) or iodine. Examples of these intermediates are given in Examples I 1 through 139 in Table 3.

Starting materials in which X = S used in Method C can be obtained by Method A or Method B.

In another aspect, the invention relates to the use of a benzimidazole ring at the N-1 position of a radical of formula

D-CHg wherein D and R are as in Formula I, which inhibit the aqueous solubility of gastric acid secretagogues by inhibiting the anhydrous benzimidazole derivatives.

The present invention also relates to benzimidazole derivatives which inhibit gastric secretion and which contain a radical of the formula N-1 of the benzimidazole ring

9th

D-CH (R) -, wherein D and R are the same as in formula I.

Preferred values of D and R are given elsewhere in the invention.

The invention also relates to the use of an agent coupled to the N-position of the benzimidazole ring to increase the water solubility of benzimidazole derivatives which inhibit gastric acid secretion. His formula

D-CH-Y wherein D, R and Y are as described in the present invention.

Pharmaceutical formulations prepared for the clinical use of the compounds of the invention are intended for parenteral, oral, rectal or other administration forms. It is particularly desirable to formulate pharmaceutical compositions for parenteral administration. The pharmaceutical preparations contain a compound of the invention in combination with a pharmacologically acceptable carrier. The carrier may be a solid, semi-solid or liquid diluent or capsule. Such pharmaceutical preparations are a further object of the present invention, typically the active compound is present in an amount of 0.1-95% by weight of the preparation: 0.2-20% by weight in preparations for parenteral use and 1-50% in preparations for oral administration.

In preparing pharmaceutical compositions containing the compound of the present invention for oral administration, the selected compound may be mixed with a solid powder carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable carrier. with fatty agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate, and polyethylene glycol paraffins. The mixture is then formed into granules or tablets. Granules or tablets containing sulfoxides can be coated with a special film that protects the compound from acid-catalyzed degradation for as long as the dosage form remains in the stomach. The coating film is made from pharmacologically absorbable materials, such as beeswax, shellac, or anionic film-forming polymers such as acetate cellulose phthalate, hydroxypropylmethyl cellulose phthalate, partially methylesterified methacrylic acid, etc., if necessary using an appropriate plasticizer. These coatings may be variously colored to distinguish between tablets or granules containing different active compounds or different amounts of active compound.

Soft gelatine capsules may be made with capsules containing a mixture of the active compound and vegetable oil, fat or other material suitable for soft gelatine capsules. Soft gelatine capsules may also be film-coated as described above. The hard gelatine capsules may contain the active compound granules or film coated granules, or the active compound in combination with a solid powder carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin. They may also be film-coated.

The dosage form for rectal administration may be presented as suppositories containing the active ingredient in admixture with a neutral fatty base, or as gelatin capsules containing the active ingredient in admixture with vegetable oil, paraffin oil or other suitable microLTL 3810 Enema B, or as a dry micro-enema, ready to be dissolved in the appropriate solvent just prior to use.

Liquid preparations for oral use may be in the form of a syrup or suspension, e.g., as solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient, the remainder being sugar or sugar alcohols and ethanol, water , a mixture of glycerin, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavoring agents, saccharine and carboxymethylcellulose or other thickening agents. Liquid preparations may also be in powder form, mixed with the appropriate solvent prior to administration.

Solutions for parenteral administration may be formulated as a solution of the compound in a pharmacologically acceptable solvent, preferably at a concentration of 0.1% to 10% by weight. These solutions may also contain a stabilizing agent and / or buffering agents and may be formulated in ampoules or bonkets of various doses. Solutions for parenteral administration may also be formulated as a dry preparation to be reconstituted with the appropriate solvent immediately prior to administration.

The typical daily dose of the active compound will vary within wide limits and will depend on a variety of factors, such as the individual requirement of each patient, the route of administration and the nature of the disease. The usual dosage for parenteral or oral administration ranges from 5 to 500 mg of active compound per day.

The invention is illustrated by the following examples.

Example 1

Preparation of 1-Methylpiperidin-4-ylcarbonic acid [2 [[4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl ester. Hydrogen bromide (Method A) was stirred with 4-carboxy-N-methylpiperidine (1.8 g, 0.01 mol) in 75 mL of acetone, treated with thietylamine (1.5 g, 0.015 mol) and isobutyl chloroformate (1.93 mL, 0.015 mol) and stirred at room temperature for 15 min. . [2 - [[(4-Methoxy-3,5-dimethyl-2-pyridinylmethyl] sulfinyl] -1H-benzimidazol-1-yl] methanol (0.01 mol) is dissolved in 15 ml of pyridine and added dropwise to the mixture which is then stirred at room temperature. The inorganic salts are separated by filtration, the filtrate is evaporated and the residue is dissolved in 100 ml of dichloromethane, the dichloromethane solution is washed twice with 0.5 M NaOH solution (10 ml) and once with water (25 ml), dried, filtered and the solvent is evaporated. Yield 0 _f 4 g (8.5%) The hydrogen bromide salt was obtained from the free base by conventional methods.

Example 2 Preparation of pN, N-Dimethylaminomethylbenzoic acid [2 - [[(4methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] -methyl ester (Method B) pN, N-Dimethylaminomethylbenzene acid (50 mg, 0.28 mmol) and triethylamine (60 mg, 0.6 mmol) were dissolved in 10 mL of methylene chloride and added to l-chloromethyl-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] ] sulfinyl] -1H-benzimidazole (100 mg, 0.27 mmol) in 5 mL methylene chloride. After 10 hours at room temperature, the methylene chloride was washed with 0.5 M NaOH (5 mL) and brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. The desired product remains practically pure. Yield: 56 mg (40%).

Example 3

The compound of this example is shown in Table 1. It is obtained by Method A as described in Example 1.

Example 10

Preparation of the sodium salt of phosphoric acid benzyl- [2 [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl diester (Method E)

Phosphoric acid dibenzyl- [2 [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -ΙΗ-benzimidazol-1-yl] methyl triester (90 mg, 0.15 mmol) was dissolved in 2 mL of methanol / water (1: 1). 58 mg (0.7 mmol) of sodium bicarbonate are added to the mixture which is heated on a water bath for 2 hours. The mixture is concentrated in vacuo and the residue is chromatographed on silica gel (ethyl acetate: methanol: water, 20: 4: 3). Practically pure desired product is obtained. Yield: 30 mg (37%).

Examples 12, 13, 15 and 16

These compounds are shown in Table 1 and obtained by Method A as described in Example 14.

Example 14

Preparation of 2 - [[(4-Methoxy23,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -5-benzimidazol-1-yl] methyl (1-methyl) -4-piperidinyl) carbonate. Hydrogen bromide (Method A) Dissolve p-nitrophenyl chloroformate (3.1 g, 15 mmol) in 75 mL of toluene and add 4-hydroxy-1-methylpiperidine (1.75 g, 15 mmol) and stir at room temperature (5 min). triethylamine solution in 75 ml of toluene. After 5 minutes at room temperature, the reaction mixture was filtered and the filtrate evaporated in vacuo. The oily residue is dissolved in 50 mL of methylene chloride and added to a solution of 10 mmol of 2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl-1H-benzimidazol-1-yl] methanol and 1 g (10 mmol) of triethylamine. ml of methylene chloride. Methylene chloride was evaporated and the residue was heated on a water bath at 70 ° C for 5 min. After cooling to room temperature, 100 ml of methylene chloride are added and the solution is extracted with sodium hydroxide (1 M, 16 ml), washed with brine and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent afforded an oily residue from which the free base of the final product was crystallized by addition of a mixture of ethyl acetate and ether. Yield 1.4 g. Lyd. temp. 134-136 ° C.

NMR (500 MHz, CDCl ₃ ): 2.22, 2.25, 2.30, 3.70, 4.96,

6.52, 7.40, 7.74, 8.14.

The hydrogen salt of bromine is obtained from the free base by known methods.

Example 23

Preparation of 1,1-Dimethyl-4- [2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methoxycarbonyloxypropyl piperazine iodide

The final product is obtained by alkylation of 2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl-3- (1-methylpiperazin-4-yl) propyl carbonate. by known methods.

Examples 29 and 32

a) Phosphoric acid [6-methoxy [2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl]] methyl ester, disodium salt and phosphoric acid [5- methoxy- [2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl]] methyl ester, disodium salt (2: 1). (Method B)

Tributylamine (14 mL, 0.059 mol) was added to a stirred solution of 85% phosphoric acid (2 mL, 0.030 mol) in 10 mL ethanol. The solvent is evaporated and the residue is taken up in 25 ml of methylene chloride. The organic layer was dried over sodium sulfate, filtered and evaporated. 1-Chloromethyl-6-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -ΙΗ-benzimidazole and 1-chloromethyl-5-methoxy-2 [[(4- methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, 2: 1 (1.0 g, 0.0025 mol) and tributylammonium salt of phosphoric acid obtained by the above method are dissolved in 50 ml. methylene chloride. Methylene chloride is distilled off and the residue is heated at 60 ° C for 5 min on a water bath. Dissolve the residue in 50 ml of methylene chloride and distil off again and heat the residue on a water bath for 5 min. At 60 ° C. This procedure is repeated 4 times until the reaction is complete. The residue was dissolved in methylene chloride and washed with 3 portions of water. The organic layer is dried, filtered and evaporated. The resulting mixture of tributylammonium salts is dissolved in 25 ml of methylene chloride and 10 ml of water, and then, while stirring, a sodium hydroxide solution is added, while carefully monitoring the pH of the aqueous layer. When the pH reaches 9.0-9.5 (0.005 mol NaOH added), the mixture was centrifuged. The aqueous layer was washed 3 times with methylene chloride (25 mL) and frozen. 760 mg (61%) of the final product is obtained. The NMR spectrum of the mixture is analogous to that of pure isomers in Table 2.

b) Preparation of phosphoric acid [5-methoxy- [2 [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl]] methyl ester, disodium salt

From a mixture of tributylammonium salts obtained in step a), phosphoric acid [5-methoxy- [2 [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -ΙΗ-benzimidazol-1-yl] methyl ester The tributylammonium salt was obtained by column chromatography on 15% acetonitrile in water as the eluent. After drying below 0 ° C, the residue is dissolved in methylene chloride and treated with sodium hydroxide as described above. Pure phosphoric acid [5-methoxy- [2 [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -ΙΗ-benzimidazol-1-yl]] methyl ester, disodium salt obtained with about 1 % yield. The NMR spectrum is shown in Table 2.

c) Preparation of phosphoric acid [6-methoxy- [2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl-1H-benzimidazol-lyl]] methyl ester, disodium salt.

Method A

The title compound is obtained analogously to that described in step a), using 1-chloromethyl-6-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole as the starting material. , 9 g, (4 mL, 0.060 mol), and 100 mL methylene

0.0048 mol), 85% phosphoric acid tributylamine (28 mL, 0.118 mol) chloride. The product was crystallized from ethanol-water to give 0.85 g (35%). The NMR spectrum of the compound is identical to that shown in the table below. 2.

Method E

The residue resulting from the synthesis of cyanoethyl 6-methoxy- [2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -11-benzimidazol-1-yl] methyl diester triethylammonium salt of phosphoric acid is added NaOH (0.30 g, 0.0075 mol) in 25 mL of water. The mixture was heated on a water bath (60 ° C) for 15 min then rinsed twice with methylene chloride (25 mL) and evaporated to dryness to give 0.25 g of the title compound. Yield 22%. Product identity confirmed by NMR spectra.

Example 33

Phosphoric acid ethyl- [6-methoxy- [2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl diester, sodium salt formation.

Pure 1-chloromethyl-6-methoxy-2 [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (0.3 g, 0.00076 mol) and phosphoric acid monoethyl of the ester mono triethylammonium salt (0.5 g, 0.0022 mol) with triethylamine (0.3 ml) and 10 ml of methylene chloride. The solvent was evaporated and the residue was heated on a water bath at 60 ° C for 5 min, quenched with methylene chloride which was evaporated and the residue re-heated for 5 min at 60 ° C. This procedure is repeated 4 times until the reaction is complete. The resulting product was purified by reverse-phase column chromatography using water-acetonitrile (90:10) as eluent. The pure fractions are combined, evaporated and one equivalent of sodium hydroxide is added to the residue. The solution was evaporated and dried in vacuo. 0.37 g, 26% pure product was obtained. The structure of the compound was determined by NMR spectra.

Examples 34 and 35

1- Piperazibutanoic acid 4-methyl-γ-oxo, [5-methoxy-2 - [[(4-methoxy-3,5-dimethyl] -2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole] -1- yl] methyl ester and 1-piperazinobutanoic acid, 4-methyl-ly-oxo, [6-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1F-benzimidazole-1- il] Preparation of a methyl ester mixture (1: 2) (Method A)

Ethanedioic anhydride (4 g, 0.04 mol), N-methylpiperazine (4 g, 0.04 mol) and triethylamine (4 g, 0.04 mol) were added to 250 ml of dichloromethane. The mixture was stirred for 10 min. at room temperature, then cooled to -15 ° C and 3.78 g (0.04 mol) of methyl chloroformate was added thereto. Isomeric mixture of 1-hydroxymethyl- (5-methoxy) - and - (6-methoxy) -2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (15 g, 0 , 04 mol) and triethylamine (4 g, 0.04 mol) are dissolved in 75 ml of dichloromethane and added dropwise to a mixed anhydride solution, then 0.49 g (0.04 mol) of dimethylaminopyridine are added and the temperature is raised to room for 90 min. . The solution is washed twice with water (150 mL), twice with 0.5 M sodium hydroxide (50 mL). The layers are separated and the dichloromethane layer is dried, filtered and evaporated. The yield of the final products is 15.2 g. The residue was recrystallized from a mixture of ether (80 mL) and ethyl acetate (80 mL) to give 12.2 g (56%) of the isomeric mixture of the basic products (1: 2).

Example 45

Preparation of phosphoric acid p-nitrophenyl- [2 [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl diester, l-Chloromethyl-2- [ [(4-Methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (0.22 g, 0.60 mmol) and p-nitrophenyl phosphate disodium salt x 6 H ₂ O (2.4 g) , 6.4 mmol) are dissolved in 15 ml of acetonitrile containing 10 ml of water. The mixture is refluxed for 1 h, the solvents are evaporated off under vacuum and the residue is dissolved in water. The aqueous layer was washed with methylene chloride and then evaporated. The resulting product was purified by chromatography on a silica plate using ethyl acetate / methanol / water (20: 4: 3) as eluent. 32 mg (10%) of pure title compound are obtained.

Example 54

Preparation of Phosphoric Acid Ethyl [2 [[(4- (2,2,2-Trifluoroethoxy) -3-methyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl]] methyl diester, l-Chloromethyl-2 - [[(4- (2,2,2-Trifluoroethoxy) -3-methyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (40.5 mg, 0.1 mmol) and ditributylammonium salt of the monoethyl ester of phosphoric acid (198 mg, 0.4 mmol) was mixed with tributylamine (19 mg, 0.1 mmol) and 10 mL of methylene chloride. The solvent was evaporated and the residue heated for 5 min. at 60 ° C on a water bath, then add methylene chloride which is distilled off and the residue re-heated to 60 ° C for 5 min. This procedure is repeated 4 times until the reaction is complete. The residue was dissolved in methylene chloride and washed with three portions of water. The organic layer is dried, filtered and evaporated. The resulting mixture of tributylammonium salts was dissolved in methylene chloride and water and sodium hydroxide solution were added to pH = 10. The mixture is centrifuged and the aqueous layer is washed with three portions of methylene chloride. Chilling below 0 ° C gives a pure final product identified by NMR spectra (Tab. 2).

Examples 57 and 58

Phosphoric acid [6-methoxy- [2 [[(4-isopropyloxy-2-pyridinyl) -methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl ester, dipotassium salt and phosphoric acid [5-methoxy- [2 [ Preparation of [(4-isopropyloxy-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazol-1-yl] methyl ester, dipotassium salt mixture

The final compounds were obtained by the method described in Examples 29 and 32, using potassium hydroxide only in place of sodium hydroxide.

Examples 63 and 64

Phosphoric acid methyl- [6-methoxy- [2 [[(4-isopentyloxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl diester, sodium salt and phosphoric acid methyl [ Preparation of 5-methoxy [2 [[(4-isopentyloxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl diester, sodium salt

The final compounds were prepared by the method described in Example 54 using ditributylammonium salt of the monomethyl ester of phosphoric acid.

Example 67

This compound is shown in Table 1 and obtained by Method B described in Examples 63 and 64 using potassium hydroxide instead of sodium hydroxide.

Examples 75 and 76

These compounds are shown in Table 1 and obtained by the method described in Example 54 using potassium hydroxide instead of sodium hydroxide.

Preparation of Intermediates

2 - [[(4-Methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methanol

2 - [[(4-Methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (3.15 g, 10 mmol) and N, N-dimethylaminopyridine (120 mg, 1 mmol) are dissolved in 50 of methylene chloride and a solution of formaldehyde (5 M, 10 mL, 50 mmol) was added. The mixture is stirred vigorously for 2 min, the layers are separated, the methylene chloride solution is dried over sodium sulfate, filtered and evaporated to dryness. The remaining light pink oil is a virtually pure final compound.

NMR Spectrum (500 MHz, CDCl ₃ ): 2.15, 2.27, 3.70, 4.89,

5.89, 7.33, 7.63, 7.96.

1-Hydroxymethyl- (5-methoxy) - and 1-hydroxymethyl- (6-methoxy) -2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl-1H-benzimidazole

5-Methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (34.5 g, 0.1 mol) was dissolved in 500 mL of methylene chloride. Formaldehyde solution (5 M, 100 mL, 0.5 mol) was added and the mixture was stirred vigorously for 2 min. The layers were separated and the methylene chloride was dried over sodium sulfate, filtered and evaporated to dryness at low temperature (<30 ° C). The light pink oil residue is a virtually pure mixture of isomers of the final products (1: 2). This oil is used in further reactions without further purification.

Example I 12 l-Chloromethyl-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

2 - [[(4-Methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methanol (4.8 g, 14 mmol) and triethylamine (1.6 g, 15 mmol). mmol) are dissolved in 100 mL of methylene chloride. Thionyl chloride (1.8 g, 15 mmol) was added to 10 mL of methylene chloride at such a rate that the reaction mixture was slowly boiling. After 10 minutes at room temperature, methylene chloride is distilled off in vacuo and the residue is taken up in 100 ml of ethyl acetate and 50 ml of water. The layers are separated, the ethyl acetate layer is dried over sodium sulfate, filtered and evaporated. Chromatography on silica gel (ethyl acetate) gave a crystalline product which was recrystallized from ethyl acetate-ether. Lyd. t. 140141 ° C. Yield 1.5 g (27%).

Similarly, compounds I 1 - I 11, I 13 - I 20, I 23 - I 39 were obtained.

Examples I 21 and I 22

1-Chloromethyl- (5-methoxy) - and (6-methoxy) -2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole

1-Hydroxymethyl- (5-methoxy) - and (6-methoxy) -2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (30 g, 0, 08 mol, 1: 2) dissolved in 500 ml of toluene and cooled to -30 ° C. A solution of thionyl chloride (19 g, 0.16 mol) in 100 mL of toluene was added dropwise and the mixture was stirred for 10 min. at -30 ° C. A solution of triethylamine (45 g, 0.45 mol) in 200 ml of toluene is then added dropwise. After the drop, the temperature was raised to room temperature and the mixture was stirred for 30 min, then evaporated and the residue (120 g) chromatographed on silica gel (ethyl acetate-methylene chloride, 50:50). The final product was obtained as a mixture of isomers (1: 3) in a yield of 11.9 g.

NMR Spectrum (500 MHz, CDCl ₃ ): 2.23, 2.25, 2.26, 3.72, 3.87, 3.92, 4.88, 4.95, 4.96, 6.17, 6.18, 6.54, 6.57, 6.95, 7.01, 7.19, 7.26, 7.43, 7.67, 8.17.

If pure l-chloromethyl-6-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole is obtained by crystallization of a mixture of isomers from acetonitrile, MHz, CDCl ₃ ): 2.23,

2.25. 3.72, 3.92, 4.88, 4.96, 6.17, 6.57, 6.95, 7.01,

7.67, 8.17.

Preparation of phosphoric acid cyanoethyl- [6-methoxy- [2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl]] methyl diester, triethylammonium salt (Method B)

1-Chloromethyl-6-methoxy-2 [[(4-methoxy-3,5-dimethyl-2-pyridinyl) -methyl] sulfinyl] -1H-benzimidazole (0.90 g, 0.0023 mol) is added to phosphoric acid under stirring. cyanethyl ester monotriethylammonium salt (0.70 g, 0.0028 mol) and triethylamine (0.65 g, 0.0064 mol) in 20 ml of methylene chloride. The mixture is refluxed overnight, methylene chloride is distilled off and the residue is heated on a water bath for 10 min. at 60 ° C and used without further purification in the following reactions.

Preparation of phosphoric acid dibenzyl- [2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazol-1-yl] methyl triester 1-Chloromethyl-2 - [[(4-methoxy) -3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (1.29 g, 3.5 mmol) and the dibenzyl ester silver salt of phosphoric acid (1.79 g,

4.6 mmol) are suspended in dry toluene. The mixture is heated at 90 ° C on a water bath for 3 hours. and toluene is evaporated off under vacuum. The residue is taken up in 50 ml of methylene chloride, filtered (Hyflo) and evaporated in vacuo. The product is obtained in the form of an oil, which is chromatographed on silica gel (ethyl acetate). In practice, the yield of the pure product as a pure oil was 0.9 g (42%).

NMR Spectrum (500 MHz, CDCl ₃ ): 2.20 (ds, 6H), 3.65 (s, 3H), 4.8-5.0 (m, 6H), 6.25-6.3 (m, 1H), 6.45-6.5 (m, 1H). , 7.15-7.40 (m, 12H), 7.65 (d, 1H), 7.80 (d, 1H),

8.1 (s, 1H).

Isomeric forms

Isomeric pure sample no. The structure of 29 was determined using the NMR method according to synthetic precursor no. I 22 structure. The structures of all other benzimidazole isomers were determined by comparing their NMR spectra with those of Example no. 29 NMR spectrum.

The synthesis of primes I 21 and II 22 results in a mixture of isomers in a ratio of 1: 2, which results in the target compounds no. 32 and 29 are formed as isomers in the same ratio of 1: 2. In other examples, the ratio of isomers varies in some cases from 1: 2 and is dependent on substituents, particularly in the benzimidazole ring.

All examples are given in Table 1.

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The identity of the compounds described in the Examples in Table 1 is given in Table 2.

Table 2

Fig. Solvent NMR data, δ m.d. (500 MHz)

DMSO-d ₆ 1.75 (q, 2H), 2.0 (d, 2H), 2.15 (s, 3H),

2.20 (s, 3H), 2.7 (m, 5H), 2.9 (q, 2H), 3.65 (s, 3H), 4.8-5.05 (dd, 2H), 6.45 (s, 2H),

7.35 (t, 1H), 7.45 (t, 1H), 7.8 (d, 1H),

7.85 (d, 1H), 8.15 (s, 1H)

CDCl ₃ 2.20-2.25 (3s, 12H), 3.45 (s, 2H), 3.70 (s, 3H), 5.00 (s, 2H), 6.70 (dd, 2H),

7.25-7.45 (m, 4H), 7.75 (d, 1H), 7.80 (d, 1H), 8.0 (d, 2H), 8.15 (s, 1H)

CD ₃ OD 3 (s, 3H), 2.35 (s, 3H), 2.7 (s, 3H),

2.7-3.0 (m, 8H), 3.6-3.85 (m, 4H), 3.8 (S, 3H), 5.0-5.15 (dd, 2H), 6.45-6.6 (dd, 2H) , 7.5 (t, 1H), 7.55 (t, 1H), 7.85 (d, 2H), 8.2 (s, 1H)

DMSO-D ₆ 2.15 (s, 3H), 2.20 (s, 3H), 3.65 (s, 3H), 4.50-4.55 (m, 2H), 4.75 (d, 1H), 5.05 (d, 1H), 5.95-. 6.0 (m, 1H), 6.05-6.10 (m, 1H),

7.10-7.40 (m, 7H), 7.75 (d, 1H), 7.85 (d, 1H), 8.15 (S, 1H)

D, O

2.00 (s , 3H), 2.20 (s, 3H), 3.50 (s, 4.85-4. 90 (m, 1H), 5.00-5.05 (m, 1H) 5.70-5. 75 (m, 1H), 5.80-5.85 (m, 1H) 7.40-7. 45 (m, 1H), 7.50-7.55 (m, 1H) (d, 1H), 7th 80 (d, 1H), 8.10 (S, 1H)

CDC1 ₃ (90 MHz)

2.23 (s, 6H), 2.53 (t, 2H), 3.66 (s, 3H), 4.2 (t, 2H), 4.91 (s, 2H), 6.47 (dd, 2H), 7.2-7.9 (m, 4H) , 8.12 (s, 1H)

Fig. Solvent

BMR data, δ m.d. (500 MHz)

Table 2, continued

CDCl ₃ 2.2 (s, 3H), 2.25 (s, 3H), 2.5 (m, 4H),

2.65 (m, 2H), 3.6 (m, 1H), 3.70 (s, 3H),

4.3 (m, 2H), 4.9-5.0 (dd, 2H), 6.42-6.58 (dd, 2H), 7.4 (t, 1H), 7.45 (t, 1H), 7.65 (d, 1H), 7.85 (d, 1H), 8.1 (s, 1H)

14th CDC1 ₃ 2.25 (s, 3H), 2.33 (s, 3H), 2.75 (s, 3H), 3.77 (s, 3H), 5.02 (dd, 2H), 6.51 (dd, 2H), 7.43 (dm, 2H) , 7.73 (dm, 2H), 8.10 (s, 1H) 15th cdci ₃ 1.8-2 .05 (m, 5H), 2.2 (S, 3H), 2.25

(s, 3H), 2.75 (s, 3H), 2.8 (d, 2H), 3.5 (d, 2H), 3.7 (s, 3H), 4.0-4.1 (m, 2H), 5.0 (dd, 2H), 6.4-6.6 (dd, 2H), 7.4 (t, 1H),

7.45 (t, 1H), 7.65 (d, 1H), 7.8 (d, 1H), 8.15 (S, 1H) 16th CDC1 ₃ 1.85 (t, 2H), 2.25 (s, 3H), 2.28 (s, 3H), 2.50 (t, 2H), 2.60 (s, 3H), 2.75 (m, 4H), 2.90 (m, 4H), 3.75 (S, 3H), 4.25 (m, 2H), 4.95 (dd, 2H), , 6.5 (dd ., 2H) , ΊΛ (t, 1H), 7.45 (t, 1H), 7.65 (d, 1H), 7.85 (d, 1H), 8.1 (s, 1H)

CDCl3

1.8 (t, 2H), 2.2 (s, 3H), 2.24 (s, 3H), 2.58 (m, 2H>, 2.75 (m, 4H), 3.5 (s, 6H), 3.6 (m, 4H), 3.75 (s, 3H), 4.26 (m, 2H), 4.74 (dd, 2H) , 6.51 (dd, 2H), 7 • 4 (t, 1H), 7.45 (t, 1H), 7.68 (d, 1H), 7.8 Δ (d, 1H),

D ₂ O

8.1 (s, 1H) 2.0 (s, 3H), 2.2 (s, 3H), 3.5 (s, 3H), 3.95 (s, 3H), 4.85-4.9 (m, 1H) , 5.0-5.05 (m, 1H), 5.65-5.7 (m, 1H) , 5.75-5.8 (m, 1H), 7.05 (dd , 1H), 7.35 (d, 1H), 7.65 (d, 1H) , 8.1 (s, 1H)

Table 2, continued

Fig. Solvent NMR data, δ m.d. (500 MHz)

D ₂ O 1.97 (s, 3H), 2.16 (s, 3H), 3.47 (s, 3H),

3.87 (s, 3H), 4.81-4.88 (m, 1H), 4.97-5.02 (m, 1H), 5.61-5.67 (m, 1H), 5.70-5.75 (m, 1H), 7.14 (dd, 1H), 7.26 (d, 1H), 7.78

(d, 1H), 8.09 (S, 1H) 33 D ₂ O 0.85 (t, 3H), 1.96 (s, 3H), 2.16 (s, 3H), 3.43 (s, 3H), 3.39-3.59 (m, 2H), 3.87 (s, 3H), 4.78-4.90 (m, 1H), 4.97-5.05 (m, 1H), 5.64-5.75 (m, 2H), 7.06 (dd, 1H), 7.22 (d, 1H) 7.67 (dd, 1H), 8.10 (s, 1H) 34 CDC1 ₃ 2.21 (s, 3H) 2.26 (s, 3H) 2.29 (s, 3H), 2.32 (t, 2H), 2.36 (t, 2H) 2.63 (t, 2H) 2.69 (t, 2H), 3.45 (t, 2H), 3.57 (t, 2H), 3.70 (s, 3H), 3.85 (s, 3H), 4.93 (s, 2H), 6.38 (d, 1H), 6.46 (d, 1H), 7.05 (dd, 1H), 7.24 (d, 1H) 7.51 (d, 1H), 8.12 (s, 1H) 35 COC1 ₃ 2.21 (s, 3H), 2.26 (s, 3H), 2.29 (s, 3H), 2.32 (t, 2H), 2.36 (t, 2H) 2.63 (t, 2H), 2.69 (t, 2H), 3.45 (t, 2H) 3.57 (t, 2H), 3.70 (s, 3H), 3.90 (s, 3H), 4.93 (s, 2H) 6.39 (d, 1H) 6.48 (d, 1H), 6.97 (dd, 1H), 7.08 (d, 1H), 7.66 (d, 1H), 8.12 (s, 1H) 36 D ₂ O 2.12 (s, 3H), 4.63-4.73 (m, 2H), 5.02 (d, 1H) * 5.13 (d, 1H) * 5.80-5.86 (m, 1H), 5.87-5.97 (m, 1H), 7.00 (d, 1H) 7.52

(t, 1H), 7.60 (t, 1H), 7.83 (d, 1H) 7.99 (d, 1H), 8.23 (d, 1H)

Table 2, continued

Fig. Solvent NMR data, δ m.d. (500 MHz)

D ₂ O 1.85 (s, 3H), 2.16 (s, 3H), 2.39 (s, 3H),

2.47 (s, 3H) 3.52 (s, 3H), 3.86-3.91 (m, 2H), 4.05-4.10 (m, 2H) 4.72 (d, 1H) *,

4.80 (d, 1H) *, 5.75 (dd, 1H), 5.90 (dd, 1H), 6.73 (s, 1H), 7.56 (s, 1H), 8.09 (s, 1H)

39l D ₂ O 1.12 (s, 6H), 1.24-2.00 (m, 20H), 1.99 40J (s, 6H), 2.56 (q, 4H), 2.66-2.80 (m, 2H), 4.81-5.99 (m, 4H) * 5.68 (dd, 1H), 5.76 (dd, 1H), 5.82 (dd, 1H), 5.91 (dd, 1H), 6.76 (s, 1H), 6.77 (s, 1H), 7.38 (d, 1H), 7.49 (d, 1H), 7.55 (s, 1H), 7.65 (d, 1H), 7.69 (s, 1H), 7.76 (d, 1H), 8.12 (s, 1H), 8.14 (S, 1H) 41 d ₂ o 2.15 (s, 3H), 2.25 (s, 3H), 2.73 (s, 3H), 4.01 (s, 3H), 5.03 (d, 1H) *, 5.10 (d, 1H) *, 5.79 (dd, 1H), 5.87 (dd, 1H), 7.21 (d, 1H), 7.80 (S, 1H), 8.09 (S, 1H), 8.29 (s, 1H) 42 d ₂ o 2.15 (s, 3H), 2.25 (s, 3H), 2.67 (s, 3H), 4.03 (s, 3H), 5.02 (d, 1H) *, 5.09 (d, 1H) *, 5.79 (dd, 1H), 5.88 (dd, 1H), 7.69 (s, 1H), 7.72 (d, 1H), 8.13 (d, 1H), 8.38 (s, 1H)

⁴³ l D ₂ O 1.31 (d, 6H), 1.33 (d, 6H), 2.19 (s, 6H), 4 4 ^ 2.25 (s, 6H), 3.11 (m, 1H), 3.13 (m, 1H), 4.91 (D ₂ H) *, 5.03 (d, 2H) *, 5.76- -5.82 (m, 2H), 5.82 -5.99 (m, 2H), 7.36 (d, 2H), 7.42 (dd, 1H) , 7.52 (dd, 1H) , 7.6 8 (d, 1H), 7.72 (d, 1H), 7.75 (d, 1H), 7.79 (d, 1H), 8.07 (d, 1H0, 08.08 (d, 1H)

Table 2, continued

Fig. Solvent NMR data , δ m.d. (500 MHz) 45 D ₂ O 2.15 (s, 3H), 2.18 (s, 3H), 3.67 (s, 3Η), 4.67 (d, 1H), 5.01 (d, 1H), 6.05 (t, 1H), 6.16 (t, 1H), 7.10 (d, 2H), 7.28 (t, 1H), 7.33 (t, 1H), 7.69 (d, 1H), 7.73 (d, 1H), 7.95 (d, 2H), 8.16 (S, 1H) 46th d ₂ o 1.95 (s, 3H), 2.11 (s, 3H), 3.45 (s, 3H), 3.79 (s, 3H), 4.48- 4.49 (m, 2H), 4.65 (d, 1H) *, 4.88 1 (d, 1H) *, 5.72 {vol , 1H), 5.80 (t, 1H), 6.81 (d, 2H), 6.97 (d, 1H), 7.09- 7.21 (m, 4H), 7.57 (d, 1H), 8.06 (S, 1H) 47 d ₂ o 0.87 (d, 3H), 0.88 (d, 3H), 1.47 -1.57

(m, 2H), 2.21 (s (m, 1H), (d, 1H) * (m, 1H), (d, 1H),

1.59-1.70 (m, 1H), 1.91 (s, 3H), 3H), 3.20-3.27 (m, 1H), 3.40-3.47

3.95 (s, 3H), 4.90 (d, 1H) *, 5.10

5.55-5.62 (m, 1H), 5.65-5.72

7.20 (dd, 1H), 7.33 (d, 1H), 7.73

8.25 (s, 1H)

D ₂ O 0.87 (d, 3H), 0.88 (d, 3H), 1.47-1.57 (m, 2H), 1.59-1.70 (m, 1H), 1.90 (s, 3H), 2.22 (s, 3H), 3.20 -3.27 (m, 1H), 3.40-3.47 (m, 1H), 3.97 (s, 3H), 4.90 (d, 1H) *, 5.09 (d. 1H) *, 5.55-5.62 (m, 1H), 5.65 -5.72 (m, 1H), 7.13 (dd, 1H), 7.39 (d, 1H), 7.73 (d, 1H), 8.25 (s, 1H)

49] D ₂ O 2 _X 00 (s, 3H), 2.02 (s, 3H), 2.18 (s, 6H),

50j 3.46 (s, 6H), 5.0 (s,) *, 5.75-5.82 (m, 2H), 5.88 (dd, 2H), 7.39-7.61 (m, 7H),

7.65-7.92 (m, 7H), 7.98 (s, 1H), 8.07 (s, 1H), 8.14 (s, 1H), 8.15 (s, 1H)

Table 2, continued

Fig. Solvent BMR data, δ m.d. (500 MHz) 51 D ₂ O 1.98 (s, 3H), 2.24 (s, 3H), 3.51 (s, 3H), 3.98 (s, 3H), 4.00 (s, 3H), 5.1 (s) *, 5.89-5.93 (m, 2H), 6.88 (d, 1H), 6.96 (d, 1H), 8.18 (s, 1H) 52 to 53j d ₂ o 2.02 (s, 6H), 2.23 (s, 6H), 4.00-4.07 (m, 2H), 4.11-4.17 (m, 2H), 4.93 (d, 2H) *, 5.08 (d, 2H) *, 5.33 (dd, 4H), 5.66-5.75 (m, 2H), 5.76-5.87 (m, 2H), 5.95-6.05

(m, 2H), (d, 1H), (d, 1H), 7.61 7.78 8.18 (dd, 1H), 7.67 (dd, 1H), 7.70 (d, 1H), (s, 2H) 8.00 (d, 1H), 8.10 0.85 (t, 3H), 1 • 99 (s, 3H) , 3.42-3.58 (m, 2H), 5.0 (s) *, 5. 78 (dd, 1H), 5. 82 (dd, 1H) , 6.92 (d, 1H) , 7 .45 (t, 1H), 7.53 (t, 1H), (d, 1H) 7.72 (d, 1H), 7th 80 (d, 1H), 8.16

55j D ₂ O 56J

0.95 (t, 6H), 2.10 (s, 6H), 2.20 (s, 6H), 3.50-3.72 (m, 4H), 4.00-4.10 (m, 2H),

4.10-4.20 (m, 2H), 5.10 (s) *, 5.37 (d, d, 4H), 5.66-5.75 (m, 2H), 5.76-5.87 (m, 2H), 5.95-6.05 (m, 2H) , 7.60-7.90 (m, 4H), 8.07 (d, 1H), 8.13 (d, 1H), 8.18 (s, 2H)

1.01 (d, 6H), 1.02 3.93 (s, 3H), 4.20

5.65-5.73 (m, 2H),

6.67-7.13 (m, 7H), (d, 2H) (d, 6H), 3 (m, 2H), δ 5.80-5.88 7.23-7.56 (s, 3H), (s) *, (m, 2H), (m, 3H), 8.23

Table 2, continued

Fig. Solvent BMR data, δ m.d. (500 MHz) 59 D ₂ O 0.88 (t, 3H), 1.76 (s, 3H), 2.06 (s, 3H), 2.35 (s, 3H), 2.37 (s, 3H), 3.46 (s, 3H), 3.49-3.60 (m, 2H), 3.79-3.80 (m, 2H), 3.94-3.96 (m, 2H), 4.62 (d, 1H), 4.82 (d, 1H), 5.65 (dd 1H), 5.78 (dd 1H), 6.60 (S, 1H), 7.32 (S, 1H), 8.03 (s, 1H) 611 D ₂ O 62j 0.95 (t, 6H), 2.07 (s, 6H), 2.25 (s, 6H), 3.48 (s, 3H), 3.51 (s, 3H), 3.45-3.58 (m, 2H), 3.58-3.71 (m, 2H), 5.2 (s) *, 5.76-5.93 (m, 4H), 7.50-7.70 (m, 6H), 7.79-7.93 (m, 7H), 7.97 (d, 1H), 8.04 (S, 1H), 8.13 (S, 1H), 8.22 (s, 2H) 63 d ₂ o 0.78 (d, 3H), 0.80 (d, 3H), 1.40 (t, 2H), 1.55 (m, 1H), 1.79 (s, 3H), 2.10 (s, 3H), 3.15 (d, 3H), 3.85 (s, 1H), 5.0 (s) *, 5.55 (dd, 1H), 5.62 (dd, 1H), 7.10 (dd, 1H), 7.28 (d, 1H), 7.54 (d, 1H), 8.15 (s, 1H) 64 d ₂ o 0.78 (d, 3H), 0.80 (d, 3H), 1.40 (t, 2H), 1.55 (m, 1H), 1.79 (s, 3H), 2.10 (s, 3H), 3.15 (d, 3H), 3.85 (s, 1H), 5.0 (s) *, 5.55 (dd, 1H), 5.62 (dd, 1H), 7.02 (dd, 1H), 7.17 (d, 1H), 7.64 (d, 1H), 8.15 (s, 1H) 65 d ₂ o 1.91 (s, 3H), 2.14 (s, 3H), 3.30 (s, 3H), 3.44-3.62 (m, 4H), 3.88 (s, 3H), 4.82 (d, 1H) *, 5.01 (d, 1H) *, 5.56-5.66 (m, 1H), 5.66-5.75 (m, 1H), 7.13 (dd, 1H), 7.24 (d, 1H), 7.66 (d, 1H), 8.12 (s, 1H)

Table 2, continued

Fig. Solvent BMR data, δ m.d. (500 MHz) 66 D ₂ O 1.91 (s, 3H), 2.14 (s, 3H), 3.30 (s, 3H), 3.44-3.62 (m, 4H), 3.90 (s, 3H), 4.82 (d, 1H) *, 5.01 (d, 1H) *, 5.56-5.66 (m, 1H), 5.66-5.75 (m, 1H), 7.03 (dd, 1H), 7.31 (d, 1H), 7.62 (d, 1H), 8.12 (s, 1H) 67 d ₂ o 1.36 (s, 3H), 1.40 (s, 3H), 1.44 (s, 3H), 1.94 (s, 3H), 3.78 (s, 3H), 5.0 (s) *, 5. 5.85 (dd, 1H), 6.88 (d, 1H) 7.80 (S, 1H), 8.17 (d, 1H) 1.42 (s, 3H), 3.18 (d, 3H), 82 (dd, 1H), , 7.78 (s, 1H), 68 d ₂ o 1.38 (s, 3H), 1.41 (s, 3H), 1.44 (s, 3H), 1.97 (s, 3H), 5.0 (s) *, 5.75 (dd, 1H), 5 6.88 (d, 1H), 7.73 (s, 1H), 8.13 (S, 1H) 1.43 (S, 3H), 3.79 (s, 3H), .84 (dd, 1H), 7.86 (s, 1H), 69 d ₂ o 1.98 (s, 3H), 2.19 (s, 3H), 3.38 (s, 3H), 3.47 (s, 3H), (m, 2H), 5.04 (s) *, 5.69-5 7.44 (d, 1H), 7.65 (S, 1H), 8.14 (S, 1H) 2.97 (m, 2H), 3.76-3.83 .80 (m, 2H), 7.76 (d, 1H), 70 d ₂ o 1.98 (s, 3H), 2.19 (s, 3H), 3.38 (s, 3H), 3.45 (s, 3H), (m, 2H), 5.04 (s) *, 5.69-5 7.36 (d, 1H), 7.70 (s, 1H), 8.14 (S, 1H) 3.07 (m, 2H), 3.76-3.87 .80 (m, 2H), 7.72 (d, 1H), 71 d ₂ o 1.26 (d, 6H), 2.10 (s, 3H), 3.03 (m, 1H), 3.20 (d, 3H), 5.01 (d, 1H) *, 5.74-5.84 (s, 1H), 7.45 (d, 1H), 7.65 (S, 1H), 8.05 (S, 1H) 2.18 (s, 3H), 4.85 (d, 1H) *, (m, 2H), 7.26 (d, 1H), 7.68

Table 2, continued

Fig. Solvent NMR data, δ m.d. (500 MHz)

1.28 (d, 6H), 2.10 (s, 3H), 2.18 (s, 3H), 3.07 (m, 1H), 3.20 (d, 3H), 4.85 (d, 1H) * 5.01 (d, 1H) *, 5.74-5.84 {m ., 2H), 7.26 (S, 1H), 7.36 (d, 1H), 7.62 (S, 1H), 7.72 (d, 1H), 8.05 (s, 1H)

73 D ₂ O 0.88 (t, 3H), 3.30 (s, 3H), (s, 3H), 5.00 7.10 (d, 1H), 8.12 (s, 1H) 1.91 (s, 3H), 2.13 (s, 3H), 3.46-3.57 (m, 2H), 3.86 (d) *, 7.27 5.64-5.75 (m, 2H), (s, 1H), 7.56 (d, 1H), 74 d ₂ o 0.88 (t, 3H), 1.90 (s, 3H), 2.13 (s, 3H), 3.30 (s, 3H), 3.46- 3.57 (m, 2H), 3.87 (s, 3H), 5.00 (d) *, 5.64-5.75 (m , 2H), 7.03 (d, 1H), 7.18 (S, 1H), 7.63 (d, 1H), 8.12 (S, 1H) -i 75 | d ₂ o 0.93 (t, 6H), 2.05 (s, 6H), 2.26 (s, 6H), 7 of 6 3.13 (t, 2H), 3.14 (t, 2H), 3.44 (s, 6H), 3.47 (s, 3H), 3.49 (s, 3H), 3.47- 3.69 (m, 4H), 3.86 (t, 4H), 5.13 (d) *, 5.74- 5.85 (m, 4H), 7.46 (d, 1H), 7.51 (d, 1H), 7.66 (s, 1H), 7.73 (d, 1H), 7.77 (s, 1H), 7.84 (d, 1H), 8.22 (s, 2H) 82 d ₂ o 2.11 (s, 3H), 2.19 (s, 3H), 3.65 (s, 3H), 4.51 (s, 2H), 5.80 (d, 2H), 7.37 (t, 1H), 7.42 (t, 1H), 7.67 (d, 1H), 7.73 (d, 1H), 8.07 (s, 1H) 83 d ₂ o 0.90 (t, 3H), 2.03 (s, 3H), 2.14 (s, 3H), 3.56 (q, 2H), 3.59 (s, 3H), 4.43 (s, 2H), 5.71 (d, 1H), 7.27- 7.38 (m, 2H), 7.53 (d, 1H), 7.63 (d, 1H), 8.02 (S, 1H)

Table 2, continued

Fig. Solvent

BMR data, δ m.d. (500 MHz)

84 D ₂ O 1.93 (s, 3H), 2.11 (s, 3H), 3.03 (t, 2H), 3.23 (d, 3H), 3.36 (s, 3H), 4.24 (t, 2H), 4.86 (d, 1H) *, 5.06 (d, 1H) * , 5. 65-5.75 (m, 1H), 5.75-5.87 (m, 1H), 7.04 (d, 1H),

7.24 (S, 1H), 7.27-7.48 (m, 5H), 7.57 (d, 1H), 8.12 (S, 1H)

85 D ₂ O 1.95 (s, 3H), 2.13 (s, 3H), 3.09 (t, 2H), 3.23 (d, 3H), 3.28 (s, 3H), 4.34 (m, 2H), 4.86 (d, 1H) *, 5.06 (d, 1H) *, 5. 65-5.75 (m, 1H), 5.75-5.87 (m, 1H), 6.97 (d, 1H), 7.20 (s, 1H), 7.27- 7.48 (m, 5H), 7.65

(d, 1H), 8.14 (S, 1H)

6j D ₂ O 87f

2.09 (s, 3H), 2.23 (s, 3H), 3 4.97 (d, 1H) *, 5.09 (d, 1H) *, (m, 1H), 5.90-6.03 (m, 1H), 7 (s, 3H), 5.78-5.90 57-7.94

(m, 5H), 7.99 (s, 2H), 8.13 (s, 1H), 8.17 (S, 1H) 88] D ₂ O 0.93 (t, 6H), 2.34 (q, 4H), 3.68 (s , 3H), 89? 3.72 (s, 3H), 4.65 (s, 4H), 5.1 (s) ★ f 5.50-5.84 (m, 4H), 6.35 (s, 2H), 6. 58-7.52 (m, 16H), 8.02 (s, 2H) 90 d ₂ o 1.76 (t, 2H), 2.01 (s, 3H), 2.11 (i.e. , 2H), 2.42 (m, 4H), 2.53 (s, 3H), 2.65-3. 83 (m, 4H), 3.12 (t, 2H), 3.46 (S, 3H), 3.87 (s, 3H), 4.81 (d, 1H) *, 5.02 (d, 1H) *, 5.95 (d, 1H), 6.15 (d, 1H), 7.05 (d, 1H), 7.17 (S, 1H), 7.87 (d, 1H), 8.07 (s, 1H)

Table 2, continued

Fig. Solvent BMR data, δ m.d. (500 MHz) 165 D ₂ O 2.0 (s, 3H), 2.2 (s, 3H), 3.5 (s, 3H), 3.9 (s, 3H), 5.9 (d, 1H), 6.0 (d, 1H), 7.1 (dd, 1H), 7.3 (d, 1H), 7.7 (d, 1H), 8.2 (s, 1H).

* Protons change by holding compounds D ₂ O.

Intermediates I 1-1 39 used to obtain the described examples are shown in Table 3.

M-l • H Φ 4-J -ΓΊ G -H φ u T5 03 M oo

Oh r · no

oh oh Oops Oops oh S 2 2 2 2 (L CO 0Ί 00 00

co ro co

o X u X o co m (N CM ΓΜ X rt X X X o U o u υ

ro k-4

O

CM

K

Oh o

co co u o co χ:

o co ni x o o o

Table 3, Intermediates oi w

Ξ * ί

Ό

N>

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X X u X X X X o o o o o o ω w co co to to

r-1 CM m LO kO M l-l M l-l 1— f l-l

cn c

cn φ ·

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Φ

P

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IdentifiU <Ū λ:

oo oi rOi

KO oh oh ro oh

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X X X X X X X X X X s s s s s 2 s 2 2 2 X X X X X X X X X X

to x

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u

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o

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X X o u X X υ u CM CM X X o o

X o o CO X o CO X o X X X u o X o o X o o X o o X o o CO CO CO ro ro ro ro ro c X X X X X X X X X X u o o u u u u u o X X X X X X X X X X

CM

m □ C f) X m o u m X to CM X o X O X o o u o X u X X X o

ro

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X X X X X X K X X X o o o o o o o o o ω ω to to ω co LT) w co CO

O r— ( CN CO Lfj Γ 00 σι i-1 i-1 r-1 T-1 c-1 i-1 t-1 HH M M 1-1 HH M 1 — i M 1-1 M

I

Φ u Ό cū l-l Oh

Ci

X X X X X X X X X X X X X 2 2 2 2 2 2 2 2 2 2 2 2 2 m m m m m m m m X X X X X

(N Csi

m X o o ro X o o X u II X u CM X u o X o II X u CM X u o ro X u o ro X o o CM ro X υ X u o CM ro X υ X o o co X u o ro X u o CO X u o ΓΟ X u o ΓΟ X u o ro X ro X ro X ro X ro X Γ0 X cn X ro X ro X u o ro X u u o u X X X X u u u X O o X X X X X X X X X X X

ro

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X CM Cx- « U X u o u co ro m o CM X X [X4 u u U X o X o X o X u

m m re 3 = <-} <_> \ /

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X CM fru O X o o u co X ΓΟ X o CM o u X o X o X u

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X o X X X X X X X X X X X o o o o o o o o o o O O O ω ω ω ω ω ω ω ω ω ω ω ω co

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r- 00 O v-1 CN 00 'ST LO kO r ^ CO CFi r-1 T - t ? —1 CN CN CN CN CN C \] CN CN CN CN M HH HH HH HH M t-l t-H HH t-1 HH HH HH

M

3 * Ί

C

H m

Of

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U-l • H (Ū -P -rl c -h φ υ Ό <0 M 32 cū n03 cn

Cl

M> 1 ra

N> 1>

ra

03 03 03 03 o3 03 03 03 o3 03 S s 2 2 2 2 2 2 2 2 m ra ra m m m ra m m ra

ŪC u u u u

03

U o m OC

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CJ CJ ra ra o u ra ra o u π

u rara cn m

CQ m

cn cn cn m

ra ra ra ra ra ra ra ra ra ra u o o o u o o u u o o o o o o o o o o o cn m cn cn cn cn cn m ra ra ra ra ra ra ra ra u u o o o o o u ra ra ra ra ra ra ra ra ra ra ra ra

cn

ra u o Cl ra u m CJ ra ra u o ra o

cn

ra o o CJ ra o cn Cl ra ra u u ra o

ra

CM

CP

O

cj ra o

cj ra u

oh ra ra ra

CJ fcl o

CJ [ij u

o o

U i ra ra

CJ ra o

Cl ra u

o ra

ra ra ra ra ra ra ra ra ra ra o o o o o o o o o o ω ω ω ω co ω co co CO CO

O i-1 CN m LT) Γ- co σι cn CO cn cn cn oo cn ΓΟ cn cn F-1 1-1 M I - Vol 1-1 H M M 1-1 l-l

The identity of the compounds described in Examples I-1 to 39 is shown in Table 4.

Table 4. NMR spectral data

Fig. Solvent NMR data, δ m.d. (500 MHz)

I 1 CDCl ₃

I 2 CDCl 3

I 4] CDC1 ₃ ¹⁵ f

I 6 CDC1 ₃

2.27 (S, 3H), 4.38 (d, 1H), 4.41 (d, 1H), 4.94 (d, 1H), 5.03 (d, 1H), 6.24 (d, 1H), 6.60 (d, 1H), 6.66 (d, 1H), 7.41 (t, 1H), 7.47 (t, 1H), 7.57 (d, 1H), 7.82 (d, 1H), 8.30am (d, 1H) 2.19 (s, 3H), 2.23 (s, 3H), 2.48 (s, 3H), 2.57 (s, 3H), 3.50 ¹ (s, 3H), 3. 76-3.78 (m, 2H), 3.97- 3.99 (m, 2H), 4.75 (d, 1H), 4.81 (d, 1H), 6.10 (d, 1H), 6.45 (d, 1H), 7.05 (S, 1H), ' 7.16 (s, 1H), 8.29 (s, 3H) 1.20 (t, 3H), 1.25- -1.95 (m, HH) , 2.21 (s, 3H), 2.60 -2.64 (m, 2H), 4. 75-4.83 (m, 2H), 6.14 -6.18 (m, 1H), 6. 44-6.49 (m, 1H), 7.03 1 (d, 1H), 7.18 (m, 1H), 7.26- • 7.45 (m u 1H), 7.65-7.73 (m, 1H), 8.31 (s, 1H) 1.18 (t, 3H), 2.61 (q, 2H), 3.85 (S, 3H), 4.78- 4.82 (m , 4H), 6.10 (d, 1H) , 6.39 (d, 1H), 6.62 (s, 1H! 1, 6.94 (d, 1H), 7.12 (dd 1H), 7.32-7 .43 (m, 5H), 7.43 (d, 1H), 8.24 (s, 1H) 1.18 (t, 3H), 2.61 (q, 2H), 3.86 (s, 3H),

4.78-4.82 (m, 4H), 6.09 (d, 1H), 6.60 (S, 1H), 6.94 (dd, 1H), 7.32-7.43 (m, 5H),

8.24 (S, 1H) (d, 1H) 6.41 (d, 1H), 7.03 7.71 (d, 1H)

I 7 CDC1 ₃

Table 4, continued

Fig. Solvent NMR data, δ m.d. (500 MHz)

I got 10,

I nJ

I 12

I 13th

CDC1 ₃ 2.29 (s, 6H), 2.78 (s, 3H), 3.93 (s, 3H), 4.97-5.05 (m, 2H), 6.19 (d, 1H), 6.50 (s, 1H), 8.18 (d, 1H), 7.00 (d, 1H), 8.41 (d, 1H), 7.39 (S, 1H) cdci ₃ 2.29 (s, 6H), 2.72 (s, 3H), 3.96 (s, 3H), 4.97-5.05 (m , 2H), 6.21 (d, 1H) , 6.51 (d, 1H), 7.00 (d, 1H), 7.65 (S, 1H), 8.16 (S, 1H), 8.18 (d, 1H) CDC1 ₃ 1.32 (d, 6H) 1.34 (d, 6H), 2.27 (s, 6H), 2.34 (S, 6H), 3.08 (m, 1H), 3.09 (m, 1H), 4.86 (d, 1H), 4.87 (d, 1H), 4.96 (d, 1H), 4.97 (d, 1H), 6.19 (d, 1H), 6.21 (d, 1H), 6.54 (d, 1H), 6.58 (d, 1H), 7. 28-7.74 (m, 8H), 8.20 (s, 2H) CDCl3 2.22 (s, 3H), 2.25 (s, 3H), 3.71 (S, 3H), 4.91 (d, 1H), 4.97 (d, 1H), 6.22 (d, 1H), 6.59 (d, 1H), 7.40 (t, 1H), 7.46 (t, 1H), 7.56 (d, 1H), 7.82 (d, 1H), 8.17 (S, 1H) CDCl3 2.26 (s, 3H), 2.36 (s, 3H), 3.79 (s, 3H), 4.83 (s, 2H), 5.94 (s, 2H), 7. 28-7.30 (m, 2H), 7.39 (dd, 1H), 7 .70 (dd, 1H), 8.23 (s, 1H) CDCl3 0.97 (d, 6H): L.65-1.69 (m, , 2H), 1.81 - 1.84 (m, 1H), 2.23 (s, 3H), 2.24 (s, 3H), 3.75-3.79 (m , 2H), 3.86 (s, 3H) , 4.90 (d, 1H), 4.95 (d, 1H), 6.17 (d, 1H), 6.51 (d, 1H), 6.95 (d, 1H), 7 .10 (dd, 1H), 7.43 (d, 1H), 8.16 (s, 1H)

I 14th

Table 4, continued

Fig. Solvent NMR data, δ m.d. (500 MHz)

I

I

I

I

I

I

I

15th CDC1 ₃ 0.97 (d, 6H), 1.65 -1.69 1 (m, 2H), 1.81- 1.84 (m, 1H), 2.23 (s, 3H), 2.24 (s, 3H), 3.75- -3.79 (m , 2H), 3.91 (s, 3H) , 4.88 (d, 11 H), 4.96 (d, 1H) ), 6.17 (d, 1H ), 6.54 (d, 11 3), 6.95 (d, 1H), 7 .01 ( dd, 1H), 7.68 (d, 1H), 8.16 (S, 1H) ¹⁶ 1 CDC1 ₃ 2.23 (s, 6H), 2.27 (s, 3H), 2.28 (s, 3H), 3.73 (s, 6H) 4.95 -4.97 (m, 4H) , 6.26 (d, ii H), 6.27 (d, 1H) ), 6.60 (d, 1H ), 6.63 (d, 11 H), 7.38-7.7 1 (m, , 14H), 7.87 (d, 11 H), 8.02 (S, 1H) ), 8.18 (s, 2H ) 18th cdci ₃ 2.24 (s, 3H), 2.27 (s, 3H), 3.73 (s, 3H), 3.97 (s, 6H), 4.90 (d, 1H), 5.05 (d, 1H), 6.58 (d, 1H), 6.65 (d, 1H), 6.76 (d, 1H), 6.83 (d, 1H), 8.21 (S, 1H) ¹⁹ l cdci ₃ 2.22 (s, 6H), 2.25 (s, 6H), 4.31 (d, 4H), 20j 4.91 (d, 2H), 4.95 (d, 2H), 5.28 (d, 2H), 5.39 (d 2H), 6.03 (m, 2H), 6.15 (d, 1H), -6.18 (d, 1H), 6.48 (d, 1H), 6.50 (d, 1H), 7.50 (d, 1H), 7.53 (d, 1H), 7.56 (d, 1H), 7.67 (d, 1H), 7.72 (s, 1H), 7.95 (s, 1H), 8.14 (s, 2H) 21st CDCl3 2.23 (s, 3H), 2.26 (s, 3H), 3.72 (s, 3H), 3.87 (s, 3H), 4.89 (d, 1H), 4.95 (d, 1H), 6.18 (d, 1H) , 6 .54 ( d, 1H), 7.19 (dd, 1H), 7.2 : 6 (d , 1H), 7.43 (d, 1H), 8.17 (d, 1H)

Table 4, continued

Fig. Solvent NMR data, δ m.d. (500 MHz)

I 22

CDC1 ₃

I 23

CDC1 ₃

I 24

CDC1 ₃

2.23 (s, 3H), 2.25 (s, 3H) , 3.72 (s, 3H), 3.92 (s, 3H), 4.88 (d, 1H) , 4.96 (d, 1H), 6.17 (d, 1H), 6.57 (d, 1H) , 6.95 (d, 1H), 7.01 (dd, 1H), 7.67 (d, 1H) ), 8.17 (S, 1H) 1.25 (d, 6H), 3.87 (s, 3H) , 4.44 (m, 1H), 4.82 (dd, 2H), 6.13 (d, 1H), 6.41 (d, 1H), 6.71 (d + s , 2H), 7.12 (dd 1H), 7.26 (d, 1H), 7.42 (d, 1H) , 8.35 (d, 1H) 1.25 (d, 6H), 3.92 (s, 3H) , 4.44 (m, 1H), 4.82 (dd, 2H), 6.13 (d, 1H), 6.43 (d, 1H), 6.71 (d + s, 2H), 6.94 (d, 1H),

7.02 (dd, 1H),

7.69 (d, 1H), 8.35 (d, 1H)

I 25 I 26j '

CDCl3 3.81 (s, 6H), 4.84 (dd, 4H), 5.97 (m, 2H), 6.16 (d, 1H), 6.18 (d, 1H), 6.39 (d, 1H), 6.41 (d, 1H) 6.77 (d + s, 4H),

7 '. 30 (dd, 1H), 7.34 (dd, 1H), 7.42 (d, 1H), 7.54 (d, 1H), 7.69 (d, 1H), 7.81 (d, 1H), 8.36 (d, 2H) i ] I 28 |

CDC1 ₃

11th (s, 6H), 2.22 (s, 6H), 3.85 (s, 6H) 99 (m, 4H), 5.24 (d, 2H), 5.27 (d, 2H) 44 (d, 2H), 6.50 (d, 1H), 6.51 (d, 1H) 68 (d, 2H), 7.36 (d, 1H), 7.42 (d, 1H) 62 (s, 2H), 7.79 (d, 2H), 8.20 (d, 2H) 40 (s, 3H), 1.41 (s, 3H), 1.44 (s, 3H) 45 (s, 3H), 2.50 (s, 3H), 3.88 (s, 3H) 95 (d, 1H), 5.00 (d, 1H), 6.28 (d, 1H) 60 (d, 1H), 6.74 (d, 1H), 7.43 (S, 1H) 70 (s, 1H), 8.29 (d, 1H)

I 29 CDCl ₃

Table 4, continued

Fig. Solvent NMR data, δ m.d. (500 MHz)

I 30, I 31!

CDC1 ₃

I 32

CDCl3

2.22 (s , 6H), 2.25 (s, 6H) , 3.01-3.07 (m, 4H), 3.36 3.37 (s, 3H) , 3.64-3.71 (m, 4H), 3.71 (s, 6H), 4.89 (d, 2H), 4.95 (d, 2H), 6.20 (d, 2H), 6.56 (d, 1H), 6.58 (d, 1H), 7.28 (d, 1H), 7.35 (d, 1H), 7.41 (S, 1H), 7.47 (d, 1H), 7.67 (S, 1H), 7.72 (d, 1H), 8.17 (s, 2H) 2.26 (s, 3H), 2.28 (s , 3H), 3.42 (s, 3H),

I 33

CDCl3

I 34

CDCl3

I 35

CDCl3

3.66-3.69 (m, 2H), 3.82 (s, 3H), 3.85-

3.93 (m, 2H), 4. (7-4.96 (m, 2H), 6.17 (d, 1H), 6.49 (d, 1H), 7 .08 (dd, 1H), 7.25 (d, 1H), 7.42 (d, 1H), 8.16 (S, 1H) 2.26 (s, 3H), 2.28 (S, 3H), 3.42 (s, 3H), 3.66- -3.69 (m, 2H), 3.89 1 (s, 3H), 3.85- 3.93 (m, 2H), 4.87-4.96 (m, 2H), 6.17 (.d, 1H), 6.52 (d, 1H), 6.98 (d, 1H), 7.00 (dd, 1H), 7.67 (d, 1H), 8.16 (S, 1H) 2.22 (s, 3H), 2.24 (s, 3H), 3.13 (t, 2H), 3.71 (s, 3H), 4.23 (t, 2H), 4.88 (d, 1H), 4.95 (d, 1H), 6.16 (d, 1H), 6.52 (d, 1H), 7.09 (dd, 1H) , 7.25 (d, H), 7.26-7.36 (m, 5H), 7.41 (d, 1H), 8.17 (s, 1H) 2.22 (s, 3H), 2.24 (s, 3H), 3.16 (t, 2H), 3.71 (s, 3H), 4.26 (t, 2H), 4.87 (d, 1H), 4.96 (d, 1H), 6.13 (d, 1H), 6.52 (d, 1H), 6.93 (d, 1H), 7.01 (dd, 1H), 7.26-7.36 (m, 5H), 7.66 (d, 1H), 8.17 (s, 1H)

Table 4, continued

Fig. Solvent NMR data, δ m.d. (500 MHz)

I 36i CDCl3 2.23 (s, 6H), 2.27 (s, 6H), 3.74 (s, 6H), I 37j 4.96-4.98 (m, 4H), 6.25 (d, 1H), 6.28 (d, 1H), 6. 55 (d, 1H), 6.57 (d, 1H), 7.48-7.87 (m, 15H), 8.03 (dd, 1H), 8.14

(S, 1H), 8.23 (S, 1H)

I 38] CDCl ₃ 3.74 (s, 6H), 4.84 (m, 4H), 5.86-6.08

39 (m, 2H), 6.16 (d, 1H), 6.18 (d, 1H), 6.39 (d, 1H), 6.41 (d, 1H), 6.77 (d + S, 4H),

7.29 (dd, 1H), 7.35 (dd, 1H), 7.42 (d, 1H), 7.55 (d, 1H), 7.69 (d, 1H), 7.82 (d, 1H), 8.36 (d, 2H)

Pharmaceutical formulations containing the jun5 derivative of the invention as active ingredient are illustrated by the following compositions.

Syrup

A syrup containing 1% (w / v) of the active ingredient was prepared from the following ingredients:

The compound described in Example 29 1.0 g

Sugar powder 30.0 g Saccharin 0.6 g Glycerin 5.0 g Flavoring 0.05 g Ethanol, 96% 5.0 g

Distilled water for dilution to 100 ml

The sugar and saccharin are dissolved in 60 ml of warm water. The solution is cooled and the active ingredient is added thereto, followed by a solution of glycerol and flavoring in ethanol. The mixture is diluted with water to a final volume of 100 ml.

Film-coated tablets

Film-coated tablets containing 20 mg of active ingredient 10 were prepared from the following ingredients:

The compound described in Example 1

Lactose

Methylcellulose

Crosslinked Polyvinylpyrrolidone Magnesium Stearate

Sodium carbonate

distilled water

200 g 700 g g 50 g 15 g g

as needed

II Acetate cellulose phthalate 200 g

Cetyl alcohol .15 g

Isopropanol 2000 g

Methylene chloride 2000 g

The compound obtained according to FIG. 5, mixed with lactose and granulated with an aqueous solution of methyl cellulose and sodium carbonate. The wet mass is squeezed through a mesh and the pellets are dried in the oven. The dried granules are mixed with polyvinylpyrrolidone and magnesium stearate. The dry mixture is compressed into tab20 sponge blocks (10,000 tablets) each containing 20 mg of active ingredient using a 6 mm diameter tablet press.

II Acetate cellulose phthalate and cetyl alcohol dissolved in isopropanol / methylene chloride are sprayed onto tablets I using an Accela Cota ^R Manesty device for coating. The tablets are 110 mg.

Solution for intravenous injection

Parenteral intravenous preparations containing 4 mg of active ingredient were prepared from the following ingredients:

The compound described in Figure 1 4 g

Sterilized water to a final volume of 1000 ml

The active compound is dissolved in water (total volume 1000 ml), filtered through a 0.22 nm filter and immediately dispensed into 10 ml sterile ampoules. The ampoules are sealed.

Pills

Tablets containing 30 mg of active compound were prepared from the following ingredients:

The compound described in fig. 33, p

Lactose

Methylcellulose

Crosslinked Polyvinyl Pyrrolidone (PVP-XL)

Disodium hydrogen phosphate

Magnesium stearate

Purified water

300 g 700 g g

g 2 g g

as needed

The active compound is mixed with lactose and a portion of PVP-XL, and granulated with a solution of methyl cellulose and disodium hydLT 3810 B phosphate. The wet mass is squeezed through a sieve and dried in a moving bed dryer. The magnesium stearate and the remainder of the PVP-XL are combined, and the mixture is compressed into 110 mg medium weight tablets, each containing 30 mg of the active compound.

Film-coated tablets

500 g of the tablets described above were coated with a film-coated roll. For this purpose, the following formulation was sprayed onto the tablets using a moving layer machine and Wurster coating technology.

Coating solution:

Acetate Cellulose Phthalate 40 g

Cetyl alcohol 2 g

Isopropanol 400 g

Dichloromethane 400 g

The final weight of the coated tablet is 117 mg.

Suppositories

The suppositories were prepared from the following ingredients using the fusing method. Each suppository contained 40 mg of the active compound.

The compound described in Figure 3, Table.1 4 g

Witepsol H-15 180 g

The active compound is mixed with Witepsol H-15 until homogenous at 41 ° C. Fused masses fill preformed suppository shapes up to a net weight of 1.84 g. When frozen, these forms are melted. Each suppository contains 40 mg of the active compound.

Syrup

Syrup containing 1% active ingredient was prepared from the following ingredients:

The compound described in fig. 33, below 1 1.0 g Sugar Powder 30.0 g Saccharin 0.6 g Flavoring 0.05 g Ethanol, 96% 5.0 g Purified water as needed up to 100 ml

The sugar and saccharin are dissolved in 60 ml of warm water. After cooling, the sugar solution is combined with the active compound and the flavoring, dissolved in ethanol. The mixture is diluted with water to a final volume of 100 ml.

Solution for intravenous or intramuscular injection

The compound described in fig. 29. Plate l 60 g

Water for injections 1000 ml

The active compound is dissolved in water to a final volume of 1000 ml. Filter the solution through a sterile 0.22 µm filter and aseptically pour into 1 ml sterile ampoules. The ampoules are sealed.

Composition for intravenous infusion

The sterile compound described in fig. 29, p. 1 60 mg

Sterile injection caps and stoppers

The sterile active compound (60 mg) is dissolved in 10 ml volume of injection buccal injection sealed with sterile rubber stoppers. The entire filling operation is performed under aseptic conditions in a sterile room using a vertical laminar current.

Immediately before use, the active compound, dissolved in 10 ml of sterile water, is transferred to 100 ml of normal physiological fluid for infusion (total volume about 110 ml). The solution is used for intravenous infusion over approximately 30 minutes.

Biological tests

In vivo inhibitory effect on canine gastric acid secretion

Test methodology

The test utilized dogs with chronic gastritis fistula who undergo surgical insertion of a catheter into the stomach and duodenal fistula used for direct administration of test compounds. 4 weeks after this operation, tests are performed once a week with each dog. 18 hours or more. before each test, food and water are removed.

Gastric acid secretion is induced for a constant 4 hours. infusion of histamine at individual doses (400600 nmol / kg h) resulting in approximately 90% of maximal gastric acid secretion. After 1 or. histamine accumulation test compounds or solvent are administered intravenously either intramuscularly (solvent = 0.5% saline) or rectally (solvent = 0.5% Methocel ^R , 90 HG 15000, Dow Chem. Corp.) via a catheter in the rectum. During the infusion of histamine, gastric juices excreted via LTT 3810 B are collected every 30 minutes. Samples are titrated to pH 7.0 with 0.1 M NaOH using an automatic titrator and the acid consumption calculated. Acid consumption over time intervals following administration of test compounds or vehicle is determined as a fraction of the amount administered prior to administration, and the percent inhibition of acid secretion is calculated by comparing the partial response to the test compounds with the response to the solvent in each dog.

The test results shown in Table 5 show the magnitude of inhibition at 2 hours post-dose.

(0

O Φ Their M (0 O σ -H C i -I 3 Φ> <z> 4-)

M o \ ° 3 {0

{0 f ^- 1 'ΓΊ Ai • H υ cn • H cn X Φ Ή 4-> x Oh c • H • H Φ -P cn 0 -ΓΊ o. • H cn O P Φ -H Uh > <J A! H 0) tO cn cn X CO Φ σ • H ε 4J > cn Ό C > □ Φ od X

CM - to »—i, —f oo

LD O O cr co oo

CM CM -— - sr CO kO I <79 t i ΙΟ 1 co to 09

tO tO to

LO σι

CM oo σ

(1) 001

Table 5. Inhibition of gastric acid in dogs w

Φ

Ό '3

Oh o

ε

H n

φ>

l-r • Φ

N

O n

o h σ c λ:

Ή '' -v. tP r-t C O □ £ • Ό 3.

cn > 1 c • H tP • C P a z • m o cn • d > N -U Ό P N • H > 1 -U > > cn l · —t CU

>>> o

Ή -H Ή -H>>

-H · Η>> • H -H

Ό Ό>

• H -H -H m lo o o is o

cn> 1 C - H> cn • H e

CM CM is co o o

CM is on «s.

cr o

CM is cn is

Solubility

The compounds described in Examples 3 (HBr salt) and 29 (disodium salt) were tested for solubility in water at room temperature and found to be greater than 60 mg / ml. In comparison, the solubility of omeprazole, 5-methoxy-2 - [[(4-methoxy-3,5-dimethylpyridinyl) methyl] sulfinyl] -1H-benzimidazole, is 0.4 mg / ml at pH 9, considered suitable for intravenous use.

Chemical stability

The chemical stability of the various compounds described in the invention was tested at 37 ° C in aqueous buffer at different pHs using low concentrations. The results, shown in Table 6, show that the compounds of the invention exhibit high chemical stability.

Table 6

The compound t 1/2 (or.) Fig. No. pH 2 pH 3 pH 5 pH 7.3 pH 9.5 Omeprazole-Na ^{+ li} 0.07 0.04 20th 3 112 32 29th 74 »600 ²⁾ 32 51 33 does not decompose after 30 or. 34 80 100 40 90 73 78 28th

Omeprazole-Na ⁺ = 5-Methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole Na salt.

i)

After 25 days at 22 ° C, decomposition is 12% at a concentration of 50 mg / ml.

Claims (1)

DEFINITION OF INVENTION A compound of the formula and a physiologically acceptable salt thereof, wherein X is -S- or -SO 2 -; R ¹ , R ² , R ³ and R ⁴ , the same or different, are (a) H (b) alkyl having 1-8, especially 1-6 carbon atoms, (c) alkoxy having 1-8, especially 1 -6 carbon atoms (d) alkoxyalkyl having 1-3 carbon atoms in each alkyl moiety (e) alkoxyalkoxy having 1-3 carbon atoms in each alkyl moiety (f) halogen (g) -CN (h) -CF ₃ (i) -NO ₂ (j) -COR ¹⁰ (k) alkylthio having 1-6 carbon atoms alkyl (l) alkylsulfinyl having 1-7 carbon atoms in the alkyl moiety (m) arylthio, -sulfinyl, -sulfonyl, sulfonyloxy, -oxysulfonyl, -sulfonamide or -aminosulfonyl groups in which each aryl group is substituted with 1 to 3 substituents, the same or different, respectively, halogen, CF ₃ , (1-5C) alkyl and (1-5C) alkoxy, optionally (n) arylalkyl or arylalkoxy having 1-6 carbon atoms in the alkyl and alkoxy moieties, and the aryl being substituted with 1-3 substituents, the same or different, halogen, CF ₃ , (1-5C) alkyl, (1-5C) alkyl ksi, optionally (o) aryl or aryloxy, wherein each aryl group is substituted with 1 to 3 substituents, respectively, the same or different - halogen, CF ₃ , (1-5C) alkyl, (1-5C) alkoxy, optionally (p) haloalkoxy having 1-6 carbon atoms and 1-11, especially 1-6 halogen atoms (q) hydroxyalkyl having 1-6 carbon atoms (r) R ¹ and R ² , R ² and R ³ or R ³ and R ⁴ together with the adjacent carbon atoms in the benzimidazole ring form one or more 5-, 6- or 7-membered rings, each of which may be saturated or unsaturated and may have 0-3 heteroatoms, optionally N, S and O, and wherein each ring may be respectively substituted with 1 to 10, preferably 1 to 6, or 1 to 4, optionally substituted alkyl with 1 to 3 carbon atoms and halogen, or the two or four of said substituents form one or two oxo groups 1 2 2 3 (-C-) whose assistance if R and R, R and R or 3 4 R and R together with the adjacent carbon atoms of the benzimidazole ring form two rings, these rings can condense with each other