DD299190A5 - DIOL-SULFONAMIDE AND SULPHINYL-RENIN HEMMER - Google Patents

Abstract

The invention relates to compounds of the general formula I in which Z denotes the groups SO or SO 2 and R 1, R 2, R 3, R 4, R 5, R 6, R 7 and X have the meanings given in claim 1. The compounds have renin-inhibiting activity and are useful in the treatment of hypertension and other diseases in which the reduction in the level of circulating angiotensin II has a beneficial effect. Formula I Drugs having effects on the cardiovascular system; Renin inhibitors; High blood pressure; Angiotensin II level}

Description

H ₂ N-CH-CH-C - C - Z - N

OH R ₅ R ₄

wherein R ₁ , R ₂ , R ₃ , R ₄ , R 5, He · R ₇ , R 12 »R 21 and Z have the meanings given in claim 1.

U.S. Patent 4,645,759 discloses renin inhibitors comprising dio compounds of the general formula

OR ₃ OR ₄ R _r OH Rg

I I M * I I

R ₁ R ₂ R ₇ R ₉

in which R2, _R4, R7, Re and Rg represents a hydrogen atom or lower alkyl, X represents an NH group, an oxygen or sulfur atom or the groups SO or SO ₂ and R ₈ is lower alkyl, cycloalkylalkyl, aryl, arylalkyl or, when X is the group NH, a protecting group of the nitrogen atom. U.S. Patent 4,657,931 discloses N- (acyldipep'.idyl) aminoglycol renin inhibitors comprising the compounds of the general formula below

0 R ₂ 0 R ₃ 0 R ₄ "R ₅

Il I Il I H I I

R ₁ - C - NH - CH - C - NH - CH - C - NH - CH - CH - (CH,) - CH

I i

OH OH

in which R is an alkoxy or alkyl radical, R _{2 is} a 3-benzyl or naphthylmethyl group, R _{3 is} an alkyl radical or an imidazolemethyl group, R _{4 is} a benzyl group, R _{5 is} a hydrogen atom or an alkyl radical and η is 0 or 1 Has.

U.S. Patent 4,680,284 and EP-A 189,203 disclose diol-renin inhibitors comprising the compounds of the general formula below.

R ₁₀ R ₃ OR ₄ OH OH

I Il III

N - CH - C - N - CH - C - C - R ^

Km £ 1 C * 7

in the Re, a hydrogen atom, a lower alkyl group, a vinyl group, an aralkyl group and the rest

^R 8

R ₈ denotes a hydrogen atom or a lower alkyl radical, X denotes an oxygen or sulfur atom or the group NH and R ₉ denotes a hydrogen atom, a lower alkanoyl or lower alkyl radical or XR ₉ denotes a lower alkylsulfonyl radical, an N ₃ group or a chlorine atom,

EP-A 229,667 describes renin-inhibiting peptidylaminodiol compounds which are the compound of the general formula

R ₃ OHR ₈ R ₆

A - CH - W - U - CH - CN - CH - CCR ₇

R ₁ R ₄ R ₅ R ₉

include, in the W a group

OH ι or -CH- means

-C-

U represents the group CH ₂ or NR ₂ , with the proviso that if W is the group

-CH-

U is the group CH ₂ , R _{4 is} an alkyl, cycloalkylmethyl radical or a benzyl group, R _{5 is} a hydrogen atom, a vinyl or formyl group or the group CH ₂ OH, R7 is a hydrogen atom or an alkyl radical, R $ and R _{9 are} the groups OH or NH ₂ and R _{6 is} a hydrogen atom, an alkyl or aralkyl radical or a vinyl group. In EP-A 230,266 Peptidylaminodiol- and triol-renin inhibitors are described, which are the compounds of general formula

0 R ₃ OH OH R ₆

I is -CH-C-N-CH-C-N-CH-CH-CH-X-R,

R ₁ R ₂ R ₄ R ₅ OH

in which R _{3 is} lower alkyl, benzyl or heterocyclomethyl, R _{4 is} lower alkyl, cycloalkylmethyl or benzyl, R ₂ , R ₅ and Re are hydrogen or lower alkyl, X is oxygen or sulfur or the like Group NH and R _{7 represents} a hydrogen atom, a lower alkyl, Alkanoylalkylsulfonylrest or the rest of the formula

ο o

1 H

C-CH-N - C- (CH ₂ ) _n - R ₁₄ ,

^R 12 ^R 13

or XR _{7 is} a Niedaralkylrest, an N ₃ -Grouppo or a chlorine atom.

! η of PCT Application 87 / 05302A, there are described ronin-inhibiting peptides which are the compounds of the general formula

XA ₆ -B ₇ -Cr-Dg-E ₁ OF _n -G ₁₂ -Hi ₃ -IM-Z include, in the E ₁₀ -F _n the remainder

-NH-CH-CH-CH-CH-C-

CH ₂ OH OH

^R l

OH OH

I II

-NH-CH-CH-CH-CH-C-

R ₁₁

^R 22 ^R 23

mean.

In GB-A-2 _# 200,115A, renin inhibitors are of the general formula

^R 2/4

acyl-BCN-CH - CH-CH ₉ -DYN

II ² \

R ₁ R ₃ R ₅

in which Y may be the group SO ₂ ; D may be a bond, the group NH or the radical CH-R; R _{3 may be} a hydrogen atom, a hydroxy group, an acyloxy radical or the group NH ₂ ; B and C bonds or amino acids wherein at least one amino acid may be present.

The present invention relates to renin-inhibiting diol sulfonamide and sulfinyl compounds of the general formula I and their salts, pharmaceuticals containing them from active substances, the use of these compounds and novel intermediates and processes for the preparation of the compounds of general formula I.

(I)

I ' in the -CH-- ^0R 6 ^R 3 Z / χ-.NH-CH - 7 is an SO or SO ₂ -GrUDDe, I C - • C - -N OH I I \ ^R 5 ^R 4

Ri and R2 are independently selected from hydrogen, Ci-7-alkyl, C2.7-alkylene -, - (CH _{2) m} -aryl -, - (CH2) _m -cycloalkyl -, - (CH2) _m -Heterocyclo -, halogen-substituted Ci-7-alkyl radicals,

- <CH ₂ ) _g -SR ₁₅ , - (CH ₂ ) _g -M

/ ^R 15

xs

^R 8

^R 15

^R 16

-CH- (CH,) -OH, -CH- (CH ₂ ) -N

8 o

- (CH ₂ ) -CH- CN

/ ^R i5

R ₈ OR ₂₀ O

I Il I Il

CH-C - NH-CH - C-OR ₁₅ , and

R ₈ 0 R ₂₀ 0

HI

H / 15

OAER

-C-NH-CH-C-N

/ l • N

-N represents a heterocyclic ring-N!

R3, R71 Rs / Ria Rm and R ₂ o are independently selected from hydrogen, Ci_ ₇ -Alkyl-, halogen-substituted Ci. ₇ -alkyl, - (CH _{2) m} -aryl, - (CH2) _m -Heterocyclo-, - (CH2) _m -cycloalkyl radicals, the radicals

- (CH,) -N ^{7 15} , - (CH ₂ ) _n -O- (CH ₂ ) -O-R ₁₅ ,

zn ν

^R 16

/ ^R 15 (CH ₂ ) _n -S- (CH ₂ ) _g -OR ₁₅ , - ₍ CH ₂ ) _n -O- (CH ₂ ) _g -N

^R 16

O / ^R 15

/ ^R 15 (CH,) - CN, - (CH,) - NH-C-0 lower alkyl,

C * Xl ν £ Ii

^R 16

Il

" ^(CH 2 ⁾ n" ^NH " ^C ~ ^{lower alk} y ¹ " ^(CH 2 ⁾ n " ¹ ^" ^C ~ ^(CH i

Il

(CH ₂ J ₁ J-NH-CO- (CH ₂ ) _m -aryl,

Il

_n - O- (CH ₂ ) - NH-C-0 lower alkyl,

J _n - O- (CH ₂ ) - NH-C- lower alkyl,

Il

- (CH ₂ ) - O- (CH ₂ ) _g -NH-C- (CH ₂ ) _m -aryl,

il

₂ J _n -O- (CH ₂ J-NH-CO- (CH ₂ J _n -ArYL

(CH ₂ ) - S - (CH ₂ ) _g - NH - C - O - ^Ν lower alkane 1,

NH-C- lower alkyl,

S ~ (CH ₂ ) _g - NH-C-

J ₅ - aryl

(CH ₂ ) - S-

g-NH-C-O - (CH ₂ ) _m -ArYL

, NH

- (CH ₂ J _n -NH-C

NR _r

ι and

 <-2> n "

R _{4 represents} a hydrogen atom or a Cu ₇ alkyl radical; R ₆ and R _{6 are} independently selected from hydrogen atoms, C ,. _7- alkyl, halogen-substituted C ^ ₇ -AlkVl -, - (CH ₂ L-ArVl -, - (CH ₂ ) _m -heterocyclo- and - (CH ₂ L-cycloalkyl radicals;

R the group

R the group

NO,

or

O Il -C-O-CH

means;

NO,

^CH 3 '" ^CH 2 \ Q / ,

or

means;

X is a hydrogen atom, one of the radicals

O Il

13

f ~ 11 '~ 2 ° "11'" "12 '

0 R

14

'21

-Y-CH-NW ₁ , -Y - CH - NC- CH- N -

15

15

'16

'13

0 R

14

-Y-CH-O - W ₃ , -Y-CH-NC-CH-CH ₂ -W ₂ ,

O II -C-O-R

0 ii -C-N

R ₁

'15

, -SO ₂ -N

, or

16

'16

13

0 R

-Y-CH-N-C-CH-O-W;

Y is a group -CH "- or -C-;

R ₁ , a C ,. _7- alkyl, halogen-substituted C ,. _7- alkyl, aryl, heterocyclo, cycloalkyl, -alkylene-aryl, alkylene-heterocyclo, -alkylene-cycloalkyl radical, one of the radicals

O 0

/ "15

- (CH ₂ ) _n -CN

'16

Ϊ / ^R 15 alkenyl-C-O-R ₁₅ , or alkenyl-CN

means;

R ₁₂ and R _{2 are} independently selected from hydrogen, C 1-4 alkyl, halo-substituted C 1-6 alkyl, aryl, heterocyclo, cycloalkyl, alkylene-aryl, -alkylene-heterocyclo, -alkylene cycloalkyl radicals, the radicals

O O

Il Il / ^R 15

(CH ₂ ) _m -COR ₁₅ , - (CH ₂ ) _ra -CN

^R 16

- lkenyl-C-0-R ₁₅ , and

Ι -alkenyl-C-N

/ ^R 15

R ₁₆ and R] _{6 are} independently selected from hydrogen, C 1-7 alkyl, - (CH ₂ ) _m cycloalkyl, - (CH ₂ ) _m -aryl and - (CH ₂ ) _m -ketocyclo groups;

W] is a hydrogen atom, one of the radicals

-CO- (CH ₂ ) _m -R ₁₇ , 0 O

_0_N- (CH _{2) m} -R ₁₇ -C- (CH _{2) m} -R ₁₇

^R 18 '

-SO ₂ -NH-R ₁₈ , - (CH ₂ JR , _or

H , -CN means;

R ₁₇ and R _17th are independently selected from hydrogen atoms, C ,. ₇ alkyl, aryl, heterocyclo and

cycloalkyl;

W _{2 is} a hydrogen atom, one of the radicals

0 0

- ^R 18 '

ϋ υ

Il Il Il

.C-NH ₂ , -C-NH-R ₁₈ , -CNR ₁₈

-SH, -SR ₁₈ , "SO-R ₁₈ " -SO ₂ -NH ₂ , -SO ₂ -NH-R ₁₈ ,

^R 18 '

^<CH 2 ⁾ n '

R ₁₇ , ^R 17 ·

0 or Ii means;

-C-N

^R 17 '

W _{3 is} a hydrogen atom, one of the radicals

0 0

-COR ₁₈ , -C-NJI ₂ , -C-NH-R ₁₈

-CNR ₁ Q, or

^χο "- means;

^R 18 '

R ₁₈ and Ria · are independently selected from C ,. ₇ -alkyl, - (CHj) _m -aryl, - (CH ₂ ) _m -cycloalkyl radicals, the radicals

⁰ ° ^R

15

- (CH,) -heterocycle », -CH ₉ -COR _n .,, -CH ₉ -CN

¹⁷²

Il /

16 OO

- (CH ₉ ) -NH-C-lower alkyl, - (CH ₉ ) "- NH-CO-lower alkyl,

£ Xl £ λ Xi

- (CH) -NH-CO- (CH ₉ ) Τ-aryl, - (CH ₂ ) -N

ΔLL L ·Xl> w ^

^R 16

NH

and - (CH ₂ ) _n -NH-C

NH ₂

(N- a heterocyclic P.inq of the formula

N- means;

(CH ₂ ]

wherein A represents a -CH ₂ group, an oxygen or sulfur atom or an NR ₁₈ -ReSt, a is an integer from 1 to 4 and b is an integer from 1 to 4, with the proviso that the sum of a and b is an integer of 2 to 5, and those mean heterocyclic rings in which a suitable carbon atom is substituted with a lower alkyl group; R _{19 represents} a hydrogen atom, a lower alkyl, - (CH ₂ ) _n -phenyl or a - (CH ₂ ) _n -cycloalkyl radical; m and m 'independently represent the value 0 or an integer from 1 to 5; η and n 'are independently an integer from 1 to 5; ρ has the value 0 or 1; g is an integer from 2 to 5.

The invention in its broadest aspect relates to compounds of general formula I above, to pharmaceutical compositions containing these compounds, to the use of these compounds for the inhibition of renin, which compounds show good pharmaceutical activity, intermediates and processes for the preparation of these compounds. The term C 1-4 alkyl used in the definition of numerous symbols means straight- or branched-chain radicals having up to 7 carbon atoms. The term lower alkyl means straight or branched chain radicals having up to 4 carbon atoms and is the preferred meaning for the term alkyl.

The term alkenyl used in the definition of numerous symbols refers to straight or branched chain radicals of 2 to 7 carbon atoms containing at least one double bond. Preferred alkenyl groups have a straight chain of 2 to 4 carbon atoms having a double bond.

The terms lower alkoxy and lower alkylthio mean those alkyl groups as defined above attached to an oxygen or sulfur atom.

The term cycloalkyl means saturated rings of 4 to 7 carbon atoms, with cyclopentyl and cyclohexyl being most preferred.

The term "alkylene" means straight-chain bridges of 1 to 5 carbon atoms bound by interchain bonds, ie, - (CH ₂ I _n -, where η is an integer of 1 to 5, such a straight-chain bridge of 1 to 5 carbon atoms one or more hydrogen atoms are replaced by a lower alkyl group, ie

-CH ₂ -CH-CH ₂ -,

CH ₃

₂ - CH - CH - CH ₂ -

CH ₃ CH _{3 is} a hydroxy- or hydroxy-substituted lower alkyl group, ie

-CH ₂ " - CH ₃ 33- 299 190 -C- CH ₂ - -CH ₀ -CH-, ¹ ι and CH ₃ CH ₂ - ι I ^C 2 ^H 5 Like.,

OH OH

-CH ₂ - CH - CH ₂ -, -CH ₂ -CH-CH ₂ -

CH ₂ CH-OH

i i

OH CH ₃

and the like, or an amino- or amino-substituted lower alkyl group, d. H.,

-CH ₂ -CH-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH-,

NH ₂

NH ₂

-CH ₂ -CH -

CH-NH ₂

The term halogen means chlorine, bromine, fluorine and iodine atoms.

The term halo-substituted alkyl radical means the alkyl radicals described above in which one or more hydrogen atoms are replaced by chlorine, bromine or fluorine atoms, such as the preferred trifluoromethyl group and the pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl group, and the like.

The term aryl means phenyl, diphenylmethyl, 1-naphthyl, 2-naphthyl groups, monosubstituted phenyl, diphenylmethyl, 1-naphthyl or 2-naphthyl groups substituted with lower alkyl groups of 1 to 4 carbon atoms, lower alkylthio groups of 1 to 4 carbon atoms, lower alkylthio radicals having 1 to 4 carbon atoms, halogen atoms, hydroxy, amino groups, -NH-alkyl radicals wherein the alkyl radical contains 1 to 4 carbon atoms or -N (alkyl) ₂ radicals wherein the alkyl radicals have 1 to 4 carbon atoms, ie -odertrisubstituted phenyl, diphenylmethyl, 1-naphthyl or 2-naphthyl groups which are substituted by methyl, methoxy, methylthio,

Hydroxy, amino and halogen atoms.

The term heterocyclo refers to fully saturated, partially saturated or unsaturated cyclic rings of 5 or 6 atoms containing one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, with the proviso that the total number of heteroatoms in the ring is 4 or less is. The heterocyclic ring is attached to an available carbon atom. Preferred heterocyclic groups include the 2-, 3-, or 4-pyridyl, 2-pyrazinyl, 4-pyridazinyl, 4-imidazolyl, 4-thiazolyl, 2- and 3-thienyl and 2- and 3- furyl group. The term heterocyclo also means acyclic rings in which the 5- or 6-membered ring containing oxygen, sulfur and nitrogen atoms as defined above, to

a benzene or pyridyl ring is condensed. A preferred bicyclic ring is the 2-indolyl group. The mono- or bicyclic heterocyclic ring may also be additionally substituted on an available carbon with C 1-4 alkyl, halogen substituted C 1-4 alkyl, hydroxy, benzyl or cyclohexylmethyl. When the monocyclic or bicyclic ring has an available nitrogen atom, this nitrogen atom can be replaced by an available nitrogen protecting group such as the groups

-SO

the 2,4-dinitrophenyl group, a lower alkyl group, a benzyl or benzhydryl be substituted.

The compounds of general formula I in which X represents a hydrogen atom and R) and R _; are selected from alkyl, alkylene-.FCH ^ m-aryl, - (CH ₂ ) _m -cycloalkyl -, - (CH ₂ ) _m -Heterocyclo- and halogen-substituted lower alkyl radicals or in which

-O

is a heterocyclic ring "N ^ J , can be prepared by reacting a Oxazolidincarbonsäureamids of the general formula II

R,

Prot -N

HO ι f

C-C-N

H ₃ C

OCH,

CH.

in which Prot is a protecting group for the nitrogen atom, such as a tert-butoxycarbonyl group, with the amide of general formula III

HC-Z-N

^K 3 2

in the presence of n-butyllithium. A compound of the general formula (IV) is obtained.

R ₇ OR ₃ R-.

H Il I Prot-N - C-C- C - Z ~ N

CH.

The oxazolidine ketone intermediate of general formula (IV) is then treated with a reducing agent such as the borane-tert-butyl-amine complex. The compound of the general formula (V) is obtained.

^R 7 OH R,

Prot

H I I

C - CH - C - Z - N

CH.

This oxazolidine alcohol is then hydrolyzed acid. The diol of the general formol (VI) is obtained.

R OH R ₃ R ₁ I /

Prot-NH-CH CH CH-C-Z-N (Vi)

I I

OH R ₄ R ₂

The removal of the protective group on the nitrogen atom from the diol of the general formula (VI) takes place, for example, by addition of HCl, if Prot denotes a tert-butoxycarbonyl group. The desired products of general formula I are obtained.

The products of the general formula I in which X is a hydrogen atom and one of the radicals R and R _{2 is} a hydrogen atom and the other E, where E is one of the radicals - (CH ₂ ) _Q -OR, ₆ , - (CH ₂ ) "- SR, ₆ ,

^R 15 °

0 R ₁₅

Il / Ρ

(CH ₂ J _n -CH, - (CH ₂ ) -CH-COR ₁₅ ,

  \

^R 16 ^R 8

p R-R ₁ c

^R 8 8 /

-CH - (CH ₂ ) _n - OH, -CH- (CH ₂ ) _n > N

^R 8 ?, Λ5 ^R 8 ° ^R 20

16 R-. r R _n O 'R " _Λ

- (CH ₂ ) -CH-CN, - (CH ₂ J-CH-C-NH-CH - ^C - ° ^R ₁₅ /

or

^R 16

\ ³ Ϊ \ ²⁰ Ϊ / * ¹⁵

j-CH-C-NH-CH-C-N

^R 16

may be prepared by reacting the oxazolidinecarboxamide of the general formula (II) with the amide of the general formula (VII)

HC - Z - NH - CH

(VII)

getting produced. Compounds of the general formula (VIII) R-,

Prot-N

-C-C-Z-NH-CH-KO

(VIII)

-.0

CH.

The intermediate of general formula (VIII) is then reacted with a reducing agent as described above. Compounds of the general formula (IX) are obtained.

R-

OH

Prot-N

£ CH-C - Z - NH-CH- | - (O)) 2

- I

0 R,

CH-

This intermediate is compounded with a compound of general fine formula (X)

Hal-E alkylates, where Hal is a bromine or iodine atom. This gives compounds of the general formula (XI)

R-

OH R,

Prot-N

C - CH - C - Ζ - CH - CH

CH ₃

The oxazolidine alcohol of general formula Xl would then be ζ. B. hydrogenated by reacting with platinum hydroxide and Wasserstotfgas. Compounds of the general formula (XII) are obtained.

Rt OH R,

Prot-N

H I I

C CH - C - Z - NH - E

(XII)

CH-

The above-described acid hydrolysis and removal of the protecting group on the nitrogen atom give the desired end products of general formula I in which X represents a hydrogen atom, Ri has the meaning E and R _{2 represents} a hydrogen atom

 The intermediate of general formula XII can be reacted with a compound of general formula (XIII)

HaI-R ₂ (XIII)

be alkylated, wherein R _{1 has} a meaning other than a hydrogen atom. Compounds of the general formula (XIV) are obtained.

^R 7 OH R ₃ ^E

H I I /

Prot-Nc-CH-C-Z-N

(XIV)

CH ₃

The above-described acid hydrolysis and removal of the protecting group on the nitrogen atom gives the final products of general formula I in which X represents a hydrogen atom, R) has the meaning E and R _{2 has} a meaning other than a water atom.

When R _{2 is} a methyl group, methyl iodide can be used as the alkylating agent as above, or instead of the halide, dimethyl sulfate can be used.

Certain groups within the definition of E may require a change in the general method described above. For example, if R _{1 is} a radical

^R 8 °

- (CH ₂ ) -CH-C-OH

is the bromide or iodide of the general formula X is a carboxylic acid ester. This ester is then saponified in the reaction with sodium hydroxide in methanol / water in the last step of the synthesis. The end product is obtained, where R) is the radical

^R 8 °

/ no \ - PW P OH

means. Similarly, the compounds wherein R _{1 is} the radical

^R 8 ° ^R 15

I Il /

- (CH ₂ ) -CH - C -N

^R 16

? ϊ

? ϊ

- (CH ₂ J-CH-C-NH - CH-C-

and the like, by coupling the protected amine or amino acid. The compounds are obtained in which R) the rest

R ₈ 0

Il - (CH ₂ ) _p -CH-C-OH

means. This gives the Arnidbinclung. This procedure is known. In this case, a coupling agent such as dicyclohexylcarbodiimide may be used or the carboxylic acid may be converted into an activated form such as an acid halogonide, an activated ester, and the like.

The compound of general formula I wherein Ri and R2 are both hydrogen and X is hydrogen can be prepared by reacting an oxazolidine carboxylic acid of general formula V in which R _{1 is} the group

OCH

and Ri represents a hydrogen atom, with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. The compound of the general formula (XIV) is obtained.

R.

OH R

Prot-N

C - CH - C - 2 - N = CH - (O / ^OCH 3

(XIV)

OCH.

CH-

By reacting with 10% HCl and acetic acid in tetrahydrofuran to give the desired product of the general formula I, in which Ri and R2 are both a hydrogen atom and X is a hydrogen atom.

The compounds of the general formula I in which R _{6 has} a meaning other than a hydrogen atom can be prepared by reacting the amide of the general formula III with an oxazolidine ketone of the general formula (XV)

R-

Prot-N '

C - C - R _r

H ₃ C

(XV)

CH.

in the presence of n-butyllithium. Compounds of the general formula (XVI) are obtained.

R.

Prot-N

OH

C - C - C - Z - N

(XVI)

• 0 R ₅ R ₄

CH.

Acid hydrolysis and removal of the protective group gives the end products of general formula I in which R _{5 has} a meaning other than sin hydrogen atom.

The products of general formula I in which X is the radical -Y-substituent and Y is the group

., By coupling the acid of general formula (XVII)

Substituent-C-OH

(XVII)

to the compound of general formula I in which X represents a hydrogen atom. This coupling is preferably carried out in the presence of a coupling agent such as ethyl S-IS-dimethyaminolpropylcarbodiimide or dicyclohexylcarbodiimide.

The products of general formula I in which X represents the radical -Y-substituent and Y represents a group -CH ₂ - can be prepared by reacting the corresponding compounds in which Y is the group

means to be prepared with a reducing agent, such as BH ₃ · dimethyl sulfide in the last step of the preparation. The products of the general formula I in which X is the radical

-SO ₂ R ₁₁ or _ _s0 '

^R 16 means may be obtained by reacting the sulfonyl chloride of the general formula (XVIII)

R ₁₁ -SO ₂ -Cl or

15 ^R 16

be prepared with the compound of general formula I in which X represents a hydrogen atom. The products of the general formula I in which X is the radical

R ₂

 can be converted by reacting the ketone of the general formula (XIX)

^{R 2} ~ V ^{= 0} (XIX)

R21

with the compound of the general formula I in which X represents a hydrogen atom. This reaction is carried out at neutral pH in the presence of sodium cyanoborohydride. When, in the above reactions, one of R ₁ , R ₂ , R ₃ , R ₆ , R ₆ , R ₇ , Re, R _n, R _12, R _n, R _14, R _y, R _16, R _w, R _y, R ₂₀ and R _{2i is} hydroxyl , Amino, imidazolyl, mercaptan or guanidyl group, then this group is protected until the last step. Suitable protecting groups include the benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, benzhydryl, trityl, and the like, and the nitro group for the guanidinyl group. The protective group is removed in a conventional manner after completion of the reaction.

The starting compounds of general formula II can be prepared by reacting an amino acid protected on the nitrogen atom of general formula (XX)

Prot-NH-CH-COOH

with N.O-dimethylhydroxylamine hydrochloride in the presence of a coupling agent such as 1,1'-carbonyldiimidazole. The compound of the general formula (XXI) is obtained.

R ₇ O OCH ₃

Prot - NH-CH C-N. (XXI)

CH ₃

The compound of general formula XXI is reduced with lithium aluminum hydride. The aldehyde of the general formula (XXII) is obtained.

The aldehyde of general formula XXII is reacted with furan in the presence of alkyllithium and zinc bromide. The alcohol of the general formula (XXIII) is obtained.

Prot

-NH CH CH-Is ₀ J

(XXIII)

OH

By reacting the alcohol of the general formula XXIII with 2,2-dimethoxypropane in the presence of acid, the oxazolidine of the general formula (XXIV) is obtained.

R.

Prot-N

H ₃ C

C O

(XXIV)

CH-

By oxidation with ruthenium tetroxide, which is prepared from a mixture of sodium metaperiodate and ruthenium trichloride, the oxazolidine of the general formula (XXV) is obtained.

Prot-N

H C

• ö

Il

C OH

(XXV)

CH-

By reacting the oxazolidinecarboxylic acid of the general formula XXV with Ν, Ο-dimethylhydroxylamine hydrochloride in the presence of a coupling agent, the starting compound of general formula II is obtained.

Preference is given to compounds of this invention of general formula I in which:

Z is an SO ₂ group;

R ₁ and R _{2 are} both hydrogen;

Ri is a straight-chain or branched-chain C 1-7 -alkyl or C 1-4 -alkylene radical having a single double bond, the rest

"· Ί

-CH (CH ₂ ) _n -

or

and R _{2 represents} a hydrogen atom or a benzyl group;

Re / Ra> R </ R5 and R ₆ are each independently a straight or branched C, _ ₇ alkyl group; R _{7 is} a - (CH ₂ ) -cycloalkyl radical;

X is a hydrogen atom, a straight or branched chain C ,. _7- alkyl, the rest

O O

O R

-Y-CH-NH-W ₁ , -Y-CH-NH-C-CH-NH-W ₁

0 R

14

-Y-CH-NH-C-CH-CH ₂ -W ₂ , -Y-CH-OW ₃

or -Y-CH - NH-SO ₂ -R ₁₈ ;

Y is -C- or ~ ^CH2 ~ means; R ₁ , a straight or branched C ,. ₇ alkyl, aryl, heterocyclo, alkylene-aryl, alkylene-heterocyclo- or

-CH = GH-CO-lower alkyl; R _{13 represents} a straight or branched chain C _1-7 alkyl or - (CH ₂ ) _m heterocyclo group; Ru is a - (CH ₂ ) _m -aryl or straight- or branched-chain C |. ₇ alkyl group; R, _{6 represents} a hydrogen atom or an alkali metal salt ion; W ₁ and W _{3 are} independently selected from hydrogen atoms, the radicals 0

¹¹ "^,

-C- (CH ₂ ) _m -R ₁₇ , or -CN )> or

the radical -SC-R ₁ Q;

W- a rest

Il

- ^c -O

R ₁₇

or -C-N};

R ₁₇ and R _{17 are} independently selected from straight or branched chain C _1-7 alkyl, aryl or heterocyclo radicals; Ria represents a straight or branched chain C 1-3 alkyl or - (CHj) _m aryl group; the term aryl, phenyl, diphenylmethyl, 1-naphthyl, 2-naphthyl groups, monosubstituted phenyl groups which are substituted by Neraleralkylresten with 1 to 4 carbon atoms, Niederalkoxyresten with 1 to 4 carbon atoms, Niederalkylthioresten with 1 to 4 carbon atoms, Hydroxy, amino groups, chlorine, bromine or fluorine atoms or disubstituted phenyl groups whose substituents are selected from methyl, methoxy, methylthio groups, chlorine, bromine, fluorine atoms, hydroxyl and amino groups.

Preferred definitions of the heterocycles of R ₁₁ mean a 2-, 3-, or 4-pyridinyl, B-hydroxy-S-pyridinyl, 4-pyridazinyl or 2-pyrazine group.

Preferred heterocycles in the definition of R ₁₃ include the groups

NH

or

Preferred definitions. ι of the heterocyclo group of R ₁₇ include the groups

, 2-, 3-, or 4-pyridyl.

^> S

N '

The preferred definitions of Wj, W ₂ and W ₃ include the groups

O-

-NO

Most preferred are the compounds of general formula I in which Z represents the group SO ₂ ; R _{1 is} the group η-butyl OdOr-CH ₂ -CH ₂ -CH = CH;

R ₃ is hydrogen or a methyl group, preferably a hydrogen atom; R ₂ , R ₄ , R ₅ and R ₆ each represent a hydrogen atom;

R _{7 is} the group

CH.

means;

X is a hydrogen atom, a straight- or branched-chain CW-alkyl radical, the rest

^{0 R} l3 OR ₁₃ ° ^R

1 or i | I

-C-CH - NH-W ₁ , _c - CH - NH - C - CH - CH ₂ - W,

means; -Cl

R _{13 is} the group -CH ₂ CH (CH ₃ ) ₂ or ^ _N ^;

the group Il / - ~ \\ rf ^ l or

R _{14 is} the group -CH.r - \ (J) and

W _{2 is} the GmPPe-SO ₂ -C (CH ₃ I ₃ .

The compounds of the general formula I form salts with a multiplicity of inorganic and organic acids. The non-toxic pharmaceutically acceptable salts are preferred, although other salts are also useful in isolating or purifying the product. Such pharmaceutically acceptable salts include the salts formed with hydrochloric acid, methanesulfonic acid, sulfuric acid, acetic acid, maleic acid and the like. The salts are obtained by reacting the product with an equivalent amount of the acid in a medium in which the salt precipitates or in an aqueous medium followed by freeze-drying.

The compounds of general formula I in which R _t or R ₂ end up having a carboxylic acid group additionally form pharmaceutical salts with alkali metals such as sodium, potassium, lithium and alkaline earth metals such as calcium and magnesium. These salts are prepared by reacting the acid form of the compound of general formula I with the desired metal ion in a medium by precipitating the salt or in an aqueous medium followed by freeze-drying. The compounds of the general formula I contain some asymmetric centers which are defined by the definitions of the radicals R ₃ , R ₄ , R ₆ , R ₇ , R e <R ₂ . Ri3 »Rm and R ₂ i depend. Therefore, the compounds of general formula I can exist in diastereomeric forms or mixtures thereof. The methods described above can use racemates, enantiomers or diastereomers as starting compounds. When diastereomeric products are prepared, they can be separated by conventional chromatographic or fractional crystallization techniques.

The compounds of the invention, including their pharmaceutically acceptable salts, are useful as substances having an effect on the cardiovascular system. They inhibit the conversion of angiotensinogon into angiotensin I and therefore prove useful in reducing or alleviating angiotensin-associated disorders. Angiotensin I is produced by the action of the enzyme renin on angiotensinogen, which in turn is converted into angiotensin II by the angiotensin converting enzyme (ACE). The latter is an effective blood pressure-raising compound, the causer

is involved in some forms of hypertension and other cardiac and circulatory disorders in mammals, such as humans. The compounds of this invention participate in the sequeliation of angiotensinogen - * (renin) -> angioiensin I -> (ACE) -> angiotensin II by inhibiting renin or reducing or preventing the formation of the hypertensive compound angiotensin II.

As a result of this action, the compounds of the invention have antihypertensive activity and are useful in any situation where the reduction in the level of circulating angiotensin II has a beneficial effect. For example, the compounds of the invention are also useful in the treatment of congestive heart failure, renin-dependent hypoaldosteronism, myocardial infarction and renal failure, such as diabetic nephropathy. The compounds may also be useful as adjuncts in the treatment of other disorders such as glaucoma and scleroderma and as diagnostic agents in determining whether disorders such as high blood pressure caused by ronin are present.

Therefore, the administration of a composition containing one (or a combination) of the compounds of the invention proves to be useful in the treatment of the disorders described above caused by angiotensin. For example, daily administration of about 0.5 to about 100 mg / kg body weight in a single dose or divided into two or four doses is found to be beneficial in reducing blood pressure in humans. The exact dose employed will of course depend on the compounds chosen and on the methods of administration, i. H. the intravenous dose is below about 1 mg / kg / day and the preferred oral dose is about 10 to about 50 mg / kg / day. In addition to oral and intravenous forms of administration, the compounds of the invention may be formulated into medicaments suitable for subcutaneous, transdermal, intramuscular or intranasal administration. Suitable oral drugs include tablets, capsules and elixirs. Suitable parenteral drugs include sterile solutions or suspensions. From about 10 to about 100 mg of a compound of the invention are formulated with one or more physiologically acceptable carriers, excipients, binders, preservatives, stabilizers, flavoring agents, and the like in unit dosage form according to procedures customary in the pharmaceutical practice.

The compounds of the invention additionally prove to be useful when used in conjunction with one or more other pharmaceutically active substances having an effect on the cardiovascular system. Such combinations may be administered as a fixed dose combination or concomitantly as separate doses. Examples of suitable agents having cardiovascular activity include diuretics such as the thiazide diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide or benzthiazide, as well as ethacrynic acid, tricrynafen, chlorthalidone, furosemide, musomine, Bumetanide, triamterene, amiloride and spironolactone and salts thereof, angiotensin converting enzyme inhibitors such as captopril, zofenopril, fosinopril, enalapril, delapril, pentopril, quinapril, ramipril, lisinopril and salts thereof, thromboxane synthetase inhibitors, thromboxane receptor: Antagonists, calcium channel blockers such as diltiazem, nifedipine, and the like, calcium channel activators, thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC , Eminase, from Beecham Lab oratories), α- and β-adrenergic receptor blocking agents such as propanolol, nadolol, metoprolol and the like, anti-cardiac vaccines, neutral endopeptidase inhibitors, cardiotonic agents and the like. When prepared as a fixed dose, such combination preparations contain the Compounds of the invention in the dose range described above and other pharmaceutically active substances within the approved dose range.

In addition to the renin-inhibiting effect described above, the compounds of the invention are also inhibitors of the retroviral protease. It has been found that the activity of the retroviral protease is necessary for the infectivity of the virus. Therefore, inhibition of such protease can provide a means of inhibiting the replication ability of such virus and may be useful in the treatment of retrovirus-induced diseases, including HTLV-I and HTLV-III. A suitable dose for this purpose is about 1 to about 500 mg / kg / day. The following examples illustrate the invention. Temperature data refer to ⁰ C.

example 1

[βR-jβR *, R *, 5S *)] - o -amino-N-butyl-β, -dihydroxy-cyclohexane-pentanesulfonamide monohydrochloride

a) N-butylmethanesulfonamide

6.76 mL (87.3 mmol, 1.0 eq. L) of methanesulfonyl chloride were dissolved in 44 mL (0.5 M) dichloromethane. The solution was cooled in an ice-bath and 17.3 mL (175 mmol, 2.0 equiv.) Of n-butylamine was added dropwise, and after complete addition, the clear solution was stirred at room temperature overnight The mixture was washed with 200 mL of chloroform washed with 2x200ml 0.5N HCl and 200ml brine, dried over magnesium sulphate and stripped of solvent under reduced pressure to give an oil which was purified by distillation to give 11.4g (86%) of N-butylmethanesulfonamide from bp 106-110 ° C / 0.5mm, which solidified on standing.

b) 1,1-Dimethylethyl (4S-tra.is) -4- (cyclohexylmethyl) -5 - [[(methoxy) methylamino] carbonyl] -2,2-dimethyl-3-oxazolidinecarboxylate

To a solution of 120g (452 mmol) (di-dimethylethoxyl-carbonyl-L-phenylalanine in 1 liter of absolute ethanol was added 5g of platinum oxide catalyst (Adams catalyst) .The mixture was placed in a Parr reduction apparatus. The reaction proceeded rapidly and the hydrogen storage tank had to be replenished continuously The reduction proceeded overnight and after 20 hours a TLC on silica gel (eluted with 4: 1 toluene-acetic acid) indicated the absence of effluent and a new spot at Rf = 0.62 was filtered through Celite and evaporated under reduced pressure to give 124.4 g of (Sl-a-Hd.i-dimethylethoxyl-carbonyl-aminol-cyclohexane-propanoic acid as a glassy colorless solid

IaIo = -9.5 ° (c = 1, methanol). TLC (silica gel, 4: 1, toluene: acetic acid) R ₁ = 0.62. C ₁₄ H ₂₆ NO ₄ :

C H N calc .: 61.97 9.29 5.16 Found .: 61.84 9.25 5.12

A solution of 93 g (343 mmol) of (S) -α- [l (1,1-dimethylethoxy) carbonyl-amino] -cyclohexanepropanoic acid in 1 liter of dry tetrahydrofuran was mixed with a 20 mol% excess of!, V- Carbonyldiimidazol added in less than 10 minutes with vigorous stirring to keep the internal temperature below 3O ⁰ C. After stirring for 30 minutes, 36.8 g (377 mmol) of Ν, Ο-dimethylhydroxylamine hydrochloride and then 38.2 g (377 mmol) of triethylamine were added. The mixture was stirred at room temperature for 4 hours and filtered. The resulting residue was evaporated under reduced pressure. The resulting 100 g amber residue was dissolved in 900 ml of ether and poured into 1 liter of 1 N HCl. The acidic aqueous phase was separated and extracted with ether. The combined ether layers were washed with water, saturated sodium bicarbonate solution, water and brine and dried over magnesium sulfate. . (Sl-a-dd.i-Dimethylethoxyl-carbonyll-amino-N-methoxy-N-methylcyclohexanpropanamid as a colorless oil Ia] ₀ = -12.9 "was obtained (c = 1, methanol) TLC (silica gel;. 1 : 1, ethyl acetate: hoxan) R ₍ = 0.58, C ₁₆ H ₃₀ N ₂ O ₄ :

CHN: 61.11 9.62 8.91

F .: 61.35 9.54 9,10

_-. 55.3g (175.9 mmol, 1 eq.) Of (Sl-a-llO.I-dimethylethoxycarbonyl-aminol-N-methoxy-N-methylcyclohexanepropanamide

> Dissolved in 1760 ml (0.1 M) diethyl ether and cooled in an ice bath. The solution was dissolved in 90 minutes with a solution of 193 ml

1 (193 mmol, 1.1 eq., 1M in tetrahydrofuran) of lithium aluminum hydride in tetrahydrofuran was added dropwise. After 75 minutes

1 liter of 1N hydrochloric acid was added cautiously and slowly. The cooling bath was removed and the mixture continued for 2 hours

\ touched. The phases were separated and the aqueous phase was extracted twice with 400 ml of ether. The United

Ether phases were dried over magnesium sulfate and freed from the solvent under reduced pressure. This gave 46.47 g of a viscous oil. This was chromatographed through 500g of silica gel (from Merck) packed in hexane. The aldehyde was eluted with ether: hexane (1: 1). There was obtained (S) -a - [[(1,1-dimethylethoxy) carbonyl] amino] cyclohexane propanal. 210ml (525mMol, 3,2Äq., 2.5M in hexane) n-butyl lithium were added to a solution of 38.1 mL (524mMol, 3,2Äq.) In 524ml furan (1 M) distilled tetrahydrofuran at -78 ⁰ C. , The mixture was stirred for 15 minutes at -78 ⁰ C. After removal of the cooling bath, stirring was continued for another 45 minutes. The mixture was cooled to ⁰ ° C. 524 ml of a 1 M solution of zinc bromide in tetrahydrofuran (524 mmol, 3.2 eq.) Was added through a tube. After 15 minutes, the mixture was cooled to -78 ⁰ C and a solution of 41,8g (163.7 mmol, 1,0Äq.) (S) -C - ([(1,1-dimethylethoxy) carbonyl) - amino) -cyclohexanopropanol in 250 ml (0.65M) tetrahydrofuran. The cooling bath was removed and the progress of the reaction was monitored by TLC. After 6 hours, the reaction was stopped by adding 840 ml of aqueous saturated ammonium chloride solution. The mixture was extracted with 3x500ml ether. The organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and freed from the solvent under reduced pressure. A viscous oil was obtained which was chromatographed through 1500 g of silica gel (from Merck) and eluted with ether: hexane (3: 5, later 1: 1). [R- (R *, S *) - ß - [((1,1-Dimethylethoxy) -carbonyl] -amino] -a- (2-furanyl) -cyclohexanepropanol was obtained as a very viscous oil, TLC (silica gel ; 1: 1, ether.hexane) R ₍ = 0.32.

41.63 g (128.9 mmol, 1 eq.) Of R- (R *, S *)] - β - [((1,1-dimethylethoxy) carbonyl] amino] -α- (2-furanyl) -cyclohexane-hexane-propanol were dissolved in 1 liter (0.129M) of distilled dichloromethane under an argon atmosphere, and 158.5 ml (1289 mmol, 10eq) of 2,2-dimethoxypropane was added. The solution was cooled in an ice bath and charged with 3.24g (12.89 mmol) , 0.1 eq.) Of pyridinium toluene-4-sulfonate, the cooling bath was removed, and the mixture was stirred at room temperature for 24 hours. Further 50 ml (407 mmol), 3.2 eq.) 2,2-dimethoxypropane and 1.5 g ( 6, OmMoI, 0.05eq.) Pyridinium toluene-4-sulfonate was added and stirred at room temperature for an additional 20 hours After addition of solid sodium bicarbonate, the solvent was evaporated under reduced pressure The residue was dissolved in 1 liter of ether and washed with 300 ml of saturated sodium bicarbonate solution and 300 ml of saturated brine, dried over magnesium sulfate and filtered under reduced pressure from the solvent b efreit. 47.04g of a yellow oil were obtained. This was chromatographed through 1300 g of silica gel (from Merck) and eluted with ether: hexane (1: 9). This gave 36.66 g (4S-trans) -4- (cyclohexylmethyl) -5- (2-furanyl) -2,2-dimethyl-3-oxazolidine-carboxylic acid 1,1-dimethyl ethyl ester as a colorless oil which crystallized on standing, mp 52-56 ⁰ C.

(a) _D = -46.9 ° (c = 1.6, methanol) TLC (silica gel, 1: 3, ethenehexane) R ₍ = 0.58.

36.66 g (101 mmol, 1.0 eq.) Of (4S-trans) -4- (cyclohexylmethyl) -5- (2-furanyl) -2,2-dimethyl-3-oxazolidinecarboxylic acid 1,1-dimethylethyl ester was dissolved in 200 Dissolve (0.5 M) of tetrachloromethane, 200 ml (0.5 M) of acetonitrile and 300 ml (0.33 M) of water. The mixture was stirred vigorously with a mechanical stirrer, cooled in a cold water bath and treated with 88.6 g (414 mmol, 4.1 eq) of sodium metaperiodate and 900 mg (3.4 mmol, 0.03 eq.) Of ruthenium trichloride. The mixture was stirred rapidly at room temperature. After 7.5 hours, a further 200 ml of acetonitrile, 200 ml of carbon tetrachloride, 300 ml of water and 21.4 g (10OmMoI, 1.0 eq.) Of sodium periodate were added and stirred for a further 16 hours. The solid was filtered off and washed with 500 ml of dichloromethane. The phases were separated and the aqueous phase was extracted with 2x 300ml dichloromethane. The combined organic phases were dried over magnesium sulfate and freed from the solvent under reduced pressure. An olive-green solid was obtained. This was chromatographed through 1300 g of silica gel (from Merck) and eluted with 1 to 2% methanol and 0.2% acetic acid in dichloromethane. 27.59 g of a pale yellow solid were obtained. A small sample was recrystallized from 1.3% ethyl acetate in 75 ml of hexane. An analytical sample of crystalline (4S-trans) -4- (cyclohexylmethyl) -2,2-dimethyl-3,5-oxazolidine-dicarboxylic acid 3- (1,1-dimethylethyl) ester, mp 147-151 ° was obtained C; [a] _D = -16.9 ° (c = 1.0, methanol). TLC (silica gel, 4% methanol in dichloromethane with 0.2% acetic acid) R ₍ = 0.35.

CIEH; ..NO ₆ : C H N 63.32 9.15 4.10 calc .: 63.33 9.09 4.33. Found .:

A solution of 2.45 g (7.18 mmol, 1.0 eq.) Of (4S-trans) -4- (cyclohexylmethyl) -2,2-dimethyl-3,5-oxazolidinedicarboxylic acid 3- (1,1-dimethylethyl) - ester in 48 mL (0.15 M) tetrahydrofuran was added at room temperature with 1.40 g (8.6 mmol, 1.2 eq.) of 1,1'-carbonyldiimidazole. The mixture was stirred for 30 minutes and then 980 mg (10, OmMoI, 1.4 eq.).

NO-dimethylhydroxylamine hydrochloride and 1.5 ml (10.8 mmol, 1.5 eq.) Of triethylamine were added. The mixture was stirred at room temperature overnight, then poured into 60 ml of 1 N HCl and extracted with 2 × 100 ml of ether. The organic extracts were washed with 60 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The product was eluted through 150g of silica gel (from Merck) chromatography and with ether: hexane (1: 3). This gave 1,945 g of (4S-trans) -4- (cyclohexylmethyl) -5- [l (methoxy) methylaminol-carbonyl] -2,2-dimethyl-3-oxazolidinecarboxylic acid 1,1-dimethylethyl ester, mp 75-77 ° C; [a] ₀ = +5.7 "(c = 0.9, methanol).

c) (4S-trans-5 - [[((butylamino) sulfonyl] acetyl] -4- (cYclohoxylmethyl) -2,2-dimethyl-3-oxazoline-1-carboxylic acid 1,1-dimethylethyl

737 mg (4.88 mmol, 2.5 eq.) Of the product from part (a) were dissolved in 24.4 mL (0.2 M) distilled tetrahydrofuran in an argon atmosphere. The solution was cooled to ⁰ -4o C to -45 ° C and 3,9ml (9.75 mmol, 5Äq.) Was added a 2.5 M solution of n-butyllithium in Hexantropfenweise. The mixture was stirred at ⁰ C for 30 minutes -4o. 750 mg (1.93 mmol, 1 eq) of the product of part (b) was added as a solid. The mixture was stirred for 75 minutes at -40 ⁰ C. Subsequently, the reaction was stopped with 5 ml of saturated ammonium chloride solution. The mixture was warmed to room temperature and strongly acidified with 1 η HCl. The product was extracted with 2x50 ml of chloroform, dried over magnesium sulphate and freed from the solvent under reduced pressure. The residue was passed through 70g silica gel (from Merck)

Chromatography and eluted with ether: hexane (1: 2). 589 mg (4S-trans) -5-l ((butylamino) sulfonyl) acetyl] -4-

(cyclohexylmethyl) -3-dimethyl-S-oxazolidinecarboxylic acid, ii-dimethylethyl ester as a waxy solid, mp 70-73 ° C; y [a] _D = + 33.3 ° (c = 0.6, methanol) TLC (silica gel; Etherhexane, 2: 1) R, = 0.66.

d) [4S- [4a, 5P (S *)]] - and [4S- [4a, 5β (R *)]] - 5-r2 - [(butylamino) sulfonyl] -1-hydroxyethyl] -4- (cyclohexylmethyl) -2,2-dimethyl-3-oxazolidinecarboxylic acid, 1,1-dimethylothylester

585 mg (1.23 mmol, 1 eq) of the product from part (c) were dissolved in 2.5 mL (0.5 M) anhydrous ethyl ether and cooled in an ice bath. 118 mg (1.36 mmol, 1.1 eq.) Of borane-tert-butylamine complex was added. The ice bath was removed and the mixture was stirred at room temperature overnight. Thereafter, the mixture was tit 20 ml of ether and 20 ml of 1 η HC! added and stirred for 10 minutes. The phases were separated and the aqueous phase extracted with 2x 20 ml of ether. The combined organic phases were dried over magnesium sulfate and freed from the solvent under reduced pressure. 571 mg of a solid were obtained. This was combined with product from an earlier batch and chromatographed through 60g of silica gel (ex Merck) packed in Hex., Η. It was then eluted with ether-hexane (2: 5). 416 mg (67.2%) of HS-4-sulfonyl-1-hydroxy-ethyl-1-cyclohexylmethy-1-dimethyl-S-oxazolidinecarboxylic acid i-imidyl ethyl ester as white solid, mp. 119 ⁰ C; [al = + 4.9 ° (c = 1.0, methanol). [4S- [4a, 5ß (R ") l] was treated with ether-hexane (1: 1) eluted to give an oil; [a] ₀ = -3.33 ° (c = 0.5, methanol) TLC (.. Kieselgol, etherhexane, 2: 1) R ₍ = 0.48 (isomer A) and Ri = 0.33 (isomer B).

e) [βR- (βR ^ γR *, δS ·)] · N · butyl · δ · [t (1,1-dimethylthio) · carbonyl · amlno] -β, γ-dihydroxycyclohexane-pentanesulfonamide 390 mg (0.818 mmol, 1 eq. ) of the [4S- [4a, 5β (S *)]] isomeric product of part (d) were dissolved in 5.1 ml (0.16 M) of distilled tetrahydrofuran and washed with 3.4 ml (0.24 M) of 10 % hydrochloric acid and 1.7 ml (0.4 · ^Λ M) of glacial acetic acid. The mixture was stirred at room temperature for 6.5 hours and then diluted with 30 ml of ether. The aqueous phases were extracted with 2x25 ml of ether. The combined organic phases were dried over magnesium sulfate and freed from the solvent under reduced pressure. 81% (288 mg) of [βR- (βR *, YR *, 5S ")] - N-butyl-δ- (((1,1-dimethylethoxy) carbonyl] amino] -β, γ-dihydroxycyclohexane pentanesulfonamide was obtained Foam [a] _D = -16.8 ° (c = 0.65, chloroform) TLC (silica gel, 5% methanol in dichloromethane with 0.2% NH ₄ OH) R ₍ = 0.36.

f) [βR- (βR-, YR ^# , öS ^# )] - ö-amino-N-butyl-β, Y-dihydroxycyclohexane pentanesulfonamide monohydrochloride

285 mg (0.05 mmol, 1 eq) of the product of part (e) were cooled in an ice bath and 4 ml (16 mmol, 25 eq) of 4 N of a cold HCl solution in dioxane were added. The mixture was stirred cold for 5 hours and evaporated under reduced pressure. The residue was chromatographed through 15 g of silica gel (from Merck) and eluted with 8% methanol in dioctomethane with 0.2% NH ₄ OH. The material was recovered and partially dissolved in 2% methanol in 10 ml of chloroform. The soluble material was filtered through a Fluoropore membrane and evaporated under reduced pressure. The residue was dissolved in 5 ml of methanol, treated with a slight excess of 1 N HCl solution and freed from the solvent under reduced pressure. The residue was dissolved in 20 ml of water, passed through a polycarbonate membrane and freeze-dried. This gave 119 mg [SSR (SSR * YR *, ATS *)] - 5-amino-N-butyl-ß, Y-dihydroxycyclohexane-pentanesulfonamide monohydrochloride as a white solid, mp 178-185 ⁰ C.

Ia] ₀ = -0.87 ° (c = 0.7, methanol). TLC (silica gel, 20% methanol in dichloromethane with 1% NH ₄ OH) R ₍ = 0.31, C ₁₆ H ₃₂ N ₂ O ₄ S -1.15 HCl:

C H N S Cl

: 47.61 8.83 7.40 8.47 10.77

F .: 47.71 9.05 7.34 8.49 10.69

Example 2 IβS-lßR ^ .YS ^ .ORR ^ U-O-amino-N-butyl-ß.Y-dihydroxy-cyclohexane-pentanesulfonamld monohydrochloride

a) [ßS * (ßR ^> , γS *, δR ·!] - N butyl · δ · [[(1,1 · dimethylthio) -carbonylo] · amlno) · β, γ · dihydroxycyclohexane · pθntansl! lfonamide The 150 mg ( 0.315 mmol, 1 eq.) Of the [4S- [4a, 5β (R *)]] isomeric product of Example 1 (d) were dissolved in 2.55 mL (0.12M) distilled tetrahydrofuran and washed with 1.7 mL (0 Hydrochloric acid and 0.85 ml (0.36M) of glacial acetic acid The mixture was stirred at room temperature for 6 hours and then diluted with ether The phason was extracted with 2x15 ml of ether and the combined organic phases were extracted with 2χ12 washed with water and 15 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate and freed from the solvent under reduced pressure to give 93 mg of [βS- (βR *, Y3 ^# , ÖR *)] -N-butyl-α-lld.i-dimethylethoxy-J-carbonyl -26.4 ° -amino-ß.Y dihydroxycyclohexanpentansulfonamid as a foam [a] _D = (c = 0.55, chloroform) TLC (silica gel; 10% methanol in dichloromethane with 0.2% NH ₄ OH).. R ₍ = 0.53.

b) [βS- (pR *, YS *, 5R *)] - 5-amino-N-butyr-β, Y-dihydroxycyclohexane pentanesulfonate monohydrochloride 90mg (0.206 mmol, 1 eq) of the product of Toil (a) The mixture was cooled in an ice-bath and 3 ml (12 mmol, 58 eq.) of cold 4 N HCl in dioxane were added, the mixture was stirred at ⁰ ° C. for 6 hours and evaporated under reduced pressure to give 82 mg of material of the deprotected amine from part (a) obtained by freeze-drying the aqueous oil and washings, the mixture was chromatographed through 8 g of silica gel (from Merck) and mixed with 10% methanol in 0.2% dichloromethane. NH ₄ OH oluiert. This gave 91 mg of foam which was dissolved in 5 ml of methanol, and 0.27 ml (0.27 mmol, 1 eq.) 1-η HCI solution was added. the solvent was removed under reduced pressure. the residue was dissolved in 20 ml of water, filtered through a polycarbonate membrane and freeze-dried to give 80 mg of βS- (βR *, YS *, ÖR * ) lo-amino-N-butyl-β, Y-dihydroxycyclohexane-pentanesulfonamide monohydrochloride, m.p. 13-14 ° C; [a) ₀ = -12.5 ° (c = 0.6, methanol). TLC (silica gel, 20% methanol in dichloromethane with 1% NH ₄ OH) R, = 0.26. C ₁₅ H ₃₂ N ₂ O ₄ S · 1.15HCl · 0.1H ₂ O.

C H N S Cl

: 47.38 8.84 7.37 8.43 10.72

F .: 47.43 9.06 7.25 8.23 10.66

Example 3

* \ [1S- (1R *, 2S ^ 3R *)] x (3-oxo-3-phenylpropyl) -N [4 - [(butylamino) sulfonyl] -1- (cycloethylmethyl) 2,3-dihydroxybutyl] - L ·

ι histidinamide monohydrochloride

a) N- (I-Oxo-3-phenylpropyl) -3 - [(phenylmethoxy) methyl] -L-hlstldln

A solution of 25 g (58.5 mmol) of N-I (1, i-dimethylethoxycarbonyl-S-phenylmethoxy-methyll-L-histidine methyl ester

(prepared by the method of Brown et al., J. Chem. Soc. Perkins Trans, Vol. 1 [1982], p. 1553) in 150 ml of acetic acid containing HCl gas (1.7 M) Stirred for 2 hours at 25 ^: C and then evaporated to dryness. The gummy residue was recrystallized in isopropanol. 19 g of 3 - [(phenylmethoxy) methyl] -L-histidine methyl ester were obtained as a white crystalline solid, mp 167-16U ⁰ C.

A mixture of 18.5 g (51 mmol) of 3 - [(phenylmethoxy) methyl] -L-histidine methyl ester, 7.7 g (51 mmol) of hydrocinnamic acid, 18 ml (128 mmol) of triethylamine, 6.9 g (51 mmol). 1-Hydroxybenzotriazole hydrate and 9.8 g (51 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 100 ml of dimethylformamide were stirred at 25 ° C. for 20 hours and then diluted with 500 ml of Mallinckrodt's pH 4 buffer solution. The mixture was then extracted with ethyl acetate and the extracts were washed with water, dried over magnesium sulfate and evaporated. This gave 18.7 g of N- (1-oxo-3-phenylpropyl) -3 - [(phenylmethoxy) methyl] -L-histidine methyl ester as a clear oil.

A mixture of 17.2 g (40.8 mmol) of N- (1-oxo-3-phenylpropyl) -3 - [(phenylmethoxy) methyl] -L-histidine methyl ester and 52 ml (52 mmol) of a 1N sodium hydroxide solution in 42 ml of methanol was stirred for 6 hours at 25 ⁰ C, then diluted with 500 ml of water and washed with ethyl acetate. The aqueous phase was neutralized to pH 5 by addition of 52 ml (52 mmol) of 1N hydrochloric acid. The mixture was extracted 5x with ethyl acetate. The extracts and aqueous washings were evaporated under reduced pressure. Both concentrates were stirred with 500 ml of hot isopropanol and filtered hot. The combined filtrates were partially evaporated until crystals formed. The crystals were collected and dried. 6.5 g was obtained N- (1-oxo-3-phenylpropyl) -3 - [(phenylmethoxy) methyl] -L-histidine as a white powder, mp 163-165 ⁰ C.

b) [1S- (1R *, 2S *, 3R *) 1 * (1 * oxo-3-phthylpropyl) * N * [4 - [(butylamino) sulphonyl] 1- (cyclohexylmethyl). 2,3- dihydroxybutyl] · 3 · [(phenylmethoxy) methyl] -L-hlstidinam! d

49.4 mg (0.12 mmol, 1 eq.) Of the product of part (a), 46.1 mg (0.12 mmol, 1 eq.) [ΒS- (βR *, YS *, 5R *)] - ö Amino-N-butyl-β, Y-dihydroxycyclohexane pentanesulfonamide monohydrochloride (product of Example 2) and 16.4 mg (0.12 mmol, 1 eq.) Of 1-hydroxybenzotriazole were dissolved in 1.6 ml (0.1 M) of distilled tetrahydrofuran. The solution was cooled in an ice bath and treated with 17μΙ (0.139 mmol, 1.15 eq.) Of 4-methylmorpholine. After 15 minutes, 25 mg (0.12 mmol, 1 eq.) Of 1,3-dicyclohexylcarbodiimide was added. The mixture was stirred for 18 hours at 5 ⁰ C, 6 hours at room temperature and finally for 16 hours at 10 to 15 ° C. The mixture was cooled to CC and diluted with 5 ml of chloroform. After stirring for 45 minutes, a small amount of a solid was filtered off. The filtrate was further diluted with chloroform, washed with aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and freed of solvent under reduced pressure. The residue was adsorbed on about 1 g of silica gel and the solvent was removed. The silica gel was placed on top of a column packed with 10g silica gel (from Merck). The dicyclohexylurea was eluted with 20% acetone in chloroform. The desired product was then eluted with 5% methanol in chloroform with 0.2% NH ₄ OH. 73mg of [1S- (1R \ 2S, 3R *)) - (1-oxo-3-phenylpropyl) -N- [4 - [(butylamino) -sulfuryl] (cyclohexylmethyl) -2,3 was obtained -dihydroxybutyl] -3- ((phenylmethoxy) methyl] -L-histidine amide, TLC (silica gel, 10% methanol in dichloromethane with 0.2% NH ₄ OHj) R ₍ = 0.42.

c) [^ - (^ », aS'.SR'll.

histidineamide monohydrochloride

71 mg (0.098 mmol, 1 eq.) Of the product of part (b) were dissolved in 2.0 ml (0.05M) methanol, 0.3 ml (0.33M) water and 100 μM (1 eq) 1N HCl, and with 20mg (20Gow .-%) added 20% palladium hydroxide on carbon. The mixture was stored for 4 days under a hydrogen atmosphere. During this time, an additional 10 mg of 20% palladium hydroxide on carbon was added. The mixture was diluted with ethanol, the catalyst was filtered through regenerated cellulose and the solvent was removed under reduced pressure. This gave 62.7 mg, which were chromatographed through 6 g of silica gel (from Merck) and eluted with 5 to 7% methanol in dichloromethane with 0.2% NH ₄ OH. 39.2 mg of L-histidine amide product were obtained. This material was dissolved in 5 ml of methanol and ΓηΗ65μΙ (1 equiv.) 1 η HCl solution. The solvent was removed under reduced pressure. The residue was dissolved in a mixture of 12 ml of water and 3 ml of ethanol, passed through a polycarbonate filter and freeze-dried. This gave 40.4 mg of [1S- (1R \ 2S \ 3R *)] - (1-oxo-3-phenylpropyl) -N- [4-

! (butylaminoJ-sulfonyll-i-teyclohexylmethyO ^ .S-dihydroxybutyll-L-histidinamide, monohydrochloride; F. 62-80 ⁰ C; [a] _D = -29.5 ° depending = 0.44, methanol). TLC (silica gel, 10% methanol in dichloromethane with 0.2% NH ₄ OH) Ri = 0.26. C ₃₀ H ₄₇ N ₅ O ₆ S-HCl-LeH ₂ O:

C H N Cl S

: 53.41 7.71 10.38 5.25 4.75

Filled: 53,39 7,40 10,32 5,32 4,62.

Example 4

[1S * (1R ^ 2R *, 3S *) 1 * (1X-oxo-3-phenylpropyl) N-t4 [(butylamino) sulfonyl] -1-cyclohexylmethyl) -2,3 * dlhydroxybutyl L-hlstidinamld-trifluoroacetate ( 1: 1) salt

a) [1S * (1R ^ 2R *, 3S *) 1 * (1-oxo-3 * p-1-nylpropyl) * N * t4 * [(butylamino) -suUonyll * 1 * (cyclohexylmethyl) -2, 3 · dlhydroxybutyll · 3 - [(phenylniethoxy) methyl] -L-hlstidInamld

97 mg (0.288 mmol, 1 eq.) (Β R - (p R *, y R *, 5 S)) - 5-amino-N-butyl-β, Y-dihydroxycyclohexane pentanesulfonamide (the free base of the product of Example 1), 117.4 mg (0.288 mmol, 1 eq.) N- (1-Oxo-3-phenylpropyl) -3 - [(phenylmethoxy) methyl] -L-histidine and 39 mg (0.288 mmol, 1 eq) of 1-hydroxybenzotriazole were partially dissolved in dissolved 2.8 ml (0.1 M) distilled tetrahydrofuran. The mixture was cooled in an ice bath and 59,4mg (0,288mMol, 1 eq.) iS-dicyclohexylcarbodiimide was added. The mixture was for 22 hours at 5 to 7 ⁰ C and The mixture was then stirred at room temperature overnight, the mixture was then diluted with 12 ml of chloroform and stirred for 1 hour at ⁰ ° C. A small amount of solid was filtered off Filtrate was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure from L solvents removed. The residue was chromatographed through 20 g of silica gel (Merck). The dicyclohexylurea was eluted with 20% acetone in chloroform. The desired product was eluted with 5% methanol in chloroform with 0.2% NH ₄ OH. The material obtained was further purified by chromatography through 10 g of silica gel (from Merck) and elution with 3% methanol in dichloromethane at 0.2% NH ₄ OH. 126mg of [1S- (1R *, 2R *, 3S ^# )] - (1-oxo-3-phenylpropyl-N - ^ -butylamino-1-sulfonyl-1-cyclohexylmethoxy) -4-dihydroxybutyl-1-kphenylmethoxylate was obtained. methyll-L-histidinamide, TLC (kiosel gel, 10% methanol in dichloromethane with 0.2% NH ₄ OH) R ₍ = 0.60.

b) [IS-dR'.aR'.SS ^ JHi-Oxo-S-phenylpropyl-N-W-Ubutylamnol-sulfonyl-i-cyclohexylmethyD ^ .a-dihydruxybutyl-L-hlstidinamyl-trifluoroacetate (1: 1) salt

112 mg (0.154 mmol, 1 eq) of the product from part (a) were dissolved in 3.1 mL (0.05 M) methanol, 0.5 mL (0.33 M) water, and 154 μΙ (0.155 mmol 1 eq) 1 η HCI dissolved and mixed with 30mg (25Gtw .-%) 20% palladium hydroxide on carbon. The mixture was placed under a hydrogen atmosphere for 4 days. During this time, an additional 20 mg of 20% palladium hydroxide on carbon was added. The mixture was diluted with methanol, the catalyst filtered through regenerated cellulose and the solvent removed under reduced pressure. This gave 97 mg of a product which was chromatographed by 10 g of silica gel (from Merck) and eluted with 5% methanol in dichloromethane. 80 mg of a material were obtained by preparative HPLC with a completely sealed C-18 column (YMC 1-15 100A, ODS, 30 × 500 mm, 15 μm spherical, 21 ml / min, UV control at 220 nm) and elution with 76.4% methanol in water was further purified with 1% trifluoroacetic acid. The peak eluted after 17.5 to 20.5 minutes was evaporated to dryness under reduced pressure. The residue was dissolved in 20 ml of 20% ethanol in water, passed through a polycarbonate filter and freeze-dried. One obtained ogmgliS-IIR 'R' ^ S'-d-oxo-S-phenylpropyD-NK-Kbutylaminol-sulfonyl-i-tcyclohexylmethyD ^ .s-dihydroxybutyl-L-histidine amide trifluoroacetate (1: 1) salt, F 60-110 ° C; [a] ₀ = -30.2 ° (c = 0.58, methanol). TLC (silica gel, 10% methanol in dichloromethane with 0.2% NH ₄ OH) R, = 0.34

C ₃₀ H ₄₇ N ₆ O ₆ S · 0.4H ₂ O · 1.15 CF ₃ COOH:

CHNFS: 52.14 6.63 9.41 8.81 4.31

F .: 52.11 6.55 9.26 8.85 4.57.

Bc; piel5

[1S- [1R * (R *), 2S * 3S *]] * [2 * [[(1,1-dimethylthyl) sulfonylmethyl] -1 * oxo-3-phenylpropyl] N- [4 - [(butylamino ) -sulfonyl] -1- (cyclohexylmethyl) -2,3-dihydroxybutyl J-L-histidine amide methanesulfonate (1: 1) salt

a) (S) N- [2 - [(1,1-Dimethylmethylsulfonyl) -1-oxo-3-phenylpropyl-3 - [(phenylmethoxy) methyl] -L-histidine A solution of 53.8 g (33 μmol Benzylacrylic acid in 830 ml (0.4 M) of tetrahydrofuran was admixed with 57 ml of (99 μmol) ethanol and 20.3 g (165 mmol dimethylaminopyridine.) The resulting mixture was pre-treated with 68.1 g (33 μmol) dicyclohexylcarbodiimide in 330 ml of tetrahydrofuran in 2 hours. the resulting mixture was stirred for 18 hours at 25 ⁰ C, fi'triert thereafter and evaporated. the residue was partitioned between 1 η hydrochloric acid and ether. the organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated. the semi-solid The residue was filtered and the filtrate was distilled under reduced pressure to give 45.3 g of ethyl α-methylenebenzenepropanoate as a colorless oil, bp 85-95 ° C / 2 Torr.

To a solution of 52 g (273 mmol) of α-methylenebenzenepropanoic acid ethyl ester in 1300 ml of ethanol was added 62.1 ml (547 mmol) tert-butylmercaptan and 19.6 g (287 mmol) sodium ethanolate powder. The resulting mixture was stirred at 25 ^° C. for 18 hours. Thereafter, the mercaptan was distilled off at atmospheric pressure (bp 65-8O ⁰ C). The residue was further evaporated under reduced pressure. The resulting syrup was partitioned between ether and water and then extracted 2x with ether. The combined ether phases were washed with water, dried over magnesium sulfate and evaporated. This gave 65.2 g of a - ([(1,1-dimethylethyl) thio] methyll-benzenepropanoic acid ethyl ester.

A solution of 42.8 g (153 mmol) of ethyl α - [[(1,1-dimethylethyl) thio] methyl benzoate in 650 ml of ethanol was stirred at ⁰ ° C. for 1 hour with a solution of 141 g potassium monopersulfate (oxone Mixture of Alfa) in 650ml of water. This formed a white precipitate. After completion of the addition, the mixture was stirred at 25 ⁰ C for 18 hours. The mixture was partially evaporated under reduced pressure to remove most of the ethanol and partitioned between ether and 1N hydrochloric acid. The aqueous phase was re-extracted with ether and the combined ether extracts saturated i

Sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated. This gave 45.6 g of a - [[(1,1-dimethylethyl-sulfonyl-methyl-1-benzolpropanoic acid ethyl ester.

A suspension of 21.3 g (68.1 mmol) of a - [[(1,1-dimethylethyl) sulfonyl] -methyl] -benzenepropanoic acid ethyl ester in 165 ml of 6N hydrochloric acid wu. stirred for 18 hours at reflux temperature and then evaporated under reduced pressure. The residue was digested with ether. 15.7 g was obtained a- [l (1,1-dimethylethyl) sulfonyl] methyl) benzenepropanoic acid as a white solid, mp 138-143 ⁰ C.

A solution before. Wg (20SmMoI) aU (1,1-dimethylethyl) sulfonyl] -methyl] -benzenepropanoic acid in 1 liter of acetonitrile was washed with eir.er L: ^ s. ., -Oi ö9g '° .08mMol) (+) - dehydroabietylamine in 500ml acetonitrile. It immediately formed a precipitate. DasGerr · '· · .ut> 18 hours stored at 25 ⁰ C. Thereafter, the solid was eingesarnmolt. The majority of the solid was dissolved in 2 liters of hot isopropanol and the resulting solution was slowly cooled to -3O ⁰ C. After 24 hours, the obtained crystals were collected. 160-170 "C, [a] ₀ = + 18.4 ° (c = 1.4, methanol) The crystals were recrystallised a further 4 times in isopropanol to give 30.5 g of (S) -a - [( (1,1-dimethylethyl) sulfonyl) -methyll-benzolpropansäuredehydroabietylamin (1: 1) salt, m.p. 181-183 ⁰ C, [a] _D = + 22.5 ° (c = 1.6, methanol) A. Solution of 30.5 g (53.5 mmol) of this dehydroabiethylamine salt in 500 ml of ethyl acetate was extracted three times with aqueous potassium carbonate solution The combined aqueous extracts were washed once with ethyl acetate and then acidified with concentrated hydrochloric acid The solution was then extracted three times with dichloromethane Extracts were dried over magnesium sulfate and evaporated The residue was triturated with ethyl acetate / hexanes to give 12.2 g of (S) -a - [((1,1-dimethylethyl) sulfonyl] methyl-1-benzene-propanoic acid as a white crystalline solid, m.p. . 97.5 to 98.5 ⁰ C. [α) ο = + 9.1 ° (c = 1.2, dichloromethane).

A solution of 5.12 g (18 mmol) of (S) -a- [i (1,1-dimethylethyl) sulfonylmethyl] -benzenepropanoic acid, 6,5 g (18 mmol) of S-KPhenylmethoxy-methyll-L-histidine. methylester dihydrochloride and 2.75 g (18 mmol) of hydroxybenzotriazole hydrate in 80 ml of dry dimethylformamide, cooled to 0 ⁰ C under argon was added 5,36g (5 ml, 53 mmol) of N-methylmorpholine. To the resulting mixture was added 3.87 g (19.8 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The mixture was warmed to room temperature overnight. After 18 hours, the dimethylformamide was removed under reduced pressure. Then, 90 ml of pH 4 phosphate buffer was added and the aqueous mixture was extracted once with 100 ml and twice with 150 ml of ethyl acetate. The combined organic phases were washed with 2 x 100 ml of water, 100 ml of semigosaturated sodium bicarbonate solution and 100 ml of brine. The organic phase was dried over magnesium sulfate and evaporated. This gave 8.37 g of an oil. Extraction of the combined water, sodium chloride and sodium bicarbonate washes further yielded 0.73 g of product (after chromatography). Overall, mang.iglSl-NU-KI.I-dimethylethyl-sulfonyl-i-cxo-S-phenylpropyl-S-Kphenylmethoxymeth-L-histidine-methyl ester was obtained; [old, = + 9.84 ° (c = 1.92, methanol). TLC (silica gel, ethyl acetate: pyridine: acetic acid: water, 180: 20: 6: 11) R ₍ = 0.55, C ₂₉ H ₃₇ N ₃ O ₅ S, 0.28H ₂ O:

CHNS: 62.11 6.75 7.49 5.72

Filled: 02.11 6.58 7.47 5.60.

A solution of 8.3 (14.9 mmol) of the above-prepared iviethyiester product in 90 ml of dry methanol was cooled to 0 ° C. and admixed with 19.4 ml (19.4 mmol) of 1.0N sodium hydroxide solution After 16 hours, methanol was removed under reduced pressure and 100 ml of water were added, the aqueous solution was acidified to pH 5 with 1N hydrochloric acid and then extracted with 4x150 ml of ethyl acetate The combined organic extracts were washed with 2x75 ml of brine, dried over magnesium sulfate After flash chromatography through 1000 g of silica gel (from Merck) and elution with 10: 1.1: 0.9 ethyl acetate / acetic acid-water, 5.0 g of (S) -N- [2] were obtained by evaporation under reduced pressure -l (1,1-dimethylethyl) sulfonyl] -1-oxo-3-phenylpropyl] -3 - ((phenylmethoxy) methyl-L-histidine; (alp = + 40.8 ° (c = 1.2, Methanol), TLC (silica gel, ethyl acetate: acetic acid: water, 8: 1.1: 0.9) R, = 0.26

C ₂₈ H ₃₅ N ₃ O ₆ S-0.43H ₂ O:

CHNS: 61.21 6.58 7.65 5.84

F .: 61.32 6.40 7.54 5.93.

b) [1S * [1R * (R *), 2S *, 3S *]] - [2- (1,1-dimethylmethyl) -1-sulfonylmethyl · 1-oxo-3-phenylpropyl] - ['x. [(butylamino) sulfonyl] -1- (cyclohexylmethyll ^^ - dihydroxybutyU-d-Llphenylmethoxyl-methyU-L-histidinamld

549 mg (1.0 mmol, 1 eq) of the L-histidine product of ¹ teU ia), 373 mg (1 eq "product of Example 1)! ΒR- (rR \ YR *, 5S *)] - 5-amino-N- butyl-.beta.-Y-dihydroxycyclohexane pentanesulfonamide monohydrochloride and 135 mg (1, OmMoI, 1 eq.) of 1-hydroxybenzotriazole were partially dissolved in 10 ml (0.1 M) of distilled tetrahydrofuran, cooled to ⁰ ° C. and washed with 110 .mu.l (1, OmMoI, 1 , 0Aq.) 4-Methylmorpholin added. The mixture became cloudy. After 15 minutes at ⁰ ° C., the mixture is mixed with 206 mg (1.0 mmol, 1 eq.) Of dicyclohexylcarbodiimide and stirred for 20 hours at 5-7 ° C. and for a further 20 hours at room temperature. 40 ml of chloroform were added and stirred at 0 ° C for 40 minutes. Then a small amount of solid was filtered off. The filtrate was washed with saturated sodium bicarbonate solution and saturated brine, dried over magnesium sulphate and distilled under reduced pressure from the solvent ¹ lb./par. The 1.05 g of the remaining material was chromatographed through 60 g of Kieselgo ¹ (ex Merck), eluting first with 20% acetone in chloroform to remove the dicyclohexylurea zm. The product was then eluted with 2.5 to 4% methanol in dichloromethane. 535 mg of H S- (1 R "(R ¹ '), 2 S *, 3 S *]] - [2- [1- (1,1-dimethylethyl) sulfonyl] methyl-1-oxo-3-phenylpropyl] were obtained. -N- [4 - ((butylamino) sulfonyl-1- (cyclohexylmethyl) -2,3-dihydroxybutyl] -3 - [(phenylmethoxy) methyl] -L-histidine amide as a foam; [a] ₀ = -i0.0 ° (c - 0.9, methanol), TLC (silica gel, 5% methanol in dichloromethane) R ₍ = 0.26.

c> [1S * [1R ¹ '(R *), 2S *, 3S *] H 2 - [[(1,1-dimethyl-thyl) -sulfonyl] -methyl] -1-oxo-3-phenyl-propyl-N * [4- [(Hutylamino) sulfonyl] (cyclohexylmethyl) -2,3-dihydroxybutyl] -L-histidine-amine-methanesulfone & t (1: 1) salt

527 mg (0.61 mmol, 1 eq.) Of the L-histidine amide product of part (b) were dissolved in 12 mL (0.05 M) methanol and 1, GmI (0.33 M) water. To this solution was added 0.61 ml (0.61 mmol, 1 eq) of 1 N hydrochloric acid and 105 mg (20 wt%) of 20% palladium hydroxide on carbon. This genius was in e ^; ner hydrogen atmosphere stirred for 24 hours at room temperature.

Selecting this time, another 30 mg of 20% palladium hydroxide was added to carbon. The mixture was then diluted with methanol and the catalyst removed under reduced pressure. The residue was chromatographed through 50g of silica gel (from Merck) and eluted with 5% methanol in dichloromethane with 0.2% NH ₄ OH. 342 mg of the free base were obtained. 342 mg (0.462 mmol, 1 eq) of this material were dissolved in 10 ml of methanol and treated with 30μΙ (0 / .62mMol, 1 eq.) Methanesulfonic acid. The solution was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in 20 ml of water, poured through a polycarbonate filter and freeze-dried. 362 mg of [1S- [1R ^# (R ^# ), 2S *, 3S "]] - [2-I [(1,1-dimethylethyl) sulfonylmethyl) -1-oxo-3-phenylpropyl were obtained as a white solid ] -N- [4 - [(butiamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dihydroxybutyl] -L-histidine amide methanesulfonate (1: 1) salt; 80-110 ° C (with decomposition); [a] ₀ = -5.0 ° (c = 0.58, methanol). DCfKieselgel; 8% methanol and dichloromethane with 0.2% NH ₄ OH) R, = 0.27

C ₃₅ H ₆₇ N ₆ O ₈ S ₂ · CH ₃ SO ₃ H · 0.6H ₂ O:

CHNS: 51.06 7.40 8.27 11.26

Filled: 51.00 7.57 8.20 11.60.

Examples

[1S- (1R ^ 2S ^ 3S *) L • N • [4 - [(butylamino) sulfonyl] 1- (cyclohexylmethyl) -2,3-dlhydroxybutyl-3-pyridinecarboxamide 41 mg (0.332 mmol, 1 eq. ) Nicotinic acid and 125mg (0.332 mmol, 1 eq.), (Β R - (β R *, y R ", 5 S))] - δ-amino-N-butyl-β, Y-dihydroxycyclohexane pentanesulfonamide monohydrochloride (product of Example 1) The mixture was cooled to ⁰ ° C. and treated with 44.9 mg (0.332 mmol, 1 eq) of 1-hydroxybenzotriazole, 69.5 μ l (0.499 mmol, 1.5 eq. Triethylamine and 63.7 mg (0.332 mmol, 1 eq) of ethyl S-fS-dimethylaminol-propyl-carbodiimide hydrochloride The mixture was warmed slowly to room temperature and stirred for 21 hours 8 mL aqueous buffer of pH 4.0 (from Mallinckrodt) were added and the mixture was stirred for 30 minutes The precipitate was filtered off, washed with more buffer and water and dried under reduced pressure overnight The solid was dissolved in about 12 ml of methanol and added to about 5 g of silica gel (ex Baker This was, after removal of the solvent, layered on a column of 10 g of silica gel (from Merck) packed in dichloromethane. The product was eluted with 5% methanol in dichloromethane with 0.2% NH ₄ OH. The crystalline solid obtained was 130 mg of [1S- (1R \ 2S \ 3S *)] - N- [4 - [(butylamino) -sulfonyl-1-fcyclohexylmethyD ^. S -dihydroxybutyl-1-pyridinecarboxamide. 173-175 ° C; (a) ₀ = -14.7 ° (c = 0.9, methanol) TLC (silica gel, 10% methanol in dichloromethane with 0.2% NH ₄ OH) R ₍ = 0.45

C ₂₁ H ₃₆ N ₃ O ₆ S:

CHNS: 57.12 7.99 9.52 7.26

Filled: 57.01 7.99 9.53 7.49.

Likewise, nicotinic acid was reacted with the product of Example 2. There was obtained [1S- (1R *, 2S *, 3R))] - N- [4 - [(Ri.itylaminol-sulfonyl-i-cyclopentylmethoxy) -1-dihydroxybutyl-S-pyridinecarboxamide, m.p. -64 ⁰ C; [a) ₀ = -19.9 ° (c = methanol). TLC (silica gel, chloroform: methanol: NH ₄ OH, 30: 3: 0.05) R ₍ = 0.24, C ₂₁ H ₃₆ N ₃ O ₅ S, 0.3H ₂ O:

CHNS: 56.43 8.03 9.40 7.17

F .: 56.48 8.04 9.18 6.82.

Example 7

[IS-ilR '^ S ^ .SS ^ Jl-NW-KButylamino-sulfonyU-i-cyclohexylmethyD ^ .S-dihydroxybutyno-pyridinecarboxylic acid amide Following the procedure of Example 6 but using equimolar amounts of 41 mg of isonicotinic acid (0.332 mmol, 1 eq.) and 125 mg (0.332 mmol, 1 eq.) of the product of Example 1 gave a crystalline solid 117 mg [1S- (1R \ 2S, 3S)} LN- (4 - [(butyiaminol) sulfonyll-i-lcyclohexylmethyD ^ .S ^ dihydroxybutyll -pyridincarbonsäureamid, F. 168-186 ⁰ C;. [o.] _D = - 5.9 ° (c = 0.66, methanol) TLC (Kieselgei; 5% methanol in dichloromethane with 0.2% NH ₄ OH) R _f = 0.22 C ₂₁ H ₃₅ N ₃ O ₆ S 0.5H ₂ O:

CHNS: 55.98 8.05 9.33 7.12

Filled: 56.01 7.87 9.41 7.28.

Examples

[1S- (1R *, 2S *, 3S *) 1 N - [4 - [(Butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dihydroxybutyl] -2-pyridinecarboxylic acid Amide According to the method of Example 6, but employing equimolar amounts of 32.7 mg (0.266 mmol, 1 eq.) Of picolinic acid and 100 mg (0.266 mmol, 1Aq.j of the product of Example 1, gave as a solid 107 mg (1S- (1R \ 2S \ 3S ^# )] - N- [4-I (Butylamino) -sulfonyl-i-fcyclohexylmethyD ^ .S-dihydroxybutyll ^ -pyridinecarboxylic acid, m.p. 167-17O ⁰ C; (a) ₀ = -15.5 ° (c - 0.64, methanol) TLC (silica gel, 7% methanol in dichloromethane with 0.2% NH ₄ OH) R ₁ = 0.46

C ₂₁ H ₃₆ N ₃ O ₆ S:

CHNS: 57.12 7.99 9.52 7.26

F .: 57.08 8.03 9.44 7.42.

Example 9

[IS-ilR ^^ S'.aS'Jl-NM-t'butylaminol-sulphonyl-i-cyclohexylmothyD ^ .S-dihydroxybutyn ^ -pyraiycarboxylic acid amide Following the procedure of Example 6 but using equimolar amounts of 33, 3 mg (0.268 mmol, 1 eq) of 2-pyrazinecarboxylic acid and 100 mg (0.268 mmol, 1 eq.) Of the product of Example 1 were obtained as solid 106 mg

[1 S- (1 R *, 2S *, 3S * ^l)] * N- [4 [(butylamino) sulfonyll · · 1- (cyclohβxylmβthyl) -2,3-dίhydroxybutvl] -2-pvrazincarbonsäure, F. 178- 180 ° C; [a] _D = -17.4 ° (c = 0.5, methanol). TLC (silica gel, 7% methanol in dichloromethane with 0.2% NH ₄ OH) R, = 0.43. C ₂₀ H ₃₄ N ₄ O ₆ S:

CHNS: 54.28 7.74 12.66 7.24

F .: 54.44 7.73 12.63 7.17.

Example 10

[IS-dR'.aS .as ^ ^ n-N-W-KButylaminol-sulfonyll-i ^ .a-lcyclohexv.methyD dihydroxybutyll-e-hydroxy-apyrldlncarbonaäureamld

Following the procedure of Example 6 but using equimolar amounts of 37.3 mg (0.268 mmol, 1 eq.) Of 6-hydroxynicotinic acid and 100 mg (0.268 mmol, 1 eq.) Of the product of Example 1, the white solid obtained was 30 mg of ILS - (1R ', 2S *, 3S ")] - N- [4 - [(butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dihydroxybutyl] -6-hydroxy-3-pyridine carboxamide; F. 247-262 ⁰ C; Ia] ₀ = -31.5 ° (c = 0.34, methanol). TLC (silica gel, ¹ % methanol in dichloromethane with 0.2% NH ₄ OH) R, = 0.30.

C ₂₁ H ₃₅ N ₃ O ₆ S:

CHNS bor .: 50.12 7.71 9.18 7.01

F: 55.08 7.76 9.01 6.97.

Example 11

[IS-ilR ^ .aS ^ .SS'Jl-NW-KButylaminol-sulfonylJ-i-cyclohexylmethyD ^ .S-dihydroxybutyU ^ -pyridazinecarboxamide Following the procedure of Example 6 but using equimolar amounts of 33mg (0.268 mmol, 1 eq.) Of 4-pyridazinecarboxylic acid and 100 mg (0.268 mmol, 1 eq.) Of the product of Example 1, as a white solid, 31 mg of [1S- (1R *, 2S *, 3S *)] - N- [4- t (butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dihydroxybutyll-4-pyridazincarbonsäureamid, F. 170-172 ⁰ C; Ia] ₀ = -29.1 ° (c = 0.43, methanol). TLC (silica gel, 10% methanol in dichloromethane with 0.2% NH ₄ OH) R, = 0.46. C ₂₀ H ₃₄ N ₄ O ₆ S:

CHN: 54.28 7.74 12.66

F .: 54.14 7.72 12.47.

Example 12

[IS-dR ^^ S'.aS'll-N-W-aButylaminoJ-sulfonyll-i ^ .a-lcyclohexylmethyD dihydroxybutyU-benzamide

Following the procedure of Example 6, but employing equimolar amounts of 32.7 mg (0.268 mmol, 1 eq.) Of benzoic acid and 100 mg (0.26 .mu.mMoI, 1 eq.) Of the product of Example 1, the solid obtained was 86.0 mg [1 S- (1 ^ RVS SML-Nt / l-KButylamino) -sulfonylJ-i-fcyclohexylmethyD ^ .S-dihydroxybutyll-benzamide, mp 153-155 ⁰ C; [a] ₀ -15.8 ° (c = 1.49, methanol). TLC (silica gel, 7.5% methanol in dichloromethane with 0.2% NH ₄ OH) R ₍ = 0.45.

C ₂₂ H ₃₈ N ₂ O ₆ S 0.37H ₂ O:

CHNS: 59.07 8.28 6.26 7.17

Filled: 59.07 8.32 5.95 7.21.

Example 13

[IS-dR1-C5-N-N-KB-butylaminol-sulfonyl-i-tcyclohexylmethyD ^ .S-dihydroxybutyl-S-dihydroxybenzamide Following the procedure of Example 6 but using equimolar amounts of 41.3 mg ( 0.268 mmol, 1 eq.) Of 2,4-dihydroxybenzoic acid and 100 mg (0.268 mmol, 1 eq) of the product of Example 1 gave as a solid 109 mg of [1 S- (1 R *, 2 S, 3 S *)]. -N-t4 - [(butylamino) -sulfonyll-1- (cyclohexylmethyl) -2,3-dihydroxybutyl] -3,4-dihydroxybenzamide, F. 162-165 ⁰ C; (Shrinking at 152 ° C); [a] ₀ = -21.9 ° (c = 0.5, methanol). TLC (silica gel, 10% methanol in dichloromethane with 0.2% NH ₄ OH) R, = 0.33.

C ₂₂ H ₃₆ N ₂ O ₇ S0,25H ₂ O: H N S C 7.71 5.87 6.72 about .; ; 55.38 7.94 5.82 6.80. Found .: 55.35

Example 14

[IS-dR ^ S'.aS ^ JJ-a ^ -diamino-N-M-Kbutylaminol-sulfonyD-i-lcyclohexylmethyD ^ .S-dihydroxybuxyll-bonzamldmonohydrochlorld

By the method of Example 6, but using equimolar amounts of 41 mg (0.268 mmol, 1 eq.) Of 3,4-diaminobenzoic acid and 100 mg (0.268 mmol, 1 eq.) Of the product of Example 1, was obtained as white, glassy Foam 73mg (^ - (^ »^ S ^ .SS'HS ^ -Diamino-NW-Kbutylaminol-sulphonyl-i-cyclohexylmethyD ^ .S-dihydroxybutyl-benzamide. 73g (0.155mmol, 1eq.) Of this material was dissolved in 5ml of methanol 0.31 ml (0.31 mmol, 2 eq.) of 1N hydrochloric acid were added and the solvent was removed under reduced pressure The remaining material was dissolved in 20 ml of water containing 5% of ethanol, passed through a polycarbonate filter and freeze-dried 65 mg of [1S-! 1R, 2S *, 3R *) l-3,4-diarrino-N-l4 - [(butylamino) sulfonyl-1- (cyclohexylmothyl) -2,3 were obtained as a white solid -dihydroxybutyl] -ben7.amidmonohydrochlorld; F. 120-142 ⁰ C (decomposition); [a] ₀ = -19.5 ° (c = 0.4, methanol) TLC (silica gel;. 10% methanol in dichloromethane containing 0 , 2% NH ₄ OH) R, = 0.43 C ₂₂ H ₃₈ N ₄ O ₆ S x 0 95HCl · 0.3H ₂ O:

C H N Cl S

: 51.74 7.81 10.97 ö, 60 6.28

F .: 51.78 7.87 11.01 6.46 6.46.

Example 15 i

butenoic acid ethyl ester

38.6 mg (0.268 mmol, 1 eq) of monoethyl fumarate and 100 mg (0.261 mmol, 1 eq) of the product of Example 1 were dissolved in 1.4 ml (0.2 M) of dimethylformamide. The mixture was cooled to ⁰ ° C. and washed with 36 mg (0.268 mmol, 1 eq.) Of 1-hydroxybenzotriazole, 56 μL, 0.5 eq., 1.5 eq.) Of triethylamine and 51 mg (0.268 mmol, 1 eq.) Of ethyl-3-one. (3-dimethylamino) -propylcarbodiimid added. The mixture was slowly warmed to room temperature and stirred for a total of 23 hours. Thereafter, 8 ml of pH 4 buffer (from Mallinckrodt) was added and stirred for a further 30 minutes. It formed a yellow, rubbery precipitate. This was extracted with 2x 10 ml of ethyl acetate, washed with aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate and freed from the solvent under reduced pressure. 129 mg of the residue were chromatographed through 12 g of silica gel (from Merck) and eluted with 30% acetone in hexane. As a brittle foam, 64.2 mg (1S- (1R- (E), 2S \ 3S)] -4- [(1S, 2R) -4 - [(butylamino) -sulfonyl-1 were obtained - (cyclohexylmethyl) -2,3-dihydroxybutyl!] - amino] -4-oxo-2-butenoic acid ethyl ester; [a] ₀ = -7.3 ° (c = 0.56, chloroform). TLC (silica gel; 30% acetone in hexane) R ₁ = 0.26

C ₂₁ H ₃₈ N ₂ O ₇ S 0.23H ₂ O:

CHNS: 54.04 8.31 6.00 6.07

F .: 54.44 8.48 6.04 6.47.

Example 16 (YR.δSJ-ö-amino-N-butyl-β.Y-dlhydroxy-a.a-dimethyl-cyclohexane pentanesulfonamyl monohydrochloride, isomer A

a) N-butyl-1-methylethanesulfonamld

60ml (4.5M) of acetic acid and about 30g of Eir were added at 0 ° C with 25ml (269mMol, 1eq) of 2-propanethiol. Thereafter, chlorine was bubbled through the mixture. The mixture turned yellow-orange, then colorless and finally pale yellow when excess chlorine was absorbed. Argon was passed through the mixture to remove excess chlorine. Thereafter, 300 ml of ether were zugegebeil. The solution was washed with 2x 150 ml of 5% sodium bisulfite solution and 200 ml of water. The organic phases were dried over magnesium sulfate and evaporated under reduced pressure. 37.45 g of 1-methylethanesulfonyl chloride were obtained.

To a solution of 10 g (7OmMoI, 1 eq.) Of 1-methylethanesulfonyl chloride in 35 mL (2.0 M) dichloromethane at ⁰ ° C was added dropwise 16 mL (161 mmol, 2.3 eq) N-butylamine. After complete addition, the ice bath was removed and the mixture was stirred at room temperature overnight. The solution was then diluted with 150 ml of chloroform and washed with 2x125 ml of 0.5 N hydrochloric acid and 150 ml of saturated brine. The organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was distilled. This gave 8.07 g of N-butyl-1-methylethanesulfonamide as a pale yellow oil, bp 95-102 ° C at about 0.1 mm.

b) (4S-trans) -4- (cyclohexylmethyl) -2,2-dimothyl-3,5-oxazolidinedicarboxylic acid 3- (1,1-dimethylmethyl) -1-methyl ester

A solution of 810 mg (2.37 mmol, 1 eq.) Of (4S-trans) -4- (cyclohexylmethyl) -2,2-dimethyl-3,5-oxazolidinedicarboxylic acid 3- (1,1-dimethylethyl) ester (mfd Example 1 (b)) in 6 ml (0.4 M) of dichloromethane was added an excess of diazomethane in ether at ⁰ ° C. A few drops of acetic acid were added to decompose the excess diazomethane The mixture was diluted with ether and washed with water The organic phases were dried over magnesium sulfate and evaporated under reduced pressure, the residue was chromatographed through 40 g of silica gel (from Merck) and eluted with dichloromethane to give 806 mg of (4S-transr) -4- (cyclohexylmethyD.sub.1) ^ dimethyl-S.ö-oxazolidindicarbonsäure-SD.I-dimethylethyD-i-methylester.

c) (4S-trans) -5- [2 - [(butylamino) sulfonyl] -2-methyl-1-oxopropyl] -4- (cyclohexylmethyl) -2,2-dimethyl-3-oxazolinedicarboxylic acid 1,1- dimethylethyl

552 mg (3.08 mmol, 1 eq.) Of N-butyl-1-methylethanesulfonamide in 6.15 ml (0.5 M) of tetrahydrofuran were added at -40 ° C. to 2.46 g. (6.15 mmol, 3 eq in hexane) of N-butyl lithium. After 10 minutes the mixture was heated for 30 minutes at -20 ° C and then cooled to -78 ⁰ C. 729mg (2,05mMol, 1 eq) (4S-trans) -4- (. cyclohexylmethyl) -2,2-dimethyl-3,5-oxazolidindicarbonsäure-3- (1,1-dimethylethyl) -1-methylester in 4 ml (0.5M) of tetrahydrofuran was added, and the mixture was a total of 3 hours at -78 ⁰ C. The reaction was quenched with aqueous saturated ammonium chloride solution, the mixture was warmed to room temperature and extracted with ether The organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and evaporated The residue was chromatographed through 70g of silica gel (from Merck) and washed Ether: hexane (1: 4) eluted, giving 300 mg of (4S-trans) -5- [2 - ((butylaminol-sulfonyl-methyl-1-oxopropyl) -cyclohexylmethoxy ^^ - dimethyl-S-oxazolidinecarboxylic acid i.idimethylethylester; IaI ₀ = + 11.7 ° (c = 1.0, methanol).

d) (4S-trans) -5- [2 - [(butylamino) sulfonyl] -1-hydroxy-2-methylpropyl] -4- (cyclohexylmethyl) -2,2-dimethyl-3-oxazoline-dicarboxylic acid i.i-dimethyl ethyl ester. Isomer A and isomer B

300Tig (0,597mMol, 1 eq.) Of 1,1 -Dimethylethylesterprodukts of part (c) in 2.0 ml (0.3M) of absolute ethanol were added at 0 ⁰ C with 24,8mg (0,656mMol, 1.1 eq.) Sodium borohydride in 2.48 ml (0.26M) absolute ethanol. After 20 minutes, the mixture was evaporated and the product was dissolved in ether and 1 N HCl. The product was then extracted with ether. The organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and evaporated. The residue was chromatographed through 10 g of silica gel (from Merck) and eluted with etherHoxan (1: 3) and then (2: 3). There was obtained (4S-trans) -5- [2 - [(butylamino-1-sulfonyl-1-hydroxy) -methyl-propyl] -cyclohexylmethyD1-dimethyl-S-oxazolidinecarboxylic acid i-imidylethyl ester, 61 mg as isomer B and 172 mg as isomer A; [a] ₀ = -19.0 ° (c = 1.0, methanol).

e) (γR, δS) -δ · amino-1-butyl-p, γ-dihydroxy-α, α-dimethylcyclohexane pentanesulfonamide monohydrochloride, isomer A.

A solution of 153 mg (0.303 mmol, 1 eq.) Of the isomeric product A of part (d) in 1.82 mL (0.17 M) tetrahydrofuran was charged with 1.21 mL (0.25 M) 10% HCl and 0 , 61 ml (0.5 M) of acetic acid and stirred for a total of 3 days at room temperature. The

The solution was then diluted with 5 ml of water and 10 ml of ether. After separation of the phases, the organic phase was extracted twice with water. The washing waters were combined and freeze-dried. The product was eluted by 10g Kieselgsl (from Merck) chromatographies and with chloroform: methanol: NH ₄ OH (30: 2.5: 0.05). 68.4 mg of the isomeric product A were obtained as the free base. The 68.4 mg (0.188 mmol, 1 eq.) Of the material obtained was dissolved in 10 ml of methanol and admixed with 0.188 ml (0.188 mmol, 1 eq.) 1 η HCl. After 30 minutes at room temperature, the solution was evaporated. The residue was dissolved in 10 ml of water, filtered through a polycarbonate filter and freeze-dried. The white solid obtained was 67 mg (YR.alpha.-O-amino-N-butyl-.beta.-Y-dihydroxy-aa-dimethylcyclohexane pentanesulfonamide monohydrochloride as isomer A, mp 74-81.degree. C. [ab = -12.7 ° C (c = 1.0, methanol) TLC (silica gel, chloroform: methanol: NH ₄ OH, 30: 2.5: 0.05) R ₁ = 0.21 C ₁₇ H ₃₆ N ₂ O ₄ S HCl 0.3 H ₂ O:

r H N Cl S

Calculated: υΰ, 24 9,33 6,89 8,72 7,89

F .: 50.22 9.23 6.78 8.68 7.83

Example 17

(YR.δSl-ö-amino-N-butyl-β, Y-dihydroxy-aa-dimethyl-cyclohexane pentanesulfonamide monohydrochloride, Isomer B A solution of 59.3 mg (0.118 mmol, IAq.) Of the isomeric product B of Example 16 ( d) in 0.7 ml (0.17M) tetrahydrofuran was added 0.45 ml (0.25 M) of 10% hydrochloric acid and 0.23 ml (0.5M) of acetic acid and stirred for 3 days at room temperature, the solution was washed with 5 ml Water and 10 ml of ether After separating the bubbles, the organic phase was extracted twice with water, the washings were combined and freeze-dried The product was chromatographed through 5 g of silica gel from Merck and washed with chloroform: methanol: NH ₄ OH (30: 2.5 17.4 mg (0.048 mmol, 1 eq) of this material were dissolved in 8 ml of methanol and extracted with 0.05 ml (0: 0.05). After stirring for 30 minutes at room temperature, the solution was evaporated and the residue was dissolved in 10 ml of water through a polycarbonate filter f filtered and freeze-dried. There were obtained 10.5 mg of white (YR, OS) -O-amino-N-butyl-β, Y-dihydroxya.a-dimethylcyclohexane pentanesulfonamide monohydrochloride as isomer B; F. 79-85 ° C. TLC (silica gel, chloroform: methanol: NH ₄ OH, 30: 3: 0.05) R, = 0.19

C ₁₇ H ₃₆ N ₂ O ₄ S · HCl · 0.7 H ₂ O:

CHN: 49.37 9.36 6.77

Filled: 49.27 9.25 6.95

Example 18 (YR.δSl-δ-Anriino-N, β-dibutyl-β / γ-dihydroxycyclohexane-pentanesulfonainide, Isomer A

a) ^ γνφγ

1.5 g (3.9 mmol, 1 eq.) Of (4S-trans) -4- (cyclohexylmethyl) -5 - [((methoxy) methyl-tiino] -carbonyl] -2,2-dimethyl-3-oxazolidinecarboxylic acid i, 1 dimethylethyl ester (prepared according to example 1 [b]) of distilled tetrahydrofuran were dissolved under an argon atmosphere in 15,6ml (0.25 M). The solution was cooled to -78 ⁰ C and treated with 1.7? ml (4,29mMol, 1 1 eq., 2.5 M in hexane) n-butyllithium was added dropwise The mixture was stirred at -78 ° C. for 30 minutes, warmed to ⁰ ° C. and stirred at -78 ° C. for a further 30 minutes, to ⁰ ° C. The reaction was quenched with aqueous saturated NH ₄ Cl solution and the mixture was extracted three times with ether The ether extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure The residue was replaced with 100 g of silica gel (of Merck) was chromatographed and eluted with ether: hexane (1: 2) to give (4S-trans) -4- (cyclohexylmethyl) -2,2-dimethyl-5- (1-oxopentyD-S-oxazo lidincarbonsäure-ii-dimethylethyl ester.

b) (AS-transl-S ^ -r.lButylaminol-sulfonyl-i-butyl-i-hydroxyethyll-cyclohexylmethyD ^^ - dimethyl-aoxazolidinocarboxylic acid ^ i-dimethyl ethyl ester, isomer A and isomer B

A solution of 846 mg (5.6 mmol, 1.4 eq.) Of N-butylmethanesulfonamide (prepared according to Example 11a!) In 16 ml (0.35M) of tetrahydrofuran was added at -40 ° C with 4.48 ml (11.2 mmol, 2.8 eq ., 2.5 M in hexane) n-butyllithium and stirred for 10 minutes. The mixture was warmed to ⁰ ° C, stirred for 30 minutes and cooled to ⁰ -4o C. Thereafter, 1.5 g (3.93 mmol, 1 eq.) Of (4S-trans) -4- (cyclohexylmethyl) -2,2-dimethyl-5- (1-oxopentyl) -3-oxazolidine carboxylic acid 1,1-dimethylethyl ester in 4 ml (1.0 M) Tetrahydrofuran added. After 90 minutes at -4O ⁰ C, the reaction was stopped with aqueous saturated NH ₄ Cl. The mixture was warmed to room temperature and extracted three times with ether. The organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and evaporated. The residue was chromatographed through 80 g of silica gel (from Merck) and eluted with hexane: acetone (10: 1). 237 mg of (4S-trans) -5- [2 - ((butylamino) sulfonyl-1-butyl-1-hydroxyethyl] -cyclohexylmethyl-1-dimethyl-S-oxazolidinecarboxylic acid 1-yl dimethyl ethyl ester, isomer A, Ia] were obtained. ₀ = + 4.2 ° (c = 1.0, methanol) and 101 mg isomer B, mp 138-14O ⁰ C, [a) ₀ = + 5.5 ° (c = 1.0, methanol) and 1.518 g of a mixture of isomer A and isomer B.

c) (YR, 6S) -o-amino-N, ß-dibutyl-ß, Y-dihydroxycyclohexanpontQnsulfonamid, isomer A.

A solution of 237 mg (0.466 mmol, 1 eq) of the isomeric product A of part (b) in 2.67 M (0.17 M) tetrahydrofuran was charged with 1.78 mL (0.25 M) of 10% hydrochloric acid and water 0.89 ml (0.5M) of acetic acid and stirred at room temperature for a total of 4 days. The mixture was evaporated. The residue was chromatographed through 10 g of silica gel (from Merck) and eluted with chloroform: methanol: NH ₄ OH (30: 1, 5: 0.05). As a white solid was obtained 127 mg (YR, 5S) -5-Amino-N, .beta.-dibutyl-.beta, Y-dihydroxycyclohexane-pentanesulfonamide isomer A, mp 164-165 ⁰ C; [a] ₀ - · -9.3 ° (c = 0.60, methanol). TLC (silica gel, chloroform: methanol: NH ₄ OH, 30: 3: 0.05) R, = 0.22

C ₁₉ H ₄₀ N ₂ O ₄ S:

CHNS: 58.13 10.27 7.14 8.17

gef. 57,81 10,37 7,13 7,87

Example 19

(YR.OSl-ö-Amino-N-β-dibutyl-p-dlhydroxycyclohexane pentanesulfonamide monohydrochloride, Isomer B A solution of 100.7 mg (0.189 mmol, 1 eq.) Of the isomeric product of Example 18 (b) in 1.13 ml (0.17 M) tetrahydrofuran was added 0.76 mL (0.25 M) 10% hydrochloric acid and 0.38 mL (0.5 M) acetic acid and stirred at room temperature for a total of 5 days, then the mixture was evaporated under reduced pressure. The residue was eluted through 5 g of silica gel (from Merck) chromatographies and with chloroform: methanol: NH40H (30: 2.5: 0.05) to give 55 mg of product, 52.4 mg (0.134 mmol, 1 eq) of this material Dissolved in 5 ml of methanol and treated with O, 13 ml (0.13 mmol, 1 eq) 1 N hydrochloric acid After 30 minutes at room temperature, the solution was evaporated under reduced pressure The product was dissolved in 11 ml of water: ethanol (10: 1) A polycarbonate filter was added and freeze-dried to give 55.7 mg of (YR, 6S) -5-amino-N, β-dibutyl β-Y-dihydroxycyclohoxane pentanesulfonamide monohydroxy drochloride, isomer B; F.80-85 ⁰ C; (alo = + 20.8 "(c = 0.50, methanol). C ₁₉ H ₄₀ N ₂ O ₄ S-HCl:

C H N Cl S

: 53.19 9.63 6.53 8.26 7.47

F .: 53.25 9.58 6.16 8.65 7.21

Example 20

[1S- (1R *, 2S *, 3S * M- (2-indolylcarbonyl) -N- [4 - [(butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dlhydroxybutyl] -L-hlstidinamide trifluoroacetic acid ( 1: 1) salt

a) N- (1H-indol-2-ylcarbonyl) -3 - [(phenylmethoxy) -methyl] -L-methyl-methylester

2,36g (6,5moles, 1eq) of methyl 3- ((phenylmethoxy) -methyl-L-histidine methyl ester were suspended in 65ml (0.1M) distilled tetrahydrofuran and cooled in an ice-bath. 13 mmol, 2 eq.) Of 4-methylmorpholine, 1.048 g (6.5 mmol, 1 eq) indole-2-carboxylic acid and 1.399 g (6.5 mmol, 1 eq.) Of IS-dicyclohexylcarbodiimide The mixture was warmed slowly to room temperature and overnight The mixture was diluted with 200 mL of chloroform and stirred in an ice bath for 45 minutes The solid was filtered off and washed with further chloroform The filtrate was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and evaporated from the solvent under reduced pressure. The residue was eluted by 160g silica gel (from Merck) chromatographies and first with 20% acetone in chloroform to remove piccyclohexylurea, the product was then treated with 4% methanol in chloroform at 0.2%. NH ₄ OH was eluted, giving 2.9 g of N-UH-indole-1-yl-carbonyl-O-S-phenylmethoxy-methyll-L-histidine methyl ester. TLC (silica gel, 10% methanol in chloroform with ΰ, 2% NH ₄ OH) R ₍ = 0.43.

b) N-IIH-indole-a-ylcarbonyO-a-Mphenylmethoxyl-methylH-hlstldnn

2.79 g (6.49 mmol, 1 eq.) Of the methyl ester product of part (a) were dissolved in 25 mL (0.25 M) of methanol and 7.8 mL (7.8 mmol, 1.2 eq.) Of sodium hydroxide solution , The mixture was stirred at room temperature for 3 hours. The methanol was evaporated under reduced pressure. About 20 ml of water was added. Any non-acidic material was washed out with 30 ml of chloroform. The aqueous phase was then adjusted to pH 3 to 4 with 1 N hydrochloric acid. A gummy precipitate formed, which was digested with 5% methanol in ethyl acetate. 2.142 g of N- (1H-indol-2-ylcarbonyl) -3 - [(phenylmethoxy) methyl] -L-histidine were obtained as a white solid; F.204-207 ⁰ C (with decomposition); [aI _D = -0.17 ° (c = 0.59, acetic acid). TLC (silica gel, ethyl acetate: pyridine: acetic acid: water, 5: 1: 1: 1) R, - = 0.36.

c) [IS-dR '^ S ^ .SS'Jl - [(phenylmethoxy-methyl-L-histidine amide

628 mg (1.5 mmol, 1 eq) of N-OH-indole-1-butylcarbonyO-S-Kphenylmethoxy-methyll-L-histidine and 564 mg (1.5 mmol, 1 eq) of iβR- (βR *, YR *, 6S *) δ-amino-N-butyl-β, Y-dihydroxycyclohexane pentanesulfonamide monohydrochloride (product of Example 1) were partially dissolved in 7.5 ml (0.2 M) of dimethylformamide. The mixture was cooled to ⁰ ° C. and washed with 202.5 mg (1.5 mmol, 1 eq.) Of 1-hydroxybenzotriazole, 315 μl (2.26 mmol, 1.5 eq.) Of triethylamine and 295 mg (1.5 mmol, 1 eq.). Ethyl 3- (3-dimethylamino) propylcarbodiimide hydrochloride added. The mixture was slowly warmed to room temperature and stirred for a total of 22 hours. 38 ml of pH 4 aqueous buffer (from Mallinchrodt) was added and the mixture was stirred for 30 minutes. The yellow precipitate was extracted with 2x75ml ethyl acetate. The combined extracts were washed with 75 ml of saturated aqueous sodium bicarbonate solution and 75 ml of saturated brine, dried over magnesium sulfate and freed of solvent under reduced pressure. This gave a yellow foam. This was eluted by 70g silica gel (from Merck) chromatographies and 3% methanol in dichloromethane with 0.2% NH ₄ OH. This gave 979 mg of [1S-UR *, 2S, 3S ")] - (2-indolylcarbonyl) -N- [4 - [(butylamino) sulfonyl-1 - (cyclohexylmethyD ^ .S-dihydtoxybutyl-S - [(phenylmethoxy ) -methyll-L-histidinamide, TLC (silica gel, 10% methanol in dichloromethane with 0.2% NH ₄ OH) R _f = 0.42.

d) [1S- (1R *, 2S *, 3S *)] - (2-indolylcarbonyl) -N- [4 - [(butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dihydroxybutyl] -L -histidinamld-trifluoro-etai (1: 1) salt

970 mg (1.13 mmol, 1 eq of the product from part (c) were suspended in 26 mL (0.05 M) methanol and mixed with 640 μΙ (20.2 mmol, about 15 eq.) Of hydrazine and 300 mg (about 30% by weight) 20%. The mixture was stirred for 5 days under a hydrogen atmosphere at room temperature during which time an additional 10 mL of methanol, 450 μΙ hydrazine and 230 mg catalyst were added three times The catalyst was filtered through regenerated cellulose and the solvent was evaporated under reduced pressure was prepared by preparative HPLC with a fully evaporated C-18 column (YMC 1-15 100A, ODS 3Ox 500mm, 15μ spherical, 25ml / min, UV control at 220μm) eluting with 72.4% methanol Purified water with 1% trifluoroacetic acid, two peaks were obtained in each of 11 injections, the slower peaks (20 minutes, 20 seconds to 24 minutes, 40 seconds) were combined and almost evaporated under reduced pressure Dry evaporated and dissolved in an ethanol: water mixture (2: 3) and freeze-dried. The material was redissolved in ethanol (3: 5), passed through a polycarbonate filter and freeze-dried. The solid obtained was 491 mg of 1S- (1R, 2S *, 3S ")] - (2-indolylcarbonyl) -N- [4-I (butylamino) -suifonyl-1- (cyclohexyl: ylrr, 3-thyl) -2, 3-ddihydroxybutyll-L-histidinamide, trifluoroacetate (1: 1) salt, m.p. 108-127 ⁰ C (with decomposition); (a) _D = -29.6 ° (c = 0.5, methanol) TLC (silica gel, 10% methanol in dichloromethane with 0.2% NH ₄ OH) R ₍ = 0.38

C ₃₀ H ₄₄ N ₆ O ₆ S 1.1 CF ₃ COOH · 0.4 H ₂ O:

C H N S F calc .: 51.61 6.17 11.21 4.28 8.37 Found .: 51,60 6.16 11.15 4.05 8.59

Example 21 (YR.10Sl-6-Amino-N-butyl-p, Y-dihydroxy-α-methylcyclohexane pentafluoromethyl-monohydrochloride, isomer B

a) N-butylethanesulfonamide

Express θ solution of 14.7 mL (156 mmol, 1 eq.) Of ethanesulfonyl chloride in 78 mL (2.0 M) dichloromethane was added dropwise at ⁰ ° C with 30.9 mL (31 Zm mole, 2 eq.) N-butylamine. The ice bath was allowed to melt and the mixture was stirred at room temperature overnight. The mixture was then diluted with 300 ml of chloroform and washed with 2 × 300 ml of 0.5 N HCl and 250 ml of saturated brine. The organic extracts were dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was distilled. This gave 22.5 g of N-butylethanesulfonamide as an oil, mp 112-114 ° C (0.5 mm).

b) 1,1-dimethylethyl (4S-trans) -5- [2-t (butylamino) -sulnyl] -1-oxopropyl] -4- (cyclohexylmethyl) -2,2-dimethyl-3-oxazolidinylcarboxylate

A solution of 1.22 g (7.4 mmol, 2,5Äq.) N-Butylethansulfona-nid in 14,8ml (0.5 M) tetrahydrofuran (-4o at ⁰ C with 5.9 ml 14,8mMol, 5Äq "2.5M in hexane) n-butyllithium. Thereafter, 1.0 g (2.6 mmol, 1 eq) of (4S-trans) -4- (cyclohexylmethyl) -5-l [(methoxy) methylamino] carbonyl] -2,2-dimethyl-3-oxazolidinecarboxylic acid 1,1-dimethylethyl ester (prepared according to Example 1 [b]), in 2.6 ml (1.0M) of tetrahydrofuran. After 1 hour at -40 ° C, the reaction was quenched with saturated aqueous NH ₄ Cl. The mixture was warmed to room temperature and acidified to pH3 by addition of 10% hydrochloric acid. The GemisL was extracted three times with ether. The organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and evaporated. The residue was chromatographed through 100 g of silica gel (from Merck) and eluted with ether: hexane (1: 2). 823mg of (4S-trans) -5- (2 - ((butylamino) sulphonyl] -1-o. <Propyl] -4- (cyclohexylmethyl) -2,2-dimethyl-3-oxazolidinecarboxylic acid was obtained as a mixture of stereoisomers _{1, 1} -dimethylethyl ester. [A] ₀ = + 65.2 ° (c = 2.0, methanol).

c) 1,1-dimethylethyl (4S-trans) -5- [2 - [(butylamino) sulfonyl] -1-hydroxypropyl] -4- (cvclohexylmethyl) -2,2-dimethyl-3-oxazolidinecarboxylate

458.1 mg (0.937 mmol, 1 eq.) Of the product of part (b) in 1.87 ml (0.5 M) of ether were dissolved at ⁰ ° C. with 89.7 mg (1.03 mmol, 1.1 eq Aldrich) borane-tert-butylamine complex. The ice bath was allowed to melt. The mixture was stirred at room temperature overnight. The reaction was stopped by addition of 1 N hydrochloric acid and the solution extracted three times with ether. The organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and evaporated. The product was chromatographed through 25 g of silica gel (from Merck) and eluted with ether: hexane (1: 2) and later (1: 1). 41 mg (4S-trans) -5 [2 - [(butylamino) sulfonyl] -1-hydroxypropyl-4- (cyclohexylmethyl) -2,2-dimethyi-3-cxazolidinecarboxylic acid was obtained as a mixture of the isomers A and B. 1,1-dimethylethyl ester; 78mg isomer B, 10Jo = -7.78 ° (c = 0.75, methanol); 202mg isomer C, [a] ₀ = + 14.6 ° (c = 0.50, methanol); and 118mg isomer D, IaI ₀ = -1.27 ° (c = 1.0, methanol).

d) (YR.oSI-ö-amino-N-butyl-β.Y-dihydroxvarnethylcyclohexane pentanesulfonamide monohydrochloride, IscmerB

A solution of 78 mg (0.159 mmol, 1 eq) of isomeric product B of part (c) in 0.96 ml (0.17 M) tetrahydrofuran was treated with 0.64 ml (0.25M) 10% hydrochloric acid and 0, 32 ml iC, 5M) acetic acid and stirred for a total of 4 days at room temperature. The mixture was evaporated and the residue was chromatographed through 5 g of silica gel (from Merck) and eluted with chloroform: methanol: NH ₄ OH (30: 3.5: 0.05). 48.5 mg of the desired product were obtained as the free base. 47.6 mg (0.136 mmol, 1 eq.) Of this material were dissolved in 10 ml of methanol and 0.136 ml (0.136 mmol, 1 eq.) Of 1 N HCl were added. After 30 minutes at room temperature was egg? Solution evaporated. The residue was dissolved in 10 ml of water, filtered through a polycarbonate filter and freeze-dried. This gave 52 mg of white (yR, 5S) -O-amino-N-butyl-β / y-dihydroxy-amethylcyclohexanpentansulfonamid monohydfochlorid, isomer B, F.89-92 ° C; [a) _D = -2.8 ° (c = 0.50, methanol). TLC (silica gel, chloroform: methanol: NH ₄ OH, 30: 3.5: 0.05) R, = 0.25

C ₁₆ H ₃₄ N ₂ O ₄ S i, 15 HCI:

C K N Cl S

Re: 48.97 9.03 7.14 10.39 8.17

F .: 49.22 9.17 6.95 10.22 7.84

Example 22

(YR, öS! -Ö-Ämino-N-butyl-ß, Y-dihyiH oxy-a-methylcyclo-he canpentansulfonamid-monohydrochloi \ ά, Isomer C A solution of 202mg (0,112mMol, 1 Aq.) Of the isomeric product C from example 21 (c) in 2.47 mL (0.17 M) tetrahydrofuran was added 1.65 mL (0.25 M) 1% hydrochloric acid and 0.82 mL (0.5 M) acetic acid and 4 days at room temperature The mixture was evaporated The residue was chromatographed through 5 g of silica gel (from Merck) and eluted with chloroform-methanol: NH ₄ OH (30: 3.5: 0.05) to give 119 mg of the desired product as the free base 119 mg (0.34 μmol, 1 eq.) Of this material were dissolved in 10 ml of methanol and 0.34 ml (0.34 mmol, 1 eq.) Of 1 N HCl were added, and after 30 minutes at room temperature the solution was evaporated 1 ml of water, filtered through a polycarbonate filter and freeze-dried to give 105 mg of white (YR, OS) -6-amino-N-butyl-β, Y-dihydroxy-amethylcyclohexane pentanesulfonamide monohydrochloride , Isomer C, mp 215-217 ° C; [a] _D = + 0.4 ° (c = 0.50, methanol). TLC (silica gel, chloroform: methanol: NH ₄ OH, 30: 3.5: 0.05) R, = 0.19

C ₁₆ H ₃₄ N ₂ C ₄ S -1.1 HCl:

C H N Cl S

Re: 49.04 9.06 7.15 9.95 8.18

F .: 49.44 9.29 7.00 9.77 7.78

Example 23

(YR.SI SI-Amine-N-butyl-β, Y-dihydroxy-α-methylcyclohexane pentanesulfonamide monohydrochloride, Isomer D A solution of 141.4 mg (0.288 mmol, 1 eq.) Of the isomeric product D of Example 21 (c) in 1.73 ml (0.17M) of tetrahydrofuran was added 1.15 ml (0.25M) of 10% hydrochloric acid and 0.58 ml (0.5M) of acetic acid and stirred for 4 days at room temperature, the mixture was evaporated. The residue was chromatographed through 5 g of silica gel (from Merck) and eluted with chloroform: methanol: NH ₄ OH (30: 3.5: 0.05) to give 64.2 mg of the desired product as the free base, 61.5 mg (0.175 1 mol) of this material was dissolved in 10 ml of methanol and 0.175 ml (0.175 mmol, 1 eq) of 1 N HCl was added, and after 30 minutes at room temperature the solution was evaporated and the residue was dissolved in 10 ml of water filtered and freeze-dried to yield 65.6 mg of white (y R, δ S) -α-amino-N-butyl-β, Y-dihydroxy-amino-cyclohexane-pentanesulfonamide monohydrochloride, Is omer D, F. 62-7O ⁰ C; [alo = -19.8 ° (c = 0.50, methanol). TLC (silica gel, chloroform: methanol: NH ₄ OH, 30: 3.5: 0.05) R ₁ = 0.19

C ₁₆ H ₃₄ N ₂ O ₄ S -1.05 HCI:

C H N Cl S

Calculated: 49.20 9.10 7.17 9.53 8.21

F .: 49.21 9.16 7.00 9.56 7.92

Example 24

(YR.δSJ-α-amyl-N-butyl-β-Y-dihydroxy-α-methylcyclohexane pentanesulfonamide monohydrochloride, mixture of isomers A and B (1: 1)

A solution of 36.8 mg (0.075 mmol, 1 eq) of the product obtained in Example 21 (c) as a mixture of isomers A and B in 0.45 mL (0.17 M) tetrahydrofuran was mixed with 0.3 mL (0.25M ) 10% hydrochloric acid and 0.15 ml (0.5M) of acetic acid and insgesarrt stirred 3Tsgs at room temperature. The mixture was evaporated. The residue was chromatographed through 5 g of silica gel (from Merck) and eluted with chloroform: methanol: NH ₄ OH (30: 3.5: 0.05). This gave 19.7 mg of the desired product as the free base. 19.7 mg (0.056 mmol, 1 eq.) Of this material were dissolved in 10 ml of methanol, and 0.056 ml (0.056 mmol, 1 eq.) Of 1 N HCl was added. After 30 minutes at room temperature, the solution was evaporated. The residue was dissolved in 10 ml of water and 1 ml of ethanol, filtered through a polycarbonate filter and freeze-dried. This gave 24.8 mg of white (YR.ÖSl-ö-amino-N-butyl-ß.Y-dihydroxy-a-methylcyclohexanpentansulfonamid monohydrochloride, mixture of isomers A and B (1: 1), mp 93-95 ⁰ C. TLC (silica gel, chloroform: methanol: NH ₄ OH, 30: 3.5: 0.05) R, = 0.25 C, ₆ H ₃₄ N ₂ O ₄ S-1.1 HCl:

CHN: 48.53 9.09 7.07

F .: 48.63 8.74 7.02

Example 25

[1S- (1R, "2S \ 33 *)] - [(1,1-Dimethy ethoxy) carbonyl] -N- [4 - [(butylamlno) sulfonyl] -1- (cyclohexylmethyl) -2,3 -dihydroxybutyll-L.

histidinamld monohydrochloride

a) ^ [(1,1-dimethylethoxy) carbonyl] -3 - [(phenylmethoxy) methyl] -L-histidine

18.66 g (43.8 mmol) of N-ld / i-dimethylethoxycarbonyl-S-phenylphenylmethoxy-methyll-L-histidine methyl ester were dissolved in 50 ml of methanol. 92 ml of 1N sodium hydroxide solution and then 83 ml of water were added. The mixture was stored at room temperature for 90 minutes, later diluted by 650 ml of water and acidified to pH 4.5 with hydrochloric acid. The aqueous solution was extracted with chloroform. The chloroform solution was evaporated and the residue recrystallized in ethyl acetate. This gave 15.3 g of N-ld.i-dimethylethoxyl-carbonyl-a-Kphenylmethoxyl-methyll-L-histidine; F. 155-157 ° C.

b) [1S * (1R ^^ S ^ 3S ·)] · [(1,1-dimethylethoxy) carbonyl] · N · [4 · [(butylamino) sulfonyl] 1 · (cyclothylmethyl) -2,3 dihydroxybutyl ] -3 - [(phenylmethoxy) methyl] -L-histidinamld

101 mg (0.268 mmol, 1 eq.) Of N-Id.i-dimethylethoxy-carbonyl-SKphenylmethoxyl-mathyl-L-histidine and 100 mg (0.268 mmol, IAq) of [βR-lβR'.YR'.S'J-O- Amino-N-butyl-β, Y-dihydroxycyclohexane pentanesulfonamide monohydrochloride (the product of Example 1) was dissolved in dimethylformamide under an argon atmosphere. The solution was cooled to ⁰ ° C. and treated with 36 mg (0.268 mmol, 1 eq.) Of 1-hydroxybenzotriazole, 56 μ l (0.402 mmol, 1.5 eq.) Of triethylamine and 51 mg (0.268 mmol, 1 eq.) Of ethyl 3 ( 3-dimethylamino) -propylcarbodiimid added. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was admixed with 7 ml of aqueous pH 4 buffer solution (from Mallinckrodt) and stirred for 30 minutes. The product was extracted into 2x 10 ml Essigsäureethylestor, dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue was chromatographed through 15 g of silica gel (from Merck) and eluted with 3% methanol in dichloromethane with 0.2% NH ₄ OH. 176 mg of 1S- (1R *, 2S, 3S *)] - [(1,1-dimethylethoxy) carbonyl] N- (4 - [(butylamino] -sulfonyl-1-cyclohexylmethoxy) -1-dihydroxybutyll-S were obtained -Phenylmethoxy-methyl-L-histidine amide, TLC (silica gel, 10% methanol in dichloromethane containing 0.2% NH ₄ OH) R ₍ = 0.59.

c) [1S - [(1R, 2S \ 3S *) M (1,1-dimethyl-ethoxy) -carbonv '*' - [4 - [(butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3- dihydroxybutyl] -L-histidinamide monohydrochloride chlorine! d

176 mg (0.235 mmol, 1 eq) of the product from part (b) were dissolved in öml (0.05M) methanol and 0.8 ml (0.33M) water. This solution was then added with 0.25 mL (0.25 mmol, 1 eq.) Of 1 N hydrochloric acid and 44 mg (25 wt.%) Of 20% palladium hydroxide on carbon. This mixture was stirred under hydrogen at room temperature for 20 hours. The mixture was then diluted with methanol and the catalyst filtered through regenerated cellulose. The solvent was removed under reduced pressure and the residue was chromatographed through 15 g of silica gel (from Merck) and eluted with 3 to 5% methanol in dichloromethane with 0.2% NH ₄ OH. 69 mg of the desired free base was obtained as a glass. This 69 mg (0.12 mmol, 1 eq.) Material was dissolved in 5 mL of methanol and 0.12 mL (0.12 mmol, 1 eq.) Of 1 N hydrochloric acid was added. The solution was removed under reduced pressure. The residue was dissolved in 20 ml of water with 15% ethanol, through a pole. jonatfiltei given and freeze-dried. The white solid was obtained as 43mg | 1S- (1R \ 2S \ 3S *) M (1,1-dimethylethoxy) carbonyl] -N-

H-Kbutylaminol-aulfonyll-i ^ .a-icyclohexylmethyD dihydroxybutyll-L-hlstidinamid monohydrochloride, mp 115-140 ⁰ C (shrinking at 9O ⁰ C); (a) _D = -27 ° (c = 0.37, methanol), TLC (silica gel, 10% methanol in chloroform, 0.2% NH ₄ OH) R ₍ = 0.44, Cj ₈ H ₄₇ N ₆ O ₇ S · HCl · H ₂ O:

C H N Cl S

Calc .: 49.7 ^ 8.02 11.15 5.64 5.10

F .: 49.76 7.92 11.23 5.91 5.30

Example? .6

[βR-lßR ^ .vR'.ÖS ¹ II-N-butyl-β.Y-dihydroxy-6-ilmethylsulfonyl-aminole-cyclohoxane pentanesulfonamide A solution of 122.8 mg (0.329 mmol, 1 eq.) of L-β- (βR \ YR 5-amino-N-butyl-β, Y-dihydroxycyclohoxane pentanesulfonamide monohydrochloride (the product of Example 1) in 1.32 ml (0.25M) dichloromethane was mixed at 0 ° C with 0.14 ml (0.823 mmol , 2.5Aq.) Of N, N-diisopropylethylamine and stirred for 15 minutes. Thereafter, 0.33 ml (1.0M) of a solution of methanesulfonyl chloride in dichloromethane (0.33 mmol, 1 eq.) Was added dropwise. The ice bath was allowed to thaw. The mixture was stirred at room temperature overnight and then diluted with 0.5 N HCl and extracted three times with ether. The organic extracts were filtered through magnesium sulfate and evaporated. The residue was chromatographed through 10 g of silica gel (from Merck) and eluted with chloroform: methanol (30: 1). 89.4 mg of [βR-fβR'.YR'.S'd-N-butyl-β, Y-dihydroxy-S-methylsulfonyl-aminol-cyclohexane pentanesulfonamide were obtained as white foam, [α] o = -6.5 ° ( c = 0.25, methanol). TLC (silica gel, chloroform: methanol, 30: 1) R _t = 0.13. C ₁₆ H ₃₄ N ₂ O ₆ S:

CHNS: 46.35 8.27 6.76 15.47

F .: 46.54 8.39 6.66 15.46

Example 27 [βR- (βR ^# , YR *, 5S *) 1S-Amino-N-butyl-β, Y-dihydroxy-N- (phenylmethyl) -cyclohexanesulfonamide monohydrochloride

a) [4S- [4α, 5β (S ^# )] L • 5- [2 * [[(butyl). (phenylmethyl) amino] sulfonyl] 1. hydroxyethyl]. 4- (cyclohexylmethyl) -2,2 -dimethyl · 3 · oxazolldlncarbonsBure-1,1-dimethylethyl ester

248 mg (0.52 mmol) of [4S- [4a, 5β (S ^# )]] - 5- [2 - [(butylamino) -syllactyl-1-hydroxyethyl-4- (cyclohexylmethyl) -2,2-dimethyl-3- 1,1-dimethyl oxazolidinecarboxylate (the product of Example 1 [d]), 97.8 mg (0.572 mmol of benzyl bromide and 359 mg (2.6 mmol) of freshly powdered anhydrous potassium carbonate were placed in 4 ml of dimethylformamide for 19 hours at room temperature The mixture was then diluted with 10 mL of diethyl ether and 10 mL of 5% aqueous potassium bisulfate added to a final pH of 2.5, water and 75 mL of ether were added and the organic phase was separated, washed with brine Dried magnesium sulfate and concentrated under reduced pressure to give 311 mg of crude product After flash chromatography through 16 g of silica gel (from Merck), which was packed with hexane: ether (5: 1) and eluted, the oil obtained was 291 mg [4S- [4a , 5ß (S *)] l-5- (2- [| (butyl) - (phenylmethyl) amino] -sulfonyll-i-hydroxyethylM fcyclohexylmethylW ^ -dimethyl-S -oxazolidincarbonsäure-ii-dimethylethyl ester. TLC (silica gel, hexane: ether, 3: 1) R | = 0.26.

b) tßR-lßR ^ .YR ^ .sol-N-butyl-.beta.-Y-dihydroxy-N-iphenylmethyD-cyclohexane pentanesulfonamide monohydrochloride 62.4 mg (0.11 mmol) of the product of part (a ) were added with a mixture of 0.9 ml of tetrahydrofuran, 0.6 ml of 10% hydrochloric acid and 0.3 ml of acetic acid and stirred for 2 days at room temperature in a stoppered flask. The reaction mixture was then evaporated under reduced pressure, evaporated with toluene and finally reacted with 15 ml of 4 N HCl in dioxane for 4 hours at room temperature. The reaction mixture was evaporated under reduced pressure, evaporated again with toluene and freeze-dried. As a pale yellow solid, 50 mg of iβR- (βR *, YR *, 5S *)) - ö-amino-N-butyl-β, Y-dihydroxy-N-phenylmethyl-cyclohexane pentanesulfonamide monohydrochloride were obtained; F. 55-11O ⁰ C; [a] o = -1.6 ° (c = 0.272, methanol) [a] _H936 6 = -4.7 "(c = 0.272, methanol) TLC (silica, chloroform: methanol: ammonia, 30: 2: 0.2) R, = 0.16 C ₂₂ H ₃₈ N ₂ O ₄ S · HCl · 0.1 H ₂ O:

C H N Cl S

calculated: 56.85 8.50 6.03 7.63 6.90

F .: 36.85 8.56 6.04 7.66 6.57

Example 28 [βS- (βR *, YS *, 5K *)] - 5-amino-N-butyl-β, Y-dihydroxy-N- (phenylmethyl) -cyclohexane pentanesulfonamide d-moriohydrochloride

a) ί.JS · [4α, 5β (R ·)] 1 · 5 · [2 - [[(butyl) - (phenylmethyl) amino] sulfonyl · 1-hydroxyethyl] -4- (cyclohexylmethyl) -2, 2-dimethyl-3-oxazolidinecarboxylic acid-ii-dimethylethyl ester

268 mg (0.562 mmol) of [4S- | 4a, 5β (R ")]] - 5- [2 - [(butylamino) sulfonyl-1-hydroxyethyl-4- (cyclonexylmethyl) -2,2-dimethyl-3-oxizolidinecarboxylic acid i-dimethyl ethyl ester, isomer B (the product of Example 1 [d]), 106 mg (0.618 mmol) benzyl bromide and 386 mg (2.81 mmol) freshly powdered anhydrous potassium carbonate were reacted according to the procedure of Example 27 (a) , The oil obtained was 303 mg of [4S- | 4a, 5β (R »))] - 5- [2 - [((butyl) - (phenylmethyl) -amino] -sulfonyl] -1-hydroxyethyl-1-cyclohexylmethy) -dimethyl -S-oxazolidinecarboxylic acid-ii-dimethylethyl ester, TLC (silica gel, hexane: ether, 3: 1) R, = 0.12.

b) [βS- (βR ^# , γS ♦, δR ·) l ·5-AmInO "N · butyl-β, γ · dlhydroxy-N · (phylmethyl) -cyclohexane-pentane-3-sulfoneamide · monohydrochloride 66mg (0.116 mmol) of the product of Part ( a) were admixed with a mixture of 0.9 ml of tetrahydrofuran, 0.6 ml of 10% strength hydrochloric acid and 0.3 ml of acetic acid for 5 days at room temperature in a stoppered flask, and the mixture was then concentrated by evaporation under reduced pressure. was evaporated with toluene and freeze-dried to give 53 mg of [βS- (βR, YS, RR *)] - δ-amino-N-butyl-β, Y-dihydroxy-N- (phenylmethyl) -cyclohexane-pentanesulphonamide as solid.

monohydrochlo <id: F. 60-110 ⁰ C; [al ₀ = 0 ° (c = 0.242, methanol). [a] n _e , ₃ 6s = -9.8 ° (c = 0.242, methanol). TLC (silica gel, chloroform: methanol: ammonia, 30: 2: 0.1) R | = 0.18

C ₂₂ H ₃₈ N ₂ O ₄ S HCl:

C H N Cl S

: 57.07 8.49 6.05 7.66 6.92

F .: 57.07 8.67 6.14 7.63 6.75

Example 29

[PR ißR'.YR ^ ^ Jl .ÖS-ö-Amlno-N-KS ^ -dimethoxyphenvD-methvll-p.Y-dlhvdroxvcyclohexanpentansuKonamldmonohydrochlorid

a) N - [(3,4-Dlmethoxyphenyl) methyl] methanesulfonamide

18ml (12OmMoI, 2aq.) Of 1- (Aminomethyl) -3,4-dimethoxybenzene was added to a solution of 4,64ml (6OmMoI, 1 eq.) In Methansulfonyichlorid 30ml (2.0M) Qichlormethan L910 ⁰ C. 90 ml more dichloromethane (final concentration 0,5M) was added. The mixture was allowed to warm to room temperature and stirred for 2 days. The solid precipitate was drained and washed with more dichloromethane. The filtrate was washed with 2 × 200 ml of 0.5 N HCl and 200 ml of water, dried over magnesium sulfate, filtered and evaporated. 13.93 g of a yellow solid were obtained. This material was recrystallized from 75 ml of ethyl acetate: hexane (1: 1). The crystalline product was washed with ethyl acetate-hexane (1: 1) and ether and dried. 12.41 g of Nl (3,4-dimethoxy) methyll-methanesulfonamide were obtained; F. 78-81 ⁰ C.

b) (4S-trans) -5 - [[[[(3,4-Dimethoxyphenyl) methyl] amino] sulfonyU-acetyl] -4- (cyclohexylmethyl) -2,2-dimethyl-3-oxazolidinecarboxylic acid-1 , 1-dimethylethyl ester

9.1 ml (22.85 mmol, 2.5 M, in hexane) of n-butyl lithium was added dropwise to a solution of 2.92 g (11.9 mmol, 2.5 eq.) Of N - [(3,4-dimethoxyphenyld-methyll methanesulfonamide placed in 33ml (0.35M) of tetrahydrofuran at -40 ⁰ C. After 10 minutes, the mixture was stirred warmed to ⁰ ° C uznci 75 minutes. the mixture was cooled to ⁰ C and -4o (with 1,83g 4, 76 mmol, 1 eq) (4S-trans) -4- (cyclohexylmethyl) -5 -. [[(methoxy) methylamino] carbonyl] ^{-2,2-dimethyl-3-r} oxazolidinca bonsäure 1,1-dimethylethyl ester After stirring for 2 hours, the mixture was warmed to ⁰ ° C. After a further 2 hours, the reaction was quenched with 10 ml of saturated aqueous NH ₄ Cl and, after 2 hours, the reaction mixture was quenched with 10 ml (0.5M) tetrahydrofuran The mixture was extracted with 2x 100 ml of chloroform, the organic extracts were dried over magnesium sulphate, filtered and evaporated 4.98 g of the residue were chromatographed through 200 g of silica gel (from Merck) and concentrated d mi \ ethenehexane (5: 3) eluted. The foam obtained was 1.6 g of (4S-trans) -5-l (| (3,4-dimethoxyphenyl) -methyl) amino] sulfonyl-acetyl] -4- (cyclohexylmethyl) -2,2-dimethyl- 3-oxazolidine-1,1-dimethylethyl.

c) [4S- [4a, Sβ (S *)]] - and [4S-i4a, 5β (R *)] - 5- [2-U [(3,4-dlmethoxyphenyl) -methyl] -amino] - sulfonyl] -1-hydroxyethyl] -4- (cyclohexylmethyO ^ -dimethyl-S-ox'jzolldincarbonsaure-ii-dlmethylethylester

A solution of 1.58 g (2.78 mmol, 1.0 eq.) Of the product from part (b) in 21 mL (0.12 M) ether was added at ⁰ ° C with 266 mg (3.06 mmol, 1.1 eq. ) Borane tert-butylamine complex. The ice bath was allowed to melt. The mixture was stirred at room temperature overnight. The mixture was then diluted with 40 ml of InHCl and extracted twice with ether. The organic extracts were dried over magnesium sulfate, filtered and evaporated. This gave 1.62 g of a crude foam. The residue was chromatographed through 100 g of silica gel (from Merck) and eluted with benzene: ether (3: 1). There were obtained 1.2 g (75%) of WS- (α, β, β, β-dimethyl) -siloxane-S-III-dimethyl-dimethoxyphenyl-methyl-aminol-sulfonyl-1-hydroxy-ethyl-1-cyclohexylmethy-D-dimethyl-S-oxazolidinecarboxylic acid-II dimethyl ethyl ester and 0.3 g (20%) of [4S- | 4a, 5β (R *) l] isomer.

d) [βR-lßR'.YR ^ SIl-ö-amino-N-US- (dlmethoxyphenyl) -methyl-β-Y-dihydroxycyclohexane pentanesulfonamide monohydrochloride

A solution of 102 mg (0.179 mmol, Ί eq.) Of the [4S- [4a, 5β (S *)]] isomeric product of part (c) in 1.08 mL (0.17 M) tetrahydrofuran was added 0, 72 ml (0.25 M) of 10% HCl and 0.36 ml (0.5 M) of acetic acid and stirred for 4 days at room temperature. The mixture was evaporated. The residue was chromatographed through 5 g of silica gel (from Merck) and eluted with chloroform: methanol: NH ₄ OH (30: 4: 0.05). 66.8 mg of the desired product were obtained as the free base. The 66.8 mg (0.155 mmol, 1 eq.) Of this material was dissolved in 10 mL of methanol and 0.155 mL (0.155 mmol, 1 eq.) Of 1 N HCl was added. After 30 minutes at room temperature, the solution was evaporated. The residue was dissolved in 10 ml of water and 1 ml of ethanol, filtered through a polycarbonate filter and freeze-dried. One was holding 75.7 mg of white (βR- (βR *, YR *, öS *)] - ö-amino-N - [(3,4-dimethoxyphenyl o-methyll-β, Y-dihydroxycyclohexane pentanesulfonamide monohydrochloride, m.p. 93 -100 ⁰ C; [a] o = -1.6 ° Jc = 0.75, methanol) TLC (silica gel; chloroform:.! Met ianol: NH "OH, 30: 4: 0.05) R, = 0 , 23 C ₂₀ H ₃₄ N ₂ O ₆ S · 1.1 HCl · 0. 'H ₂ O:

C H N Cl S

: 50.65 7.55 5.91 8.22 6.76

F .: 50.61 7.80 5.79 8.20 6.55.

Example 30 TβR-iβR'.YR'.δS'Jl-δ-Amino-β, Y-dihydroxycyclohexane-pentanesulfonamyl-monoacetate salt

a) [4S- [4a, 5β (S *)]] - 5- [2 - [[[(3,4-dimethoxyphenyl) methylene] amino] sulfonyU-1 hydroxyethyl] -4- (cyclohexylmethyl) - 2,2-dimethyl-S-oxazolIdincarbonsüure-ii-dimethylethyl ester

130.3mg (0.574mmol, 1.3Aq) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were added to a solution of 252mg (0.441mmol, 1eq) (4S-I4a, 5β (S *)]) - 5-t2- [H (3,4-dimethoxyphenyl) -methyll-amino] sulfonyl) -1-hydroxyethyl] -4- (cyclohexylmethyl) -2,2-dimethyl-3-oxazolidincarbonsäure- ii-dimethyl ester (prepared according to Example 29 (c)) in 4,4'-dichloromethane: water (18: 1, 1, 1 M) was added at room temperature and stirred for 1 hour. Thereafter, 130.3 mg (0.574 mmol, 1, 3eq.) Additional ilor-5,6-dicyano-1,4-benzoquinone was added and stirred for one hour and the mixture was diluted with dichloromethane, filtered, and the filtrate washed twice with aqueous sodium bicarbonate solution Dried, filtered through magnesium sulphate and evaporated The residue was chromatographed through 10 g of oil (from Merck) and eluted with ethenehexane (2: 3, then 1: 1, then 3: 1) - [4a, 5ßiS ⁵ )) l '''"M! 3,4-dimethoxyphenyl) -methylenI-aminol-sulfony II-i-hydroxyethyl-1-cyclohexylnosilyl-D-dimethyl-S-oxazolidine-carboii-acid-1-dimethyl-dimethylester.

b) [βR- (βR ^# , YR •, ÖS'Jl-6-Amino-pY-dihydroxycyclohexane pentanesulfonamide monoacetate Sail A solution of 136 mg (0.24 mmol, 1 eq) of a solution of the product of part (a) in 1 1.0 ml (0.25M) of 10% ignr HCl and 0.5 ml (0.5M) acetic acid were added to 5 ml (0.17 M) tetrahydrofuran and the mixture was stirred for a total of 6 days at room temperature was chromatographed through 5g of silica gel (from Merck) and eluted with chloroform: methanol: NH 4 OH (30: 8: 0.05) to give 71.7 mg of the desired product as the free base: 71.7 mg (0.256 mmol, 1 eq. This material was dissolved in 10 ml of methanol and 0.256 ml (0.256 mmol, 1 eq) of 1 N HCl was added and the solution was evaporated at room temperature for 30 minutes The residue was dissolved in 10 ml of water, passed through a polycarbonate filter and freeze-dried 51.6 ml crude monohydrochloride salt product This material was chromatographed through 5 g silica gel (from Merck) and with acetic acid ethyl ester: pyridine: acetic acid: water (10: 1-1: 1) eluted. The product was evaporated, dissolved in 10 ml of water and freeze-dried. 55.3 mg of material were obtained. This was dissolved in 10 ml of water and 1 ml of ethanol, filtered through a polycarbonate filter and freeze-dried. This gave white 39,3mg (pR (SSR *, Y R *, 6 S *)) - S-Amino-ß, Y-dihydroxycyclohexanpentansulfonamic: monoacetate salt, m.p. 168-17O ⁰ C (shrinking at 68 ⁰ C); [a) ₀ = -6.8 ° (c = 0.40, Mathanol). TLC (silica gel, ethyl acetate: pyridine: acetic acid: water, 10: 1: 1: 1) R, = 0.25. CuH ₂₄ N ₂ O ₄ S · CH 3 COOH · 0.4H ₂ O:

CHNS: 44.91 8.35 8.06 9.22

F .: 44.93 8.15 8.30 9.34.

Example 31

[βR-iβR'.YR'.δS'n-ö-amino-N-butyl-Y-hydroxy-β-methoxycyclohexenesulfonamide

a) ^ S-Ma.SßtS'lll-B-U-lllButyl-lphenylmethyD-amlnol-sulfonyil-i-methoxyethyll ^ -cyclohexylmethyD ^ .a-dimethyl-S-oxazolldincarboxylic acid-i.i-dlmethylethylestor

A solution of 222mg (0.392 mmol), | 4S- [4a, 5β (S »)]] - 5- (2 - [[(butyl) - (phenylmethyl) amino) -sulfonyl-1-hydroxyethyl) - 4- (cyclohexylmethyO ^^ - dimethyl-S-oxazolidine carboxylic acid, ii-dimethylethyl ester (the product of example 27 [a)) in 7 ml dry tetrahydrofuran was added at -2O ⁰ C under argon with 14.1 mg (0,588mMol) 60% sodium hydride dispersion in oil. After 15 minutes, 84 mg (0.666 mmol) of dilute dimethyl sulfate was added. The temperature was raised to ⁰ ° C. and then to room temperature for 1 hour. During this time, the reaction was complete. The mixture was diluted with 15 mL of ether and stirred for about 15 minutes with 5 mL of 5% aqueous potassium bisulfate solution. The organic phase was then separated and combined with further ethereal extracts of the aqueous solution. The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. One kept 278mg of crude product. After flash chromatography through 34 g of silica gel (from Merck) and elution with hexane: ether (5: 1, one kept 210 mg of I4S- [4a, 5β (S *) l] -5- (2 - ([(butyl) - (phenyimethyl) -amino] sulfonyl] -1-methoxyethyl] -4- (cyclohexylmethyl) -2,2-dimethyl-S-oxazolidinecarboxylic acid U-dimethyl ethyl ester, TLC (silica gel, hexane: ether, 2: 1) R, = 0.50 ,

b) [4S- [4a, 5β (S *)]] - 5- [2 - [(butylamino) sulfonyl] -1-methoxyethyl] -4- (cyclohexylmethyl) -2,2-dimethyl-3-oxazolidinecarboxylic acid 1,1-dimethylethylesterund [SSR (ßR "YR" 5S ")] - N.Butvl-ö - [[(1,1-dimetliylethoxy) carbonyl] -amlno] -Y-hydroxy-ßmetrioxycyclohexanpentansulfonarnid

To a solution of 108 mg (0.186 mmol) of the product of part (a) in 1.4 ml of glacial acetic acid was added 150 mg of 20% palladium hydroxide on carbon. The mixture was hydrogenated for 16 hours in a Parr apparatus at 50 psi, then evaporated under reduced pressure and partitioned between 30 ml of ethyl acetate and 8 ml of saturated aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulfate and evaporated. 81.2 mg of crude product were obtained. Flash chromatography on 9g of silica gel (from Merck) and elution with etherhexane (2: 1) gave 27.5 mg of [4S- [4a, 5β (S)]] - 5- [2 - [(butylamino) sulfonyl ] -1-methoxyethyl] -4- (cyclohexylmethyl) -2,2-dim9thyl-3-oxazolidine carboxylic acid, ii-dimethylethyl ester; TLC (silica gel; etherhexane 2: 1) R | = 0.57 and 43.6 mg of IBR- (βR ^# , YR *, ö5 *)] - N-butyl-S-Kd.i-dimethylethoxyl-carbonyl-aminol-Y-hydroxy-β-methoxycyclohexane pentanesulfonamide; DCfKieselgel; Etherhexane, 2: 1) R, = 0.14.

c) [.beta .- (.beta.R *, YR.sup. +, .sym.)) - .alpha.-Amino-N-butyl-Y-hydroxy-.beta.-methoxycyclohexane pentanesulfonamide

To a mixture of the two products of part (b) (0.346 mmol, in the ratio of about 1: 1) was added a mixed solvent of 2.4 ml of tetrahydrofuran, 1.6 ml of 10% hydrochloric acid and 0.8 ml of acetic acid. The mixture was stirred for 4 days at room temperature in a stoppered flask, then evaporated under reduced pressure and evaporated in the presence of toluene. The residue was taken up in chloroform-methanol and combined with solid potassium carbonate, filtered and evaporated. 135ml of crude product were obtained. Flash chromatography on 10g of Kies Igol (from Merck) and elution with chloroform: methanol: ammonia (22: 2: 0.1) gave as a white solid 101mg of IβR- (βR \ YR *, OS »)] - 5-amino -N-but \ .- v-hydroxy-ß-mothoxycyclohexanpentansulfonamid; F. 154-156 ⁰ C; [a) _D = -8.5 ° (c = 1.19, methanol). TLC (Kiec Ige ', chloroform: methanol: ammonia, 17: 2: 0.1) R, = 0.32. C ₁₆ H ₃₄ N ₁ CS C.28I \ O:

r. η N s

Calculated: 54.05 9.80 7 BB 9.02

r "-!? .. 54.05 9.74 7.80 8.86

Bohpie! · 1

iβS-fP ¹ ISyS * WN-δ-amino-N-butyl-δ-hydrox'-β-methoxycyc. jhexanpentansulfonamld

a) r / Sr... 5ß (R))]] - 5 · l2 [[(Buiv ^) · (phenylmethyl) · amlno] sulfonyl · 1 · mθthoxyethyl] -4 (cyclohexylmethyl) -2,2-dlmθthvl · 3 · 0 .jZjdinecarboxylic acid-II-dimethylethyl estr

Egg, ieLODiungvon211mg (0.372 mmol) (4S- [4a, 5β (R ")] 1-5 - [2 - [[(butyl) - (phenylmethyl) -amino] -sulfonyl] -1-hydroxyethyl] -4 · ( cyclohexylmethyO ^ -dimethyl-S-oxazolidine carboxylic acid, i, 1-dimethylethyl trr (the product of example 23 [a]) in 7 ml /:. k (, ie, -i tetrahydrofuran was added at -15 ⁰ C under argon with 13, 4 mg (0.588 mmol) of a 60% sodium hydride dispersion in oil was added to 79.8 mg (0.633 mmol) of undiluted dimethyl sulfate for 15 minutes

The procedure of Example 31 (a) was worked up. 199mg of [4S- [4a, 5β (R ^ll ) -5- | 2 - [((butyl) - (phylmethyl) -amino] -sulfonyl-1-methoxyethyl) -cyclohexylmethyDi-dimethyl-S-oxazolidine was obtained. carboxylic acid, ii-dimethyl ester, TLC (silica gel, hexane: ether, 2: 1> R, = G, 35.

b) [4S- [4a, 5β (R)]] - 5- [2 - [(butylamino) -sul (unyl) -1-methoxyethyl] -4- (cyclohexylmethyl) -2,2-dlmethyl-3- oxazolldlncarbonsäure-

niotlioxycyclohexanpentanßulfonamld

To a solution of 168 mg (0.289 mmol) of the product from part (a) in 1.5 mL of glacial acetic acid was added 320 mg of 20% palladium hydroxide on carbon. The mixture was hydrogenated according to Example 31 (b) and worked up. 36mg of [4S- [4a.5β- (R *)]) - 5- [2- (butylamino) sulfonyl] -1-methoxyethyl] -4- (cyanohexylin, ^n- thyl) -2, '? climethyl-S-oxazolidine carboxylic acid, ii-dimethylethyl ester; TLC (Kieselgö: Ethei: hexane, 3: 1) R, = 0.66 and 92m [j ("S- (R, * S, 6R ^ll ) 1N-butyl-O- [I (1,1-dimethylethoxy ) carbonyl) amino] -Y-hydroxy-ß-methoxycyclohexanpentansulfqnn.nid; Dc (silica gel, ether: hexane, 3: 1) R ₁ = 0.21.

c) [βS-fβR '^ S ^ .SR ^ ll-ö-Amino-N-butyl-Y-hydroxy-p-mothoxycyclohexane pontanesulfonamide The mixture of the two products of part (b) (0.277 mmol, in the ratio 1: 3) was added the same solvent mixture and worked up by the method of Example 31 (c). As a waxy solid, 81 mg of .beta.S- (.beta.R.sup.- YS.sup.5R.sup.-)] - 6-amino-N-butyl-Y-hydroxy-.beta.-methoxycyclohexane pentanesulphonamide, mp.72-82.degree. C .; [a) _D = -26.9 ° (c = 0.92, methanol). TLC (silica gel, chloroform: methylthanol: ammonia; 17: 2: 0.1) R _f = 0.21.

C ₁₆ H ₃₄ N ₂ O ₄ S 0.13H ₂ O:

CHNS: 54.46 9.79 7.94 9.09

F .: 54.46 9.79 8.81 8.79.

Example 33 [βR- (βR *, YR *, 5S ^# )] - 5-amino-β, Y-Dlhydroxy-N- (2-hydroxyethyl) cyclohexane pentanesulfonamide monoacetate salt

a) [4S-t4α, 5β {S ·)] l · 4 · (cyclohexylmethyl) -5 · [2 - [[[(3,4-dlmethoxy-phenyl) -methyl] - (2-θthoxy · 2 · oxo-ethyl) · amlno] sulfonyll · · 1-hydroxyethyl] -2,2-dimethyl-3-oxazolidinecarboxylic acid, 1,1-dlmethylethylester

0.18 ml (1.66 mmol, 1.1 eq.) Of ethyl bromoacetate was added to a solution of 858.8 mg (1.5 mmol, 1 eq) of [4S- [4a, 0β (S ^# )]] - 4- (cyclohexylmethyl ) -5- [2 - [(l (3,4-dimethoxyphenyl) -methyll-amino] -sulfonyl-1-hydroxyethyl] -2,2-dimethyl-3-oxazolidinecarboxylic acid, ii-dimethylethyl ester (the product of Example 29 [ c)) and 1.04 g (7.52 mmol, 5 eq.) of potassium carbonate in 12.0 ml (0.125M) of dimethylformamide. The mixture was stirred at room temperature for 90 minutes and diluted with ether. Aqueous potassium bisulfate solution was added until the pH was 2. Then, water was added to dissolve the salt. The mixture was extracted with 3x 50 ml of ether. The organic phase was dried over sodium sulfate, filtered through magnesium sulfate and evaporated. The residue was chromatographed through 60 g of silica gel (from Merck) and eluted with etherhexane (1: 1). 980 mg of [4S- [4a, 5β (S *)] - 4- (cyclohexylmethyl) -5-l2 - [[[(3,4-dimethoxyphenyl) -methyl] - (2-ethoxy) -oxoethyl-aminol- sulfonyll-i-hydroxyethylj ^^ - dimethyl-S-oxazolidine carboxylic acid, ii-dimethylethyl ester; IaI ₀ = -7.4 ° c = 1.0, methanol).

b) t4S- [4a, 5β (S ")] - 4- (cyclohexylmethyl) -5- [2 - [[[(3,4-dimethoxyphenyl) methyl] - (2-hydroxyethyl) -amino] -su ( fonyl] -1-hydroxyethyl] -2,2-dimethyl-3-oxazolldincarbonsäure-1,1-dlmethylethylest.3r

A solution of 301,9mg (0.46 mmol, 1 eq.) Of the product vonTeil (a) in 4,6ml (0.1 M) ether was added at 0 ⁰ C was treated dropwise with a solution of 0, P.9ml (0, 69 mmol, 1.5 eq.) Of lithium aluminum hydride in tetrahydrofuran (1.0M). After 30 minutes, the reaction was stopped by dropwise addition of 1 η hydrochloric acid. The mixture was extracted with 3x 20 ml of ether. The orrjaniscben extracts were dried over sodium sulfate, filtered through magnesium sulfate and evaporated. The residue was chromatographed through 10 g of silica gel (from Merck) and eluted with etherhexane (3: 1). 256mg of [4S- (4a, 5β (S *)] 1-4- (cyclohexylmethyl) -5- [2-l (((3,4-dimethoxyphenyl) methyl] (2-hydroxyethyl) amino] was obtained. -sulfonyl] -1-hydroxyethyl] -2,2-dimethyl-3-oxazolidinecarboxylic acid 1,1-dimethylethyl ester; [a] ₀ = -5.3 ° (c = 1.0, methanol).

c) [4S- [4a, 5β (S) '' J 4- (Cyclohexylmethyl) -5- [2-t- (2-hydroxyethyl) -amino] -sulfonyl] -1-hydroxyethyl] -2,2-dlmethyl -3-oxazolidincarbons & acid-1,1-dimethylethyloster

231,3mg (0.38 mmol, 1 eq.): '(Ι product of part (b) were mixed with 57,8mg (25Gew .-%) palladium hydroxide on carbon in 3,76ml (0.1 M) ethanol A further 2 x 60 mg palladium hydroxide on carbon was added to the reaction after the 2nd and 3rd day After 5 days, the mixture was filtered through regenerated cellulose and evaporated The residue was dissolved in 4 ml (0 1M) ethanol, 120mg (50wt%) palladium hydroxide on carbon and stirred under hydrogen balloon for 1 day Additional 120mg palladium hydroxide-on-carbon was added and reaction was continued for a further 4 days until no The mixture was diluted with methanol, filtered through regenerated cellulose, and evaporated The residue was chromatographed through 10g of silica gel (from Merck) and eluted with chloroform: methanol (30: 1) to give 94.2mg of l4S- as a solid. [4a , 5ß (S *) l] -4- (cyclohexylmethyl) -5-l2 - [[2-hydroxyethyl) amino] sulfonyl) -1-hydroxyethyl] -2,2-dimethyl-3-oxazolidine-1-carbonsöure , 1-dimethylethyl ester; F. 174-177 ⁰ C; Ia] ₀ = + 14.5 ° (c = 1.0, chloroform: methanol, 10: 1).

d) tβR- (βR ^# , YR ^# , öS ^# )] 6-Amino-β _/ Y-dihydroxy-N- (2-hydroxyethyl) cyclohexane pentanesulfonamide monoacetate salt

A solution of 94 mg (0.21 mmol, 1 eq.) Of the product from part (c) in 1.18 mL (0.17 M) tetrahydrofuran was added with 0.85 mL (0.25 M) 10% hydrochloric acid and 0.42 ml (0.5M) of acetic acid and stirred for a total of 6 days at room temperature. The mixture was evaporated. The residue was eluted by 5 g of silica gel (by Merck) chromatography and ethyl acetate pyridine: acetic acid: water (15: 1: 1: 1 (and then (10: 1: 1: 1).) 82.5 mg of crude product were obtained was dissolved in 10 ml of water and 1 ml of ethanol, filtered through a Polyc uonatfilter and

freeze-dried. ;, Ö-amino-ß, Y-dihydroxy-N- (2-hydroxyethyl) -cyclohexanpentansulfonamid monoacetate salt F.60- 65 ⁰ C - SSR (SSR *, YR \ ATS ^#)] | were obtained as a solid 68mg [al ₀ = -1.7 ° (c = 1.0, methanol). TLC (silica gel, ethyl acetate: pyridine: acetic acid: water, 10: 1: 1: 1) Ri-0.21.

8.18

7.90

Example 34 [βR- (βR *, YR *, ÖS *)] - 5-Amino-N-butyl-β, Y-dihydro (Y-N-methylcyclohexane pentanesulfonamide monohydrochloride

C _n H ₂₈ N ₂ O ₅ S • CH ₃ COOH -0.4H ₂ O: N C H 7.15 calc .: 46,00 8.44 7.21 Found .: 46.06 8.44

a) ^ S ^ oxazolide! ncarbons8ure-1,1-dimethylethyl ester

100 g (0.21 mmol, 1 eq.) Y

Hydroxy oxazolidinecarboxylate, prepared according to Example 1 (d), was dissolved in 0.84 ml (0.25M) of dimethylformamide. The mixture was treated with 145 mg (1.05 mmol, 5Äq.) Kaliumcarbonatpulverund99pl (1.05 mmol, 5AU. ₁₎ of dimethyl sulfate was added and stirred under an argon atmosphere. After 24 hours, another 2.5 eq. Potassium carbonate and 5 eq. Added dimethyl sulfate. It was stirred for 8 hours at 45 ⁰ C on. The reaction was quenched with a 10% potassium bisulfate solution until the mixture was acidic. The mixture was extracted with 3x 30 mL of hexane: ether (1: 1) and washed with saturated brine and water. The organic phase was dried over magnesium sulfate and freed from the solvent under reduced pressure. The crude product was purified by flash chromatography with 6 g of silica gel and with ether: hexane (1: 2) as eluent and freed from the solvent under reduced pressure. There was obtained 62mg (4S- [4a, 5β (S ^# ))] - 5- [2 - [(butyl) - (methylamino) sulfonyl] -1-hydroxyethyl] -4- (cyclohexylmethyl) -2,2-dimethyl -3-oxazolidincarUonsäure-ii-dimethylethyl ester. TLC (silica gel, ether: hexane, 1: 1) R _f = 0.5.

b) [β R- (β R ^# , Y R, δ S *)] - 5-amino-N-butyl-β, Y-dihydroxy N-methylcyclohexane pentanesulfonamide monohydrochloride

62 mg (0.126 mmol) of the product from part (a) were dissolved in a 3: 2: 1 mixture of 6 ml of tetrahydrofuran, 4 ml of 10% HCl and 2 ml of glacial acetic acid and stirred for 48 hours at room temperature. The solvents were removed under reduced pressure and the product was then subjected to 5g gravel, gel (by Merck) chromatography and 5% methanol in dichloromethane with 0.2% NH ₄ OH. The solvent was evaporated under reduced pressure to give 40 mg of a white solid, this product was dissolved in methanol, and 0.114 ml (1 eq) of 1 η / iCI was added, and the solution was rotary evaporated to dryness then dissolved in 6 ml of water, filtered through a polycarbonate filter and freeze-dried to give as solid 26mg of (βR- (β-R-y-R 6S ^# )) -α-amino-N-butyl-β, γ-dihydroxy-N-methylcyclohexane pentanesulfonamide monohydrochloride 103-107 ⁰ C (Schrumpfenbeil00 ⁰ C), F;. [a] ₀ = -2.04 ° (c = 0.5, methanol), TLC (silica gel; 5% methanol in dichloromethane with 0.2% NH ₄ OH) R ₍ = 0.1, C ₁₆ H ₃₄ N ₂ O ₄ S · HC! · 0.8 H ₂ O:

C H N Cl S

calculated: 47.88 9.19 6.98 8.83 7.99

F .: 47.86 9.09 6.79 8.93 7.96.

In a similar manner there was obtained [SSS (SSR * YS *, OER *)) - ö-amino-N-butyl-ß, Y-dihydroxy-N-methylcyclohexanpentansulfonamidmonohydrochlorid, F. 70-83 ⁰ C (shrinking at 60 ⁰ C); (a) ₀ = -6.4 ° (c = 0.6, methanol) TLC (silica gel, 5% methanol in dichloromethane + 0.2% NH ₄ OH) R, = 0.21

C ₁₆ H ₃₄ N ₂ O ₄ S HCl · 0.25 H ₂ O:

C H N Cl S

: 49.09 9.14 7.16 9.06 8.19

F .: 49.16 9.23 7.08 9.18 8.01.

Example 35 [βS-ißR ^ .YS ^ .oR'Jl-ö-Amino-.beta.-Y-dihydroxy-N-tZ-hydroxyethyl-cyclohexane pentanesulfonamide dl acetate salt

a) N- (diphenylmethyl) -methanesulfonamld

6.92 g (31.5 mmol 1, ObAq.) Of aminodiphenylmethane hydrochloride were dissolved in 150 mL (0.2 M) dichloromethane and cooled in an ice bath. To the mixture was added 10.5 ml (75 mmol, 2.5 eq.) Of triethylamine and stirred for 15 minutes. At ⁰ ° C, 2.32 ml (30 mmol, 1 eq.) Of methanesulfonyl chloride was added dropwise. After the addition, the mixture was warmed to room temperature and stirred overnight. The mixture was washed with 2 × 100 ml 0.5 N hydrochloric acid and 1 N, saturated brine, dried over sodium sulfate and magnesium sulfate and freed from the solvent under reduced pressure. This gave 7.66 g of N- (diphenylmethyl) methanesulfonamide as a solid, mp 148-15O ⁰ C. TLC (silica gel, ether hexane, 1: 1) R, = 0.31.

b) (4S-trans) -5 · t [[(Dhlethylnylmethyl) sulfonyl] allyl acetyl] -4- (cyclohexylmethyl) 2,2 · dimothyl · 3 oxazolidinecarboxylic acid · 1,1-dimethylethyl ester

6.34g (19.5mmol, 2.5eq.) Of N- (diphenylmethyl) -methanesulfonamide and 1.05g (39mmol, 5eq.) Of lithium chloride were partially dissolved in 78ml (0.2Γ M) of distilled tetrahydrofuran and evaporated to -40 ⁰ C cooled. 15.6 ml (39 mmol, 5 eq., 2.5M in hexane) of n-butyllithium were added slowly. The mixture was stirred for 30 minutes at ⁰ -4o C and then warmed to ⁰ ° C for 30 minutes. After cooling to -40 ° C, 3.0 g (7.8 mmol, 1 eq.) Of (4S-terbb) -4- (cyclohexylmethyl) -5 - [[(methoxy) -methylsilylcarbonyl] -dimethyl-S-oxazolidinecarboxylic acid ii-dimothylethyl ester, prepared according to Example 1 (b) was added. The mixture was stirred for 30 minutes büi -4o ⁰ C and then 30 minutes at ⁰ ° C. Thereafter, the reaction was stopped with 50 ml of 1 η HCl. The product was extracted with 3x 75 ml of ether, dried over sodium sulfate and magnesium sulfate and freed from the solvent under reduced pressure. The product was purified by chromatography through 270g of silica gel (from Merck) eluting with etherhexane (1: 3) and then (1: 2). 4.45 g of (4S-trans) -5- [([(diphenylmethyl) sulfonyl] amino] acetyl] -4- (cyclohexylmethyl) -2,2-dimethyl-3-oxazolidinecarboxylic acid 1,1-dimethylethyl ester were obtained [α] ₀ = + 30.3 ° (c = 1.0, methanol) TLC (silica gel, etherhexane, 1: 1) R, = 0.56.

c) [4S- [4a, 5p (S *)]] - and [4S- [4a, 5p (R *)]] - 5- [2 - [[(diphenylmethyl) sulfonyl] -amino-hydroxyethyl] - 4 '', cyclohexylmethyl) -2,2'-dimethyl-3-oxazoline-1,1'-dimethylcarboxylate

4.43g (7.566mmol, 1eq.) Of the product of Tell (b) was dissolved in 30.3ml (0.25M) ether, cooled to ⁰ ° C and added dropwise with 15.2ml (15.2mmol, 2eq .) Of a 1M solution of potassium triethylborohydride added. The mixture was stirred at ⁰ C for 1 h. Thereafter, 41.2 mg (1.894 mmol, 0.25 eq.) Of lithium borohydride were added and the mixture was stirred at ⁰ ° C. for 1 hour and then at room temperature for 1 hour. The mixture was added with an additional 41.2 mg (1.894 mmol, 0.25 eq.) Of lithium borohydride and stored at room temperature overnight. After cooling to 0 ° C, the reaction was stopped with 50 ml of 1 η HCl. The product was extracted with 3x 50 ml of ether, dried over magnesium sulfate and sodium sulfate and freed from the solvent under reduced pressure. The residue was chromatographed through 100 g of silica gel (from Merck) and eluted with ether: hexane (1: 2.75, later 1: 1.5 and then 2: 1). This gave 886,6mg isomer A as a solid foam, mp 58 to 65 ⁰ C, TLC (silica gel; Ether.Hexan, 1: 1) R ₁ = 0.43; 2.55 g isomer B, TLC (silica gel, ethenehexane, 1: 1) R _f = 0.35 and 990 mg of a mixture of isomers A and B.

d) [4S- [4a, 5β (R ^# )]] - 5- [2-it (diphenylmethylthyl) (2-ethoxy-2-oxoethyl) amino] sulfonyl] -1-hydroxyethyl] -4 - (cyclohexylrr.ethyl) -2,2-dimethyl-S-oxazolldlncarbonsäure-ii-dlmuthylethylester

600mg (1.022mmol, 1eq) of a solution of isomer B of part (c) in 2.0ml (0.5M) dimethylformamide were added 710mg (5.125mmol, 5eq) of potassium carbonate powder and 227μΙ (2.044mmol, 2eq) of ethyl bromoacetate , The mixture was stirred overnight at 45 ± 5 ^° C. The reaction was quenched with 10% aqueous potassium bisulfate solution and extracted with 3x 30 ml ether: hexane (1: 1) The combined extracts were washed with 50 ml water and saturated brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by chromatography through 60g of silica gel (from Merck) and elution with ether: hexane (1: 2) to give 520mg of [4S- (4a, 5β (R))] - 5- [2 - [[( diphenylmethyl) - (2-ethoxy-2-oxoethyl) amino] sulfonyl] -1-hydroxyethyl] -4- (cyclohexylmethyD-2,2-dimethyl-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester.

oxazolldincarbons & acid, 1,1-dimethylethyl

A solution of 514 mg (0.764 mmol, 1 eq) of the product of part (d) in 3.0 mL of a mixture of ethanol: tetrahydrofuran (3: 1, 0.25M) was mixed with 10 mg (20 wt%) of 20% palladium hydroxide on carbon catalyst and 84μΙ (0.764 mmol, 1 eq.) of triethylamine. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. Thereafter, the mixture was diluted with ethanol, filtered through re developed cellulose and evaporated under reduced pressure. 515 mg of crude product were obtained. This residue was purified by chromatography through 40 g of silica gel (from Merck) and eluting with ethenehexane (1: 2). This gave 339ma [4S, 4a, 5β (R ') II-5- [2 - [[(2-ethoxy-2-oxoethyl) amino] sulfonyl] -1-hydroxyethyl] -4- (cyclohexylmethyl) -2 , 2-Dimethyl ioxnzolidincarbonsäure-ii-dimethyl ethyl ester.

f) i.i.-dimethyl oxazolidinecarboxylate

200 mg (0.39 mmol, 1 eq) of the product of part (e) was dissolved in 3.9 ml (0.1 M) of anhydrous ether. After cooling to 0 ⁰ C 0.59 ml (0.59 mmol, 1.5 eq., 1M in tetrahydrofuran) was added dropwise lithium aluminum hydride. The mixture was stirred at ⁰ C for 1 h. Then the reaction was stopped with 1 η hydrochloric acid. The mixture was extracted with ether and the ether phases were dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. One received 177mg of a white foam. This material was purified by chromatography through 15 g of silica gel (from Merck) packed in acetone-hexane (1: 4) and eluting with acetone: hexane (1: 4 and 1: 3). 129 mg of I4S- (4a, 5β (R) -1] -5- [2-l [(2-hydroxyethyl) amino] sulfonyl-1-hydroxyethyl] -4- (cyclohexylmethyl) -2 were obtained, 2-dimethyl-3-oxazolidine carboxylic acid, ii-dimethylethyl ester.

g) TssS (βR », YS ^# , 5R ^# )] - ö-Amino-p, Y-dihydroxy-N- (2-hydroxyethyl) -cyclohexane pentanesulfonamide diacotate salt

126 mg (0.271 mmol) of the product from part (f) were dissolved in a mixture of 3 ml of distilled tetrahydrofuran, 2 ml of 10% HCl and 1 ml of acetic acid. The mixture was stirred at room temperature for 4 days, evaporated under reduced pressure and evaporated with toluene. The residue was purified by chromatography. The product was absorbed on 2 g of kifisel gel (ex Baker), added to a column of 8 g of silica gel (from Merck) and eluted with acetic acid: ester: pyridine: acetic acid: water (10: 1: 1: 0.5). The combined product fractions were evaporated to near dryness and evaporated with toluene. The residue was dissolved in 15 ml of water and 5 ml of ethanol and freeze-dried. The compound was dissolved in 20 ml of water and freeze-dried. 77 mg of product were obtained. This was dissolved in 20 ml of water and 2 ml of ethanol, filtered through a polycarbonate membrane and freeze-dried. As a solid to give 57 mg [SSS (pR * YS \ ER ") - ö-amino-p, Y-dihydroxy-N- (2-hydroxyethyl) -cyclohexanpentansulfonamid diacetate salt, m.p. 57-160 ⁰ C; [a] ₀ = -18.2 ° (c = 1.5, methanol: water, 1: 1). TLC (silica gel, ethyl acetate: pyridine: acetic acid: water, 5: 1: 1: 1) R _f = 0.35

Ci ₃ H ₂₈ N ₂ O ₆ S · 2 CH ₃ COOH · 1.1 H ₂ O:

CHNS calc .: 43.97 8.29 6.03 6.90

F .: 43.93 7.97 6.14 7.05

Example 36

[2S- (2R ^# , 3S ^# , 4R))] - N - [(4-Amino-5-cyclohexyl-2,3-dlhydroxypentyl) -sulfonyl] -glycine monolithic salt 140mg (0.276 mmol) [4S- [4a , 5p (R ")]] - 5- [2-l [(2-ethoxy-2-oxoethyl) amino] sulfonyl] -1-hydroxyethyl] -4- (cyclohexylmethyl) -2,2-dimethyl-S -oxazolidinecarboxylic acid-ii-dimethyl ethyl ester, prepared according to Example 35 (e), were mixed with 3 ml of distilled tetrahydrofuran, 2 ml of 10% hydrochloric acid and 1 ml of acetic acid. The solution was stirred for 5 days at room temperature and then evaporated to dryness under reduced pressure. The residue was chromatographed through silica gel (from Merck) and eluted with ethyl acetate: pyridine: acetic acid: water (10: 1: 1: 0.5, then 8: 1: 1: 1 and finally 5: 1: 1: 1) , The combined product fractions were evaporated to near dryness under reduced pressure. 20 ml of water were added and the solution was freeze-dried. 91 mg of a sparingly soluble material were obtained.

The material was mixed with 5 ml of water and added to the Sus. ..3ns'un with 0,29ml 1 η lithium hydroxide solution. Most of the solid dissolved. The solution was washed with 2 × 10 ml of dichloromethane and then freeze-dried. The luckstand was passed through an LH-20 column and eluted with water. The combined product fractions were freeze-dried. 91 mg of product were obtained, which was again freeze-dried. Half of this material was purified in a column packed with 22 ml of HP-20 by elution with 150 ml of water and then 5% acetone in water. The combined phases with the pure product were freeze-dried. As a white solid 32mg [2S- to give (2R \ 3S *, 4R *) lN - [(4-amino-5-cyclohexyl ^ .S-dihydroxypentyO-sulfonyll-glycine-mono-lithium salt; F. 220-242 ⁰ C. (under decomposition), shrinking at 13O ⁰ C; [a | o = -6.6 ° (c = 0,2,10% methanol in water) TLC (silica gel, ethyl acetate: pyridine: acetic acid: water, 5: 1. : 1: 1) R, = 0.23

C ₁₃ H ₂₅ N ₂ O ₆ S · Li · 0.4 H ₂ O:

C H N. S

Calculated: 44.41 7.40 .7.97 9.12

F .: 44.53 7.65 7.75 8.99

Example 37

(IS ^ R.SRl-N-U-IiButylamlnol-sullonyn-i-cyclohexylmethyl) -dihydroxybutyD-.beta.-ethyl-IH-imidazole ^ -propanamide, isomer 1 and isomer 2

a) α-ethyl-1H-imidazole-4-propanoic acid

To a suspension of 500 mg (12.6 mmol) of 60% sodium hydride dispersion in oil in 20 ml of dimethylformamide was added 0.64 ml (4.2 mmol) of diethyl malonate. The resulting mixture was stirred for 30 minutes at 25 ° C and then with 760mg (4.2 mmol, prepared according to Kelley and Mitarb, in o. Med. Chem., Vol. 20 (1977) p.721) 4- (1 The mixture was stirred for 18 hours, poured into 200 ml of water and extracted with 3x 75 ml of ethyl acetate The extracts were dried and evaporated The residue was purified by 65 g of silica gel and eluting with ethyl acetate: (pyridine 20: 1). Acetic acid 6: water 11) (10: 1) flash-chromatographed to yield 700 mg of [1- (1H-imidazol-4-yl) -propyl] -propanedioic acid diethyl ester.

A mixture of 709 mg (2.6 mmol) of this diethyl ester, 7 ml (7 mmol) of 1.0 N sodium hydroxide solution and 7 ml of ethanol was stirred for 7 days at 25 ⁰ C and then evaporated under reduced pressure. The residue was dissolved in 15 ml of 1 N HCl and added to a column of AG-50W-X2 ion exchange resin in proton form. The column was eluted with water until the eluent showed a neutral pH and then eluted with 2% aqueous NH ₄ OH solution. The combined phases containing the desired product were evaporated. The residue was recrystallized from absolute ethanol. This gave 330 mg a-ethyl-1 H-imidazole-4-propanoic acid, mp 166-168 ⁰ C.

b) (1S, 2R, 3R) -N- [4 - [(butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dihydroxybutylJ-.beta.-ethyl-1H-imidazole-4-propanamide, isomer 1 and isomer 2

A mixture of 186 mg (0.5 mmol) of [βR- (βR, yR *, öS ^# )] - 5-amino-N-butyl-β, Y-dihydroxycyclohexane pantanesulfonamide monohydrochloride (the product of Example 1) 102 mg (0, 5 mmol) of a-ethyl-1 H -imidazole-4-propanoic acid, 96 mg (0.5 mmol) of i-O-dimethylaminopropyD-S-ethyl-carbodiimide hydrochloride, 77 ml (0.5 mmol) of 1-hydroxybenzotriazole hydrate and 0 , 14 ml (1 mmol) of triethylamine in 1.0 ml of dimethylformamide was stirred for 17 hours at 25 ° C and then evaporated under reduced pressure. The residue was flash chromatographed through silica gel eluting with chloroform: methanol: NH ₄ OH (90: 10: 1). One main fraction was obtained from two components. This major fraction was evaporated and chromatographed by elution with chloroform: methanol: NH ₄ OH (95: 5: 1). 40 mg product of isomer 1 and isomer 2 were obtained. The product isomer 1 was freeze-dried from aqueous ethanol. As a white solid (1S, 2R, 3R) -N- [4 - [(butylaminol-sulfonyN-i-icyclohexylmethyD ^ S-dihydroxybutyl-β-ethyl-IH-imidazole] -propanamide, isomer 1; 100 ° C, [α] ₀ = -17 ° (c = 0.1, methanol), TLC (silica gel, chloroform: methanol: NH ₄ OH, 80: 20: 1) R, = 0.7, C ₂₃ H ₄₂ N ₄ O ₆ S x 0.32 H ₂ O:

CHNS: 56.10 8.73 11.38 6.51

Filled: 56,10 8,78 11,20 6,69

The product isomer 2 was also freeze-dried from aqueous ethanol. As white solid (1S, 2R, 3R) -N- [4 - [(butylamino) sulfonyl] -1- {cyclohexylmethyl) -2,3-dihydroxybutyl] -β-ethyl-1H-imidazole-4- was obtained. propanamide, isomer 2; F. 60-90 ° C; [aI _D = -27 ° (c = 0.1, methanol). TLC (silica gel, chloroform: methanol: NH ₄ OH, 80: 20: 1) R, = 0.65. C ₂₃ H ₄₂ N ₄ O ₆ S x 0.32 H ₂ O:

CHNS: 56.10 8.73 11.38 6.51

Filled: 56.09 8.76 11.21 6.32

Example 38

[1S- (1R *, 2S *, 3S *)] - N- [4 - [(Butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dlhydroxybutyl] -4-methylpentanamide A solution of 310mg (0 , 83 mmol) [βR-fβR ^ R ^ S''II-ö-amino-N-butyl-β'-dihydroxycyclohexane pentanesulfonamide monohydrochloride (the product of Example 1) 92.8 mg (0.83 mmol) of 4-methylpentanoic acid and 112 mg (0 , 83 mmol) of 1-hydroxybenzotriazole hydrate in dimethylformamide was added at 5 ⁰ C with 0.32 ml (1.83 mmol) of diisopropylethylamine and then treated in portions with 159mg (0.83 mmol) of i-ß-DimethylaminopropyD-S-ethylcarbodiimide hydrochloride added. The mixture was stirred at room temperature overnight. The mixture was diluted with 10 ml of water and the product extracted with 2 x 50 ml of ethyl acetate. This was washed with saturated aqueous bicarbonate solution and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography through silica gel with a hexane: ethyl acetate (7: 3) solvent system. The combined product fractions were evaporated. The white solid obtained was 270 mg of [1S- (1R \ 2S *, 3S *) 1 N- (4-I (butylamino) sulfonyl] -1- (cyclohexylmethyl) -1-dihydroxybutyl-1-methylpentanamide, m.p. 104 -105 ⁰ C; [a] ₀ = -17.5 ° (c = 0.57, methanol) TLC (silica gel; methanol: chloroform, 1: 9). R _f = 0.66.

C ₂ IH ₄₂ N ₂ O ₆ S C H N S 58.03 9.74 6.45 7.38 calc .: 58.19 10.05 6.34 7.40 Found .:

In a similar manner, 4-methylpentanoic acid was reacted with the product of Example 2. There was obtained [1S- (1R *, 2S *, 3R *)) - N- [4 * [(butylamino) sulfonyl] -1- (cyclothylmethyl) -2,3-dihydroxybutyl-4-methylthienepentanamide, m.p. 88-92 ° C; Ia] ₀ = -25.1 ° (c = 0.45, methanol). TLC (silica gel, Mathanoh chloroform, 1: 9) R _t = 0.71

C ₂₁ H ₄₂ N ₂ O ₆ S:

CHNS: 58.03 9.74 6.45 7.38

found: 57,76 9.83 6.43 · 7.36

Example 39

[2S-I2R *, N (1R *, 2S *, 3S *)]] - N- [4 - [(butylamino) sulfonylM- (cyclohexylmethane) -2,3-dlhydroxybutyl] -2-hydroxy-4-methylpentanamide

A solution of 250 mg (0.67 mmol) of [βR- (βR *, YR \ 6S ^# )] - 5-amino-N-butyl-β, v-dihydroxycyclohexane pentanesulfonamibmonohydrochloride (the product of Example 1) 88.5 mg (0 , 67 mmol) La-hydroxyisocaproic acid, 90.6 mg (0.67 mmol) of 1-hydroxybenzotriazole hydrate and 0.23 ml (1.34 mmol) of diisopropylethylamine in 8 ml of dimethylformamide was added portionwise with 128.5 mg (0.67 mmol) i -li'-dimethylaminopropyl-S-ethylcarbodiimide hydrochloride added. The mixture was stirred overnight at room temperature under argon and diluted with 20 ml of water. The product was extracted with 2x 100ml ethyl acetate. This was washed with buffer solution of pH 7 and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product vv, de chromatographed through 80 g of silica gel (from Merck) with 2% MethanohDichlormethan. The combined product fractions were evaporated. A white solid was obtained as a white solid, O, Sg, S, R, N, R, N, R, N, R, N, R, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, N, R) -145 ° C; [a] _D = -38 ° (c = 0.4, methanol). TLC (silica gel, methane-chloroform, 1: 9) H, = 0.46. C ₂₁ H ₄₂ N ₂ O ₆ S · 0.01 H ₂ O:

CHNS: 55.95 9.40 6.21 7.11

Filled: 56.09 9.80 6.07 6.88

Example 40 (1R ^# , 2S ^# , 3S *) - (1-Oxo-3-phenylpropyl) -N- [4 - [(butylamino) sulfoyl] -1- (cyclohoxy) / 1-methyl) -2,3-dihydroxybutyl ] -L-leucinamld

a) N- (1-oxo-3-phenylpropyl) -L-leuein

7.87 g (60 mmol, 1 eq.) Of L-leucine were dissolved in a solution of 4.8 g of sodium hydroxide (120 mmol, 2 eq.) In 40 ml of 1.5M water. 40 ml of diethyl ether was added. The mixture was cooled in an ice-bath and 10.1 g (8.92 ml, 60 mmol) of hydrochloric acid chloride were added dropwise with vigorous stirring in 30 minutes. The ice bath was removed and the mixture was stirred for 2 hours at room temperature, maintaining a weakly basic pH by periodic addition of small amounts of 1N sodium hydroxide solution. The phases were separated. The ether phase was extracted with 1N sodium hydroxide solution. The combined aqueous phases were washed once with ether and then acidified with concentrated HCl. The product was extracted with chloroform, dried over magnesium sulfate and freed of solvent under reduced pressure. This gave 13.36 g of a white solid. This material was recrystallized from 65 ml of ethyl acetate. This gave 8.37 g of N- (1-oxo-3-phenylpropyl) -L-leucine, mp 129-13O ⁰ C (shrinking at 120 ⁰ C); (a) _D = -41.3 ° (c = 1.3, methanol).

b) {IR ^^ S ^ .SS'i-d-Oxo-S-phenylpropyl-NW-butylamino] -sulfonyl-1-cyclohexylmethyDa-α-hydroxybutyl-L-leuclamide 56.5 mg (0.2145 mmol, 1 eq. ) N- (1-oxo-3-phenylpropyl) -L-leucine and 80 mg (0.2145 mmol, 1 eq) of | β R- (β-R-y-R, 5S *) -O-amino-N-butyl β / y-dihydroxycyclohexane pentanesulfonamide monohydrochloride (the product of Example 1) was dissolved in 1.1 ml (0.2 M) of dimethylformamide. The mixture was cooled to 0 ° C. in an ice-bath and washed with 29 mg (0.214 mmol, 1 eq.).

1-hydroxybenzotriazole hydrate, 45μΙ (0.32 mmol, 1.5Aq.) Of triethylamine and 41.1 mg (0.214 mmol, 1 eq.) Of ethyl 3- (3-dimethylamino) -propyl-carbodiimide hydrochloride were added. The mixture was stored at room temperature overnight. To the mixture was added 6 ml of pH 4 buffer (from Mallinckrodt). The mixture was stirred for 30 minutes and then extracted with ethyl acetate. The combined ethyl acetate extracts were washed with 10 mL saturated sodium bicarbonate solution and 10 mL saturated brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. This gave 124mg of crude product. This residue was purified by chromatography through 13 g of silica gel (from Merck) packed in chloroform and eluting with acetone: chloroform (1: 6, then 1: 4). The product fractions were pooled. 120mg product was obtained. This was purified by preparative HPLC with a completely closed C-18 column (YMC 1-15100AODS, 30χ500mm, 15μ spherical, 25ml / min, UV control at 215nm) and eluting with 84% methanol in 0.1% water. Trifluoroacetic acid purified. The combined product phases were evaporated under reduced pressure, evaporated with toluene and dried under reduced pressure overnight. As a white solid, 77 mg (1R ^# , 2S *, 3S *) - 1-oxo-3-phenylpropyl) -N- | 4- (butylamino) sulfonyl] -1- (cyclohexylmethyl) -4-dihydroxybutyl- L-leucarnamide, m.p. 63-73 ⁰ C [a) ₀ = -53.6 ° (c = 0.5, methanol). TLC (silica gel, chloroform, acetone, 2: 1) R ₍ = 0.60.

C30H51 ! N ₃ O ₆ S-3H ₂ O: H N S C 8.86 7.16 5.46 calc .: 61.36 9.05 6.86 5.09. Found .: 61.45

Example 4!

(1R ^# , 2S ", 3S *} - [(phenylmethoxy) -catLionyl] -N- [4 - [(butylamino) sulfonyl-1- (cyclohexylmethyl) -2,3-dlhydroxybutyl] -L-leuclamide

59.4 mg (0.2238 mmol, 1 eq.) Of N-KPhenylmethoxycarbonylR-leucine and 83.5 mg (0.2238 mmol, 1 eq.) Of [βR- [βR-, YR-, 5S ") 1-6 Amino-N-butyl-β / y-dihydroxycyclohexane pentanesulfonamide monohydrochloride (the product of Example 1) was dissolved in 1.1 ml (0.2 M) of dimethylformamide, the mixture was cooled to ⁰ ° C. in an ice bath and washed with 30.2 g mg (0.2238 mmol, 1 eq) of 1-hydroxybenzotriazole hydride,> t, 47 μl (0.336 mmol, 1.5 eq.) of triethylamine and 49.2 mg (0.2238 mmol, 1 eq.) of ethyl 3- (3-dimethylamino) The mixture was stored overnight at room temperature To the mixture was added 6 ml of pH 4 buffer solution (from Mallinckrodt) The mixture was stirred for 30 minutes and then extracted with ethyl acetate Washed 10 ml of saturated sodium bicarbonate solution and 10 ml of saturated brine, dried over magnesium sulfate, filtered and the solvent under reduced pressure The product was 123 mg of oil. The residue was purified by chromatography through 12 g of silica gel (from Merck) packed in chloroform and eluting with acetate. Chloroform (1: 6). The combined product fractions gave 118mg of material. This was chromatographed through 12 g silica gel (from Merck) packed in dichloromethane and eluted with 1 to 2% methane 3 l in dichloromethane. The combined product fractions were evaporated under reduced pressure. 97 mg (1R *, 2S *, 3S *) - [(phenylmethoxy) carbonyl] -N- [4-l (butylamino) sulfonyl-1- (cyclohexylmethyl) -2,3-dihydroxybutyl] were obtained as a white solid. -L-leucinamide, m.p. 50-70 ⁰ C; Ia] ₀ = -36 ° (c = 0.5, methanol). TLC (silica gel, 4% methanol in dichloromethane) R ₁ = 0.30. C ₂₉ H ^ N ₃ O ₇ S x 0.35 H ₂ O:

CHNS: 59.03 8.49 7.12 5.43

Filled: 59.36 8.59 7.01 5.03

Example 42

(1R ", 2S *, 3S) - N-t4 - [(butylamino) sulfonyl] -1- (cyclohexylmethane) -2,3-dihydroxybutyl] -L-leuclamide 76 mg (0.128 mmol, 1 eq) of the product from Example 41 were dissolved in a solution of 2.6 mL (0.05M) methanol, 0.42 mL (0.33M) water, and 0.13 mL (0.13 mmol, 1 eq) of 1 N HCl and washed with 20 mg (25 wt 20% palladium hydroxide-on-carbon catalyst was added and stirred overnight under a hydrogen atmosphere When the reaction was complete, the mixture was diluted with methanol and filtered through regenerated cellulose to give 64 mg of crude product which was purified by evaporation chromatography through 10 g of silica gel (Merck), gas \ r. Dichlormethqn packed, and eluting with 3% methanol in dichloromethane and 0.2% NH ₄ OH was purified. The combined product fractions were evaporated under reduced pressure. This gave a white solid 53,8mg (1 R \ 2S *, 3S *) - N-I4 - [(butylamino) sulfonyl] -1 - (cyclohexylmethyD-2,3-dihydroxybutyll-L-leucinamide, F. 99-109 ⁰ C. | | a] _D = -1 7.1 ° (c = 0.6, methanol). TLC (silica gel, 8% methanol in dichloromethane + NH ₄ OH) R, = 0.39

C ₂₁ H ₁₃ N ₃ O ₆ S:

C H N S-

reported: 56.09 9.64 9.35 7.13

Filled: 55.95 9.92 9.20 6.83

Example 43

[1S.t1R ^β (R *), 2S *, 3S *]]. [2-l [(1, ^ dimethylethyl) sulfonyl] methyl] -1-oxo-3 phθnylpropvl] · N · [4 [( butylamlno) sulfonyl] -1- (cyclohexylmethyll ^ .S-dihydroxybutyll-L-leucinamide

245 mg (0.86 mmol, 1 eq) of (S) -a - [[(1,1-dimethylethyl) sulfonyl] -methyl] -benzenepropanoic acid prepared according to Example 5 (a) and 387 mg (0.86 mmol ) (IR ^^ S'.SS'l-N ^ -Kbutylaminol-sulphonyl-i-fcyclohexylmethyD ^ .S-dihydroxybutyl-L-leucine amide (the product of Example 42) were dissolved in 4.6 ml of dimethylformamide 0 ⁰ C and cooled with 116 mg (0.86 mmol, 1 eq.) 1 -Hydroxybenzotriazolhydrat and 165 mg (0.86 mmol, 1 eq.) of ethyl 3- (3-dimethylamino) propyl-carbodiimide hydrochloride were added. The mixture After 6.5 hours, the mixture was cooled and 60 μM (0.43 mmol, 0.5 eq.) of triethylamine was added and the mixture was stirred overnight at room temperature, followed by further 60 μM (0.43 mmol, 0 Triethylamine was added and stirred for a further 2 hours at room temperature After mixing with 20 ml aqueous buffer solution of pH 4 (by Mallinckrodt), the mixture was stirred for 20 minutes The product was washed with 2x40 ml of ethyl acetate extracted, washed with 30 ml of saturated sodium bicarbonate solution and 30 ml of saturated brine, dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue was chromatographed through 60g of silica gel (from Merck) and eluted with 4% methanol in dichloromethane. It was then dissolved in 30 ml of benzene, filtered and freeze-dried. 5G3mg of [1S- [1R- (R *), 2S-, 33-) 1- [2- [(1,1-dimethylethyl) sulfonyl] methyl] -1-oxo-3 was obtained as a fluffy white solid phenylpropyl] - N - (4- (butylamino) sulfonyl] -1- {cyclohexylmethyl) -2,3-dihydroxybutyll-L-leucine amide, m.p. 87-101 "C, [α] ₀ = -20.8 ° (c = 0.6, methanol) TLC (silica gel, 4% methanol in dichloromethane) R, = 0.37.

C ₃₅ H ₈₁ N ₃ O ₁ , S ₂ 0.3 H ₂ O: H N S C 8.61 5.82 8.89 calc .: 58.27 9.01 5.88 8.72. Found .: 58.31

Example 44

[β R- (β R *, y R *, 5 S *)] - N -butyl-β, Y-dihydroxy-5 - [(4-methylpentyl) -amino] -cyclohexane pentanesulfonamide monoacetate salt A solution of 100 mg (0, 23 mmoles) of [1S- (1R, 2S *, 3S), 1N- (4 - (butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dihydroxybutyl] -4-methylpentanarride (the product of example 38) in 3 ml of tetrahydrofuran (0.9 ml 9 mmol, 10M) borane-dimethyl sulfide complex was added dropwise. The mixture was stirred for 1 hour at 5O ⁰ C. The reaction was quenched with 10ml 1 η HCI. After 30 minutes The product was extracted with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure The crude product obtained was purified by chromatography through 20 g of silica gel (from Merck) with methanol : Acetic acid: chloroform (2.5: 0.1: 100), Ce suitable fractions

were combined and evaporated to give, as a glassy, very hygroscopic white solid, 63 mg of [βR- (β-R-y-R-ÖS *)) -N-biityl-p _; v-dihydroxy-5 - [(4-mothylpentyl) amino] -cyclohoxan-pentanesulfonamide monoacetate salt, mp 68-82 ⁰ C, [a] _D = + 14 ° (c = 0.5, methanol). TLC (silica gel, methane-chloroform, 1: 9) R ₍ = 0.46

C ₃₁ H ₄₄ N ₂ O ₄ S · 1.15 H ₂ O · 0.9 CH ₃ COOH

CHNS calc .: 55.27 10.15 5.65 6.47

F .: 55.27 9.95 6.05 6.70

Example 45

(IR ^ .aS'.aS'l-tia-PhenylothyD-sL'lfonyll-N-K ^ butylamlnol-suifonylJ-McyclohexylmethyD ^ .a-dihydroxybutyU-L-histidinamide

a) 3 - [(phenylmethoxy) -methyl] -lithium-dihydrochloride

1 g (2.6 mmol) of N-Ki.i-DimathylethoxyJ-carbonyl-S-Kphenylmethoxyl-methyll-L-histidine was cooled in an ice bath and treated with 8ml of 4n HCl in dioxane. The mixture was stirred cold for 3 hours, then evaporated under reduced pressure, evaporated with toluene and dried. This gave 1.21 g of 3 - [(phenylmethoxy) methyl] -L-histidine dihydrochloride as a white foam.

b) [(2-phenylethyl) -8-sulfonyl] -3 - [(phonylmethoxy) -methyl] -L-histidine

2.66 mmol of (1.0Αψ) 3 - ((phenylmethoxy) methyl-L-histidine were extensively garbed in a solution of 426 mg (10.6 mmol, 4 eq.) Of sodium hydroxide in 10 ml (0.27 M) of water After cooling in an ice-bath, a solution of 545 mg (2.6 mmol, 1 eq) of (2-phenylethyl) -sulfonyl chloride in 10 mL (1/7 M) of ether was added Mixture was added with vigorous stirring with 1N sodium hydroxide solution to make the mixture basic, n After 3 hours, an additional 545 mg (2.66 mmol, 1 eq) were added and the mixture stirred vigorously for 45 minutes. The phases were separated and the ether phase was extracted with 10 ml of 1N sodium hydroxide solution and the aqueous phases were washed with ether and concentrated to pH 6 to 7 with concentrated hydrochloric acid. (2-phenylethyl) -sulfonyll-3 - [(phenylmethoxy) methyl] -L-histidine, F.223-233 ° C.

c) (1R *, 2S ^# , 3S *) - [(2-phenylethyl) sulfonyl] -N- [4 - [(butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dlhydroxybutyl] -3 - [(phenylmethoxyl-methyU-L-hlstidinamid

196mg (0.44mmol, 1eq) of ((2-phenylethyl) sulfonyl] -3 - [(phenylmethoxy) methyl] -L-histidine and 165mg (0.44mmol, 1eq.) [ΒR-lpR ^ The mixture was partially dissolved in 4.4 ml (0.1 M) of dimethylformamide and the mixture was dissolved in 4.4 ml of (0.1 M) -dimethylformamide cooled with an ice bath and treated with 60, ng (0.44 mmol, 1 eq.) of 1-hydroxybenzotriazole hydrate, 84.5 mg (0.44 mmol, 1 eq.) of ethyl 3- (3-dimethylamino) -propylcarbodiimide monohydrochloride and 93 μl The mixture was removed overnight and the mixture was stirred at room temperature overnight After a further 4 hours the mixture was treated with 20 ml pH 4 buffer (from Mallinckrodt) and stirred for 20 minutes The mixture was extracted with 2 × 40 ml of ethyl acetate and dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure The residue was purified by chromatography through 30 g of silica gel (ex Merck), d which was packed in dichloromethane and eluted with 2.5% methanol in dichloromethane at 0.2% NH ₄ OH. There were obtained 268 mg (1 R 2 S *, 3S ^# ) - [(2-phenylethyl) sulfonyl] -N- | 4 - [(butylamino) -sulfonyl-1-cyclohexylmethyD ^. S -dihydroxybutyl-S-Kphenylmethoxy] -methyll -L-histidinamide.

d) (1R ", 2S ^# , 3S ^# ) - [(2-Plienylethyl) sulfonyl] -N- [4 - [(butylamino) sulfonyl] -1- (cyclohexyethyl) -2,3-dihydroxybutyl ] -L-histidinamide

314 mg (0.412 mmol, 1 eq) of the product from part (c) were dissolved in 8.3 ml (0.05 M) methanol and 1.2 ml (0.33 M) water. While stirring at room temperature, 0.41 ml (0.41 mmol, 1 eq) of 1 N HCl and 63 mg (20 wt%, from Aldrich) of 20% palladium hydroxide on carbon were added. The mixture was stirred for 24 hours under a hydrogen atmosphere. The mixture was diluted with methanol, filtered through a regenerated cellulose layer and washed with methanol. The material was purified by chromatography through 20g of silica gel (from Merck) and eluting with 3 to 5% methanol in dichloromethane at 0.2% NH ₄ OH. 200mg (1 R 2 S ^# , 3S ") - [(2-phenylethyl) sulfonyl] - N - [4- (butylamino) sulfonyl) -1-cyclohexylmethyl) -2,3-dihydroxybutyl] was obtained as a white solid. -L-histidinamide, m.p. 208-210 ⁰ C; [a] _D = -30.3 ° (c = 0.6, methanol). TLC (silica gel, 8% methanol in dichloromethane + 0.2% NH ₄ OH) R ₁ = 0.35. C ₂₉ H ₄₇ N ₆ O ₇ S _2:

CHNS: 54.27 7.38 10.91 9.99

F .: 54.26 7.27 10.66 10.18

Examples 46-63

In a similar manner, the following compounds were prepared:

[1S- (1R ^#, 2S ", 3R ^lt JN | 4 - ((Butylamino) -8ulfonyl) -1- (cyclohexylmethyl) _-2-l 3 dihydroxybutyll-acetamide as a white foam; _{[a] D} = -19, 7 ° (c = 0.6, methanol), TLC (silica gel, acetone: chloroform, 1: 2) R ₍ = 0.19.

C ₁₇ H ₃₄ N ₂ O ₅ S -0.25 H ₂ O:

CHNS: 53.31 9.08 7.31 8.37

F .: 53.29 9.24 7.22 8.26.

[1S- (1R ', 2S', 3S ^#) -N- [4 - [(butylamino) sulfonyl] -1- [cyclohexylmethyl) -2,3-dihydroxybutyl] acetamide as a white solid, mp 51-54 ° C; | a] _D = -15.4 ° (c = 0.50, methanol). TLC (silica gel, chloroform: acetone, 4: 1) R ₍ = 0.32, C ₁₇ H ₃₄ N ₂ O ₆ S-0.8 H ₂ O:

CHNS: 51.96 9.13 7.13 8.16

F .: 52.16 "8.75 6.93 7.77.

[IS-dR'-S'-S'-d-oxo-a-phenylpropyl-N, -butyl-aminol-sulfonyl-i-cyclohexylmethyDi, a-dihydroxy-butyl-histidine-amide trifluoroacetate salt (1: 1) as solid residue from freeze-drying, mp 70-88 ° C (under Zers.i; [α] ₀ = -1.7 ⁰ lc = 0.6, methanol). TLC (silica gel, 10% methanol in dichloromethane containing 0.2% NH ₄ OH) R ₁ = 0.34. C ₃₀ H ₄₇ N ₅ O ₆ S CF ₃ COOH:

CHNSF: 52.09 6.83 9.49 4.35 7.72

Filled: 52.09 6.50 9.48 4.11 7.99.

(βRiYR) -Si-N-butyl-6-IKI.I-dimethylethoxy-carbonyl-aminol-pY-dihydroxycyclohexane pentanesulfonamide as a tacky semi-solid; [a] _D = -21.8 ° (c = 2.24, methanol). TLC (Silica gel, dichloromethane: methanol, 20: 1) R, = 0.41 C ₂₀ H ₄₀ N ₂ O ₆ S:

CHNS: 55.02% 9.23 6.42 7.34

F: 55.08 9.48 6.22 7.20.

(β-S-R ^ SJ-N-butyl-δ-dd.i-dimethylethoxyl-carbonyl-arninol-pY-dihydroxycyclohexane pentanesulfonamide as a sticky, semi-solid, [ α ] ₀ = -15.1 "(c = 2, 62, methanol) TLC (silica gel, dichloromethane.methanol, 20: 1) R, = 0.34 C ₂₀ H ₄₀ N ₂ O ₆ S 0.5 H ₂ O:

CHNS: 53.91 9.27 6.29 7.19

F .: 54.08 9.44 5.97 7.23.

(1S, 2R, 3S) -N- [4 - [(butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dihydroxybutyl] -1H-imidazole-4-propanamide as a white solid; F. 50-9O ⁰ C; [a] ₀ = -20 ° (c = 0.3, methanol). TLC (silica gel, chloroform: methanol: NH ₄ OH, 80: 20: 1) R, = 0.2. C ₂₁ H ₃₈ N ₄ O ₆ S 0.75 H ₂ O:

CHNS: 53.42 8.43 11.87 6.79

F .: 53.39 8.23 12.07 6.47.

(IS ^ R.SRJ-NW-KButylaminol-sulfonyll-i-tcyclohexylmethyD ^ .S-dihydroxybutyll-IH-imidazoM-propanamide as a white solid with a melting point 65-9O ⁰ C; [a] _D = -17 ° (c = 0.6, methanol), TLC (silica gel, chloroform: methanol: NH ₄ OH, 80: 20: 1) R, = 0.4, C ₂₁ H ₃₈ N ₄ O ₆ S:

CHNS calculated: 54.99 8.35 12.22 6.99

Filled: 54.75 8.35 12.31 7 ^

(2S, 3R, 4S) -N ² - [(4-Amino-5-cyclohexyl-2,3-dihydroxypentyl) sulfonyl) -N ² -butylglycine amide monohydrochloride as a white solid residue from freeze-drying, mp 100-125 ° C (shrinking at 72 ^° C.); Yes) ₀ = -1.9 ° (c = 0.6, methanol). TLC (silica gel, 15% methanol in dichloromethane with 0.2% NH ₄ OH) R ₍ = 0.19, C ₁₇ H ₃₅ N ₃ O ₆ S · HCl · 0.9 H ₂ O:

C H N Cl S

Cons .: 45.76 8.54 9.42 7.95 7.18

Filled: 45.80 8.63 9.35 8.05 7.10

(2R, 3R, 4S) -N ² - ((4-Amino-5-cyclohexyl-2,3-dihydroxypentyl) -sulfonyl) -N ² -butylglycine amide mono-di-chloride as a white residue; [a] ₀ = -2.2 ° (c = 0.5, methanol). TLC (silica gel, ethyl acetate: pyridine: acetic acid: water, 8: 1: 1: 1) R, = 0.36. C ₁₇ H ₃₆ N ₃ O ₆ S · HCl · 0.7 H ₂ O:

C H N Cl S

: 46.13 8.52 9.49 8.01 7.24

F .: 46.48 8.31 8.91 7.83 7.02.

(YR.öSl-ö-iAcetylaminol-N-butyl-ß.Y-dihydroxy-a-methylcyclohexanpentansuifonamid, isomer C as a solid residue from the freeze-drying; F. 53-64 ⁰ C (shrinking at 42 ⁰ C); [al = ₀ -24.6 ° (c = 0.5, methanol), TLC (silica gel, acetone, chloroform, 1: 2) R, = 0.44

C ₁₈ H ₃₆ N ₂ O ₆ S:

CHNS reported: 55.097 9.24 7.14 8.17

F .: 55.12 9.63 7.08 7.89.

| 1R * (R '), 2S', 3S *] - ( "- | ((1,1-dimethylethyl) sulfonyl] methyl) -1-oxo-3-phenylpropyl) -N- [4 - [( 3-butenylamino) -sulfonyll-1- (cyclohexylmethyO ^ S-dihydroxybutyll-L-histidinamide, methanesulfonate salt (1: 1) as a solid; F. 80-121 ° C (shrinking at 7O ⁰ C); [ab = -3 , 2 ° (c - 0.54, methanol), TLC (silica gel, dichloromethane: methanol: ammonia 38: 2: 0.1) R ₍ = 0.09, C ₃₆ H ₆₅ N ₆ O ₈ S ₂ .CH ₄ O ₃ S -1.5 H ₂ O:

CHNS calculated: 50,21 7,26 8,13 11,17

F .: 50.21 7.21 7.99 11.39.

[IS-dR'-S'SR'HNH-KButylamino] -sulfonyl-i-tcyclohexylmethyld ^. S-dihydroxybutyl-D-hydroxy-methylpentanamide as a white solid; F. 125-140 ° C; [al _D = -25.1 ° (c = 0.45, methanol). TLC (silica gel, methane-chloroform, 1: 9) R _f = 0.5. C ₂₁ H ₁₂ N ₂ O ₆ S -0.31 H ₂ O:

C H N S calc .: 55.28 9.42 6.14 7.03 Found .: 55.19 9.52 5.92 6.78.

[NtSi.YR.öSJ-S-amino-ß.Y-dihydroxy-N-li-thydroxymethyD ^ -methylpropyll-cyclohexanpentansulfonamid-monohydrorhlorid, on Isomer A as a white solid residue from Gefriertrockr, F. 242-247 ⁰ C; [a) _D = + 16.9 ° (c = 0.45, methanol). TLC (Kieselgol, 15% methanol in dichloromethane with NH ₄ OH) R ₁ = 0.24. Ci ₆ H ₃₄ N ₂ O ₆ S · HCl · 0.4 H ₂ O:

C H N S Cl

Calc .: 46.85 8.80 6.83 7.82 8.64

F .: 46.80 8.94 6.78 7.88 8.63.

[NfSJ.YR.sup.1-O-amino-.beta.-Y-dihydroxy-N-li-ihydroxymethyl-1-methylpropyl-cyclohexane pentanesulfonamide monohydrochloride, isomer B as a white solid residue from freeze-drying; F. 142-147 ^C C; [al _D = + 6.4 ° (c = 0.5, methanol). TLC (silica gel, 20% methanol in dichloromethane with NH ₄ OH) R ₁ = 0.32. C ₁₆ H ₃₄ N ₂ O ₆ S · HCl · 0.8 H ₂ O · 0.6 NH ₄ Cl

C H N S Cl

Cons .: 42.75 8.75 8.10 7.13 12.62

Filled: 42.89 8.57 7.77 6.93 12.50.

[β R- (β R *, Y R *, 5 S *)] - N -butyl-β, Y-dihydroxy-6 - [(3-pyridinylmethyl) amino] cyclohexane pentanesulfonamide dihydrochloride as a white solid residue from freeze drying, F. 100- 106 ⁰ C (shrinking at 8O ⁰ C); [a] _D = + 17.6 ° (c = 0.5, methanol). TLC (silica gel, 10% methanol in dichloromethane with NH ₄ OH) R _f = 0.44. C ₂₁ H ₃₇ N ₃ O ₄ S -2 HCI -0.5 H ₂ O:

C H N S Cl

: 49.50 7.91 8.25 6.29 13.92

F .: 49.56 8.25 8.02 6.37 14,11.

[ßS- (ßR *, YS *, öR *)] - 5-amino-N- (4-hydroxybutyl) -β, Y-dihydroxycyclonexanpentansulfonamido monoacetate salt as a white residue from freeze drying, mp 51-53 ⁰ C; Ia] ₀ = -13.6 ° (o = 1.0, methanol). TLC (silica gel, ethyl acetate: pyridine: acetic acid: water, 9: 1: 1: 1) R ₁ = 0.20. C ₁₆ H ₃₂ N ₂ O ₆ S · CH ₃ COOH · 0.7 H ₂ O:

CHNS: 48.03 8.87 6.59 7.54

F .: 47.98 8.86 6.45 7.49

(βS- (βR *, YS *, 5R *) 1-N-butyl-β, Y-dihydroxy-6-l (4-methylpentyl) -amino] -cyclohoxane pentanesulfonamide-moriohydrochloride as a white solid, m.p. 64-80T; Ia] ₀ = + 7.2 ° (c = 0.32, methanol) TLC (silica gel, methanol: chloroform, 1: 9) R ₁ = 0.52 C ₂₁ H ₄₄ NsO ₄ S-HCl-LIH ₂ O:

C H N S Cl

Re: 52.89 9.98 5.87 6.72 7.43

Filled: 53.20 9.63 5.72 6.26 7.57

IβS- (βR », YS *, oR *)] - N -butyl-β, Y-dihydroxy-6 - [(2-hydroxy-4-methylpentyl) -aminol-cyclohexane pentanesulfonamide monoacetate salt as a white solid, m.p. -60 ° C; [a] _D = + 12.0 ° (c = 0.3, methanol). TLC (silica gel, methanol: chloroform: acetic acid, 15: 85: 0.2) R, = 0.46

C ₂₁ H ₄₄ N ₂ O ₆ S · CH ₃ COOH · 1.75 H ₂ O:

CHNS: 52.30 9.83 5.31 6.07

Filled: 52.27 9.60 5.58 5.69

Examples 64-87

Below, further compounds according to the invention of the following general formula are listed:

| 14 ° j 13 y 7

W ₂ -CH ₂ -CH-CN-CH-Y-NH-CH-CH-CH-CH-ZN

ι ι \

R ₁₅ OH OH R

example

66

W IH, C) .- C-SO ₂ (H ₃ C) ₃ C-SO ₂ - (H ₃ C) ₃ -C-SO ₂ -

14

-CH-Γ- ί · Η

NH

CO

CH. CO

O- Q

CH, -

• like this

so so.

- (CH ₂ J ₃ -CH ₃ -CH ₂ -CN

example

08

69

(HC) ₁ -C-SO ₂ -

qVch.-

-CH.-rΨ -CH- ™

CO

COCO

SO,

So so.

O Il

-CH-C-OH- (CH ₂ J ₆ -COOH

R ₁₅ η

Example 70

71

72

(H ₃ C) ₃ -C-SO ₂ -

(H ₃ C) ₃ -C-SO ₂

14

[OW

CO

co

co

CH ₂ -

-CH ₂ -

SO,

so"

so.

- (CH ₂ J ₃ -CH ₃

- (CH ₂ J ₃ -CH ₃

15 H

CH.

Example ' ³

74

(H ₃ C) ₃ -C-SO ₂ - (H ₃ C) ₃ -C-SO ₂ - (H ₃ C) ₃ -C-SO ₂ -

14

H.C- (H, C)

3

13

-CH ₂ -S-CH ₃

-CH

ng?

CH.

CO

CO

CH-

so.

so.

so.

- (CH ₂ J ₃ -CH ₃

- (CH ₂ J ₃ -CH ₃

- (CH ₂ J ₃ -CH ₃

Example ^{7 &}

78

(HC), -C-SO-

(HC) -C-SO- (H.C) .- C-SO-

3 3 2 3 j 2

14

H ₃ CO

CH.

13 - ^CH -T ~ | ^NH

NH

co

CO

O"-

so.

so.

- (CH ₂ J ₃ -CH ₃

Beisniel

30

81

/ -Ν Ι « ² ο *"<>

H, C-N N-C

O Il

OC ₂ H ₅

CH-

- - ^cR - ;;

NH

NH

co

co

co

O-

CH _- -

Z ^S0 2

So so.

- (CH ₂ J ₃ -CH ₃

Example _g2

HS

33

84

(H.C) -N-C-

J 2

O / ^CH 2 "

CH ₂ -

MH-CH ~ I7-NH

TJ

co

CO

CO

O-

CH-

so.

so so.

Example 35

86

HC (HC) -U-SO.

H ₃ CCS

O> ^c v

CH, -

-CH ₂ - ^ - NH

NH

-CH

CO

CH.

CO

CH-

Ο "-

•so

So so.

- (CH ₂ J ₃ -CH ₃ - (CH ₂ J ₃ -CH ₃

Examples 88-36

Below, further compounds according to the invention of the following general formula are listed:

O R

13

I /

-N - CH-C-N-CH-Y-NH-CH-CH-CH-CH-SO- -

^R 16 ^R 14 ^R 15

OH OH

ßeisoiel 33

.c; , -Hc-so

O Il

90

H.C-O-C

D 2

H ₃ C

OK

CK ₂ -

OV

CH-

" _CH -. NH

CO

CO

O-

- (CH ₂ J ₃ -CH ₃ - (CHJ ₃ -CH ₃

example

O N-C-

ι- \ H

U ' ^c '

93

/ i

H.C-N M-C-

³ \ _y

16

H .

14

CH-

^R 15

CH.

13 -CHr-T MH

NH

¹ T /

CO

co

co

BeisOiel 95

96

HOOC- (H ^ C) _- C- H-N- (H.C) .- C-

2 o 2 2a

-CH -, - NH

² TJ

coco

co

CH ₂ -

~ ^(CH 2 ⁾ 3 " ^CH 3

" ^(CH 2 ⁾ 3 ^CH 3

Examples 97-101

Below sir.d further compounds according to the invention of the following general formula:

13

/ ^l

_W - _N - _CH - yn - CH - CH - CH - CH-- ZN

15

OH OH R,

Beisniel

99

U / ~ ^cH , 7T ^cH - ^c -

R ₁₅ η

CH.

13 -CH, -Γ ^m

co

co

CO

O-

so.

so.

so

- (CH ₂ J ₃ -CH ₃

- (CH ₂ J ₃ -CH ₃

Example loo

101

(H ₃ O ₃ -C-SO-

CH-HN-SO. -

-CH £ -: NH

NH

CH.

CO

CH.

SO.

SO,

- (CH ₂ J ₃ -CH ₃

Examples 102-109

Below, further compounds according to the invention of the following general formula are listed:

R ₇ R _{3 t} R ₁

X-NH-CH-CH-CH-CH-Z-N

ι ι \

OH OH, R ₂

Example 102 103

O CH

Il

H ₃ CNC CH

-CH ₃

SO ₂ .SO

Example -35

106

107

(H-C) -CH-CH-CH 3 2, 2

OH

SO.

SO.

SO.

Example:; 3 109

Ν ι

t ¹ L

\, S- CH-C N

CH.CH-CH- X, S - CH-CH.-CH.

21 2 N, 2,

OH ^{Η 0Η}

so ₂ so ₂

^R l - (CH ₂ J ₃ -CH ₃ - (CH ₂ J ₃ -CH ₃

Example 110

1000 tablets are produced, each containing the following ingredients:

dihydroxycyclohexanpentansulfonamid- 250mg monohydrochloride 100 mg corn starch 20 mg gelatin 50 mg Avicel (microcrystalline cellulose) 5 mg magnesium stearate

425mg

The tablets are prepared in suitable batch sizes by mixing the monohydrochloride salt active ingredient of Example 1 and corn starch with an aqueous solution of gelatin. The mixture is dried and ground to a fine powder. Then, Avicel and the magnesium stearate are mixed with granulation. This mixture is then compressed in a tablet press into 1000 tablets, each containing 250 mg of the active ingredient. Similarly, tablets containing 250 mg of the product of any one of Examples 2 to 109 can be prepared. Following a similar procedure, tablets containing 500mg of active ingredient can be prepared.

Bolsplel 111

An injection solution is prepared as follows: [1S- [1R "(R *), 2S", 3S "]] - [2 - [[(1,1-dimethylethyl) sulfonyl) methyl] -1-oxo-3 phenylpropyl] -N- [4 - [(butylamino) sulfonyl] -1- (cyclohexylmethyl) -2,3-dihydroxybutyl] -L-hisiidinai di-methane-sulfonate (1: 1) salt 10QF

Methylparaben 5g

Propylparaben 1g

Sodium chloride 5g

The active ingredient, preservatives and sodium chloride are dissolved in 3 liters of water. It is then made up to a volume of 5 liters. The solution is sterile filtered through a filter and aseptically filled into pre-sterilized tubes containing

Pre-sterilized rubber closures are closed. Each tube contains 5 ml of solution containing the active substance at a concentration of 200 mg per ml of solution for injection.

In a similar manner, an injection solution containing, as active ingredient, 200 mg of the product of any one of Examples 1 to 4 and 6 to 109 per ml of solution can be prepared.

Example 112 500 mg 300 mg 1000 tablets are produced, each containing the following ingredients: 1'4,5mg (YR, 6S) -o-amino-N-butyl-ß, Y-dihydroxy-a- 113 mg methylcyclohexanpentansulfonamid mono- 15.5mg hydrochloride, isomer C 7 mg Avicel hydrochlorothiazide lactose corn starch stearic acid

950 mg

The tablets are prepared in suitable batch sizes by forming lumps of the (vR, 5S) -5-amino-N-butyl-β, Y-dihydroxy-α-methylcyclohexane pentanesulfonamide monohydrochloride, isomer C, Avicel and a portion of the stearic acid are ground and passed through a # 2 sieve and mixed with the hydrochlorothiazide, lactose, corn starch and the remainder of the stearic acid. The mixture is compressed in a tablet press to 950 mg of capsular tablets. The tablets are notched to halve them.

In a similar manner, tablets containing 500 mg of the product of any one of Examples 1 to 21 and 23 to 109 can be prepared.

Claims (12)

1. Compounds of the general formula: R ₇ OR ₆ R ₃ A I! I
X_NH - CH - CH - C - C - ϊ. -Η III \ OH R ₅ R ₄ A ₂ or their pharmaceutically acceptable salts in which Z is an SO or SO ₂ group, R ₁ and R ₂ is selected independently from Jen who Wasserstoffaiomen, C ^ alkyl, C ₂ _ ₇ · alkylene, - (CH _{2) m} -aryl, - (CH _{2) m} -cycloalkyl, - (CH ₂ ) _m -heterocyclo-, halogen-substituted C, _ ₇ - Alkyl radicals, the radicals - (CH ₂ J ₉ -OR ₁₅ , / ^R 15 ^R 16 o R ₈ Ρ / ^R 15 I - (CH ₉ ) -C-IT, - (CH ₂ ) - CH-COR ₁₅ , L. Iu χ. * · Tr ^R 16 ^R 8 ^R 8 ^R 15 -CH- (CH ₉₎ OH, -CH (CH ₉₎ ^ - N ^R 16 ^R 8 ° ' ^R 15 - (CH ₉ ) - CH - C - N ^R 16 R ₈ OR ₂₀ O - (CH ₂ ) -CH- C -NH-CH - C - OR ,. , ^una R ₈ OR ₂₀ 0 - (CH ₉ ) ^ - CH-C-NH-CH-C-N, _o the ζ ρ ^ /H ν is a heterocyclic pino "" N j ; ^R 2 ^ R3, R7 / Re <Ri3 / Ri4 and R ₂ o are independently selected from hydrogen atoms, C ₁ -V-AlCl yl, halo-substituted C 1-6 alkyl-, - (CH ₂ ) _m -aryl -, - (CH ₂ ) _m -heterocyclo, - (CH ₂ ) _m -cycloalkyl radicals, the radicals / ¹⁵ , - (CH ₂ J _n -O- (CH ₂ ) _g -OR ₁₅ ' ^R 16 - (CH ₂ ) _n -S- (CH ₂ ) _g -OR ₁₅ , - (CH ₂ J _n -O- (CH ₂ JN ₁ / ^R 15 (CH ₂ J _n -S- (CH ₂ Jg-N / ^R 15 , ^R 16 0 / ^R 15 Il (CH ₀ J-- CN , - (CH ₉ ) - NH-C-O-lower alkyl, ^R 16 0 Il (CH ₂ ) _n -NH-C-lower alkyl, - (CH ₂ J _n -NH-C- (CH ₂ O Il (CH ₂ J-NH-CO- (CH ₂ J _n- J-aryl, Il - (CH ₂ ) - O- (CH ₀ J - NH-CO -silylalkyl, Il - (CH ₂ J _n - O- (CH ₂ J_- NH-C- lower alkyl, (CH ₂ ) _g -NH-C- (CH ₂ ) _m -aryl, - (CH ₂ I _n -O- (CH ₂ L-NH-CO - (CH ₂ ) _m -aryl, ii rT " ^S ~ ^ ⁰¹ Vg" ^ " ^c ~ ° - ^N - (CH ₂ ) -S- (CH ₂ ) -NH-C-Miederalkvl, ) - S - (CH ₂ ) - ^ H - C - (CH ₂ ) _m - Aryl, (CR,) -S- (CH ₉ ) -NH-C-O- (CH,) -aryl, Ca Ii ^ CJ / L ΙΠ - NH-C N "I ^R 10 R _{4 represents} a hydrogen atom or a C 1-4 -alkyl radical; R ₅ and R _{6 are} independently selected from hydrogen, C _1-7 alkyl, halo-substituted C 1-6 alkyl, - (CH ₂ ) _m -aryl, - (CH ₂ ) _m -heterocyclo and - (CH ₂ ) _m -cycloalkyl radicals; R the group ~ "^ or · -CH ₂ -K (J ^ means; the group q > ₂ '-CO-CH ₂ - (O) NO ₂ ^or X is a hydrogen atom, jinen of the radicals 0 H means; , -SO ₂ -R ₁₁ , -CH-R ₁₂ , ^R 13 15 ^R 13 0 R 14 16 21 -Y-CH-NW ₁ , -Υ-CH-NC-CH-NW ₁ , 13 0 R 14 -Υ-CH-O-W ₃ , -Y-CH-NC-CH-CH ₂ -W ₂ , 15 SO_-N , or 16 16 0 R 14 -Y-CH. N-C-CH-O-W. 3 means; 15 Y represents a -CH ₂ - or-C- group; R _{11 is} a Ο, _ ₇ -ΑΙΙ <γΙ-! Lalogensubstituierten C ^ alkyl, aryl, heterocyclo, cycloalkyl, -Alkylenaryl-, -alkylene-heterocycloalkyl, -alkylene-cycloalkyl, one of the radicals / ^R 15 ^R 16 - (CH ₂ J _n -COR ₁₅ / ^R 15 Alkenyl COR _c , or alkenyl CN; ¹⁵ \ R ₁₂ and R ₂ ! are independently selected from hydrogen, C 1-6 alkyl, halogen substituted C _1-7 alkyl, aryl, heterocyclo, cycloalkyl, alkylene aryl, alkylene heterocyclo, alkylene cycloalkyl, the radicals O O Il ζ * « ) _m -CN ^R 16 ii
Alkenyl-C-OR ₁₅ , and P / ^R 15
Alkenyl-CN ^No. 16 Ria and R ₁₆ are independently selected from hydrogen atoms, CI_ ₇ -alkyl, - (CH _{2) m} -cycloalkyl -, - (CH _{2) m} aryl and - (CH _{2) m} -Heterocycloresten; W _{1 is} a hydrogen atom, one of the radicals
0 -CO- (CH ₂
O -CN- (CH ₂ J _n -R ₁₇ , -C- (CH ₂ J _1n- R ₁₇ ^R 17 '
-SO ₂ -R ₁₈ , -SO ₂ -NH ₂ , "SO ₂ ^R 18 ' SO ₂ -NH-R ₁₈ , - (CH ₂ ) _m -R ₁₇ , or jj means; -C-N R ₁₇ and R ₁₇ - are independently selected from hydrogen, C 1-4 alkyl, aryl, heterocyclo and cycloalkyl;
W _{2 is} a hydrogen atom, one of the radicals -e- 299 no I _'n -C-NH _9, -C-NH-R ₁₈ - ^R 18 '- ^C " ^R 18' - ^C - ° - ^R 18 ' -SH, "SR ₁₈ , -SO-R ₁₈ , -SO ₂ -NH ₂ , -SO ₂ -NH-R ₁₈ , -P- (CH ₂ J _n -R ₁₇ -SCR ₁₈ - R ₁₇ . ο ° Il -PO- (CH ₂ J _n -R ₁₇ , -PO- (CH ₂ (CH ₀ ) 2'n ¹ R ₁₇ . or -C-N); W _{3 is} a hydrogen atom, one of the radicals Il -R ₁₈ , -CR ₁ J 0 0 0 Il Il Il -C-NH ₂ , -C-NH-R ₁₈ , -CNR ₁₈ , ^R 18 · ^R 18 ' _R O ^K 18 · or "' ^ means; - ^c -O R ₁₈ and R ₁₈ - are independently selected from C _1-7 -alkyl, - (CH ₂ ) _m -aryl, - (CH ₂ ) _m -cycloalkyl, the radicals Il Ii / - ^(CH 2> nf ^heteroC y ^c3 · ⁰ 'is -CH ₃ -COR _17' is -CH ₂ -CN ^R 16 OO ) _n -NK-C-lower alkyl, - (CH ₂ ^ -NH-CO-lower alkyl ί Λ " - (CH ₉ ) -NH-CO- (CH ₉ ) TA.ryl, - (CH ₉ J _n -N L * Il L ·, Il L · Il ^R 16 NH and - (CH ₂ J _n -NH-C \
NH, N- a heterocyclic ring of the formula (CK ₂ ) ^ ^N ~ means; ^ - (CH ₂ ) _b / wherein A represents a -CHr group, an oxygen or sulfur atom or an NR ₁₉ radical, a is an integer from 1 to 4 and b is an integer from 1 to 4, with the proviso that the sum of a and b is an integer of 2 to 5, and those mean heterocyclic rings in which an available carbon atom is substituted with a lower alkyl group; R _{19 represents} a hydrogen atom, a lower alkyl, - (CH ₂ ) _n -phenyl or a - (CH ₂ ) _n -cycloalkyl radical; m and m 'independently represent the value 0 or an integer from 1 to 5; η and n 'are independently an integer from 1 to 5; ρ has the value 0 or 1; g is an integer from 2 to 5; the term "C 1-4 -alkyl" denotes straight-chain or branched-chain radicals having up to 7 carbon atoms; the term "lower alkyl" means straight or branched chain radicals of up to 4 carbon atoms; the terms "lower alkoxy" and "lower alkylthio" mean the alkyl groups defined above attached to an oxygen or sulfur atom; the term "alkenyl" means straight or branched chain radicals of 2 to 7 carbon atoms containing at least one double bond; the term "cycloalkyl" means saturated rings of 4 to 7 carbon atoms; the term "alkylene" means straight-chain bridges of 1 to 5 carbon atoms bound by mono link bonds and those straight-chain bridges of 1 to 5 carbon atoms, in which one or more hydrogen atoms are substituted by a lower alkyl radical, a hydroxy radical. Amino group, a hydroxy substituted lower alkyl or amino substituted lower alkyl group; the term "halogen" means chlorine, bromine, fluorine and iodine atoms; the term "halogen-substituted alkyl" means an alkyl group having one or more hydrogen atoms replaced by chlorine, bromine or fluorine atoms; the term "aryl", phenyl, diphenylmethyl, 1-naphthyl, 2-naphthyl, mono substituted phenyl, diphenylmethyl, 1-naphthyl or 2-naphthyl group which are substituted with lower alkyl having 1 to 4 carbon atoms, lower alkylthio ^- esters having up to Λ carbon atoms, lower alkoxy radicals having from 1 to 4 carbon atoms, heloyene atoms, hydroxyl, amino groups, -NH-alkyl radicals, where the alkyl radical has from 1 to 4 carbon atoms, or -N (alkyl) 2-radicals, where the alkyl radical is from 1 to 4 Having di-or trisubstituted phenyl, diphenylmethyl, 1-naphthyl or 2-naphthyl groups which are substituted with methyl, methoxy, methylthio, hydroxy, amino and halogen atoms; is the term "heterocyclo" completely saturated, partially saturated or unsaturated monocyclic rings of five or six atoms containing one or two oxygen or sulfur atoms and / or one to 4 nitrogen atoms, with the proviso that the total number of heteroatoms in the ring 4 or is less, acyclic rings in which the 5- or 6-membered ring containing oxygen, sulfur and nitrogen atoms as described above is fused to a benzene or pyridyl ring, the monocyclic or acyclic ring being attached to an available carbon atom, and substituted monocyclic and acyclic ^ rings, as described above, relates to substituted on an available carbon atom with C ^ alkyl, C ₁ halosubstituted ^, - Alkylreston, hydroxy, benzyl or cyclohexylmethyl, and if said monocyclic or Acyclic ring having an available nitrogen atom, the nitrogen atom optionally sub is constituted by the groups -CH ₂ -O-CH ₂ or 2,4-nitrophenyl, benzyl or benzhydryl groups or C 1-6 lower alkyl groups. 2. Compounds according to claim 1, in which Z represents an SO ₂ group. 3. Compounds according to claim 1 or 2, in which R ₁ and R _{2 are} both hydrogen atoms, or R _{1 is} a straight- or branched-chain C 1-4 -alkyl-, C 1-4 -alkylene radical having a single double bond, the C 1-6 -alkylene radical ? _d ι ⁸ ; -CH- (CH ₂ J-OH, or. ^, _ Ch _ _c - O - R ₁₅ and R _{2 represents} a hydrogen atom or a benzyl group; R3 "R41R5 / R6 and _R8 are independently selected from hydrogen atoms and straight or branched chain C ^ alkyl; R _{7 is} a - (CH ₂ ) _n -cycloalkyl radical; X is a hydrogen atom, a straight-chain or branched-chain C _1-7 -alkyl radical, one of the radicals 0 0 -COR ₁₁ , " ^S0 2" ^R ii ' R ₁₃ R ₁₃ OR ₄ i IPI CH-NH-W ₁ , -Y-CH-NH-C-CH-NH-W ₁ , ¹³ y -Y-CH-NH-C-CH-CH ₂ -W, -Y-CH-OW ₀ ^{z Δ} 3 'or ^R 13 -Y-CH NH-SO ₀ -R ₁₀ bedeutst; Y represents a-C or -CH ₂ -GrUpPe; R-1 is a straight- or branched-chain C _1-7 -alkyl, aryl, heterocyclo, alkylene-aryl, Alkylenheterocyclo-, or -CH = CH-C-O-lower alkyl radical, wherein "heterocyclo" means a 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 6-hydroxy-3-pyridinyl, 4-pyridazinyl or 2-pyrazinyl group; R _{13 is} a straight- or branched-chain C _w -alkyl radical, the rest means; Ru is a - (CH ₂ ) _m -aryl or straight or branched chain C 1-4 alkyl group; R _{15 represents} a hydrogen atom or an alkali metal salt ion; W _{1 is} a hydrogen atom, Il a radical -C- (CH ₂ ) _m -R ₁₇ or -SO ₂ -R ₁₈ , one of the groups 0 ° 0 Z is N or R, -CN, O, -CN Jih ^ _ _C _ _N N means; W _{2 is} a radical -SO ₂ -R ₁₈ or 0 PO- (CH ₂ one of the groups OO _ON O, -CN NH or -CN N-CH ₃ means; W _{3 is} a hydrogen atom a -C- (CH ₂ ) J _n -R ₁₇ -ReSt, one of the groups 0 means; R ₁₇ and R _{17 are} independently selected from straight or branched chain C _w alkyl, aryl, 2-pyridyl, 3-pyridyl, 4-pyridyl and the group I H R _{18 is} a straight or branched chain C ₁ _ ₇ alkyl or- (CH _{2) m} -a''ylrest means; and the term "aryl" means a phenyl, diphenylmethyl, 1-. ' R 1 is phenyl, 2-naphthyl or monosubstituted phenyl which is substituted by a C 1-4 alkyl, C ₁ C 12 alkylthio, hydroxy, amino, chloro, bromo or fluoro, or disubstituted phenyl which is substituted by methyl, methoxy, methylthio, hydroxy, amino groups and chlorine, bromine and fluorine atoms. 4. Compounds according to any one of claims 1 to 3, in which R _{1 is} an η-butyl-oxygen radical CH _{2 is} -CH ₂ -CH = CH ₂ -GrUpPe; R _{2 is} hydrogen, R _{3 is} hydrogen or methyl, R _{4 is} hydrogen, R _{5 is} hydrogen, R _{6 is} hydrogen; R _{7 is} a group " ^cH 2 \ __ /; X is a hydrogen atom, a straight- or branched-chain CW-alkyl radical, the rest OR.- ¹³ 0 R ₁₃ 0 R, " -C-CH-NH-W ₁ , ^or 1 -C-CH-NH-C-CH - CH ^ -W ₂ means; R _{13 represents} a group -CH ₂ CH (CH ₃ ) ₂ or -CH, -'- ^NH ; one of the groups
O or means; R ₁₄ the group W _{2 represents} an -SO ₂ -C (CH ₃ ) ₃ group. 5. A compound according to any one of claims 1 to 4, wherein X represents a hydrogen atom; R _{1 represents} an n-butyl group and R _{3 represents} a hydrogen atom. A compound according to any one of claims 1 to 4, wherein X represents a hydrogen atom; R _{1 represents} an n-butyl group and R _{3 represents} a methyl group. A compound according to any one of claims 1 to 4, wherein X is the radical (CH ₂ ) ₃ CH (CH ₃ ) ₂ ; Ri represents an n-butyl group and R _{3 represents} a hydrogen atom. 8. A compound according to any one of claims 1 to 4, wherein means; and O R X is the radical -C-CH-NH-C-CH - R _{1 is} an n-butyl group, R _{3 is} a hydrogen atom; R _{13 is} the group "CE ₂ 1. N, 2 means; R ₁₄ the group means; and ^ ^H means; -ch ₂ -h (o) W _{2 represents} an -SO ₂ -C (CH ₃ ) ₃ group. 9. A compound according to any one of claims 1 to 4, wherein O R Il X is the radical -C-CH - NH-W ₁ ; R _{1 represents} an n-butyl group; R _{3 represents} a hydrogen atom; NH R _13, the group _ _CH W _{1 is} the group -SO ₂ - (CH ₂ ) ₂ means; and means. 10. A compound according to any one of claims 1 to 4, both O R -C-CH NH-C - CH CH ₂ X the rest R _{1 represents} an n-butyl group, R _{3 represents} a hydrogen atom; R _{13 is} the group -CH ₂ -CH (CH ₃ ) ₂ ; means; R ₁₄ the group means; and W _{2 is} a group -SO ₂ -C (CH ₃ ) ₃ . 11. A compound according to any one of claims 1 to 4, wherein O R 13 _C - CR "- NH-W-.
X represents the rest; R _{1 represents} an n-butyl group; R _{3 represents} a hydrogen atom; R _{13 is} the group -CH, -Γ-NH; and W _{1 is} the group -C- (CH ₃ means. 12. A compound according to any one of claims 1 to 4, wherein OR ₁₃ -C-CH-NH-W ₁ X the remainder R _{1 represents} an n-butyl group; R _{3 represents} a hydrogen atom; R _{13 is} the group _ _cu NH means; means; and the group means. 13. A compound according to any one of claims 1 to 4, wherein X the ReBt -C - CH - NH - C - CH - CH - W, ^^ _? R _{1 is} the group -CH ₂ -CH ₂ -CH = CH ₂ ; R _{3 represents} a hydrogen atom; -CH ₀ -Tj- i ^H R _{13 is} the group 2 μλ; CH ₉ (O / R _{14 is} the group 2 \ ^ j , and W _{2 is} the group -SO ₂ -C (CH ₃ ) ₃ . 14. Compounds of the general formula I
T represents a -C or -CH group; Z represents an SO or SO 2 group; R 1 and R ₂ are independently selected from C _1-7 alkyl, C 2-7 alkylene, - (CH ₂ ) m aryl, - (CH ₂ ) m cycloalkyl, - (CH ₂ ) m heterocyclo and halo substituted CW alkyl radicals, or / ^R l / ^ N N is a heterocyclic ring -NJ ^R 2 means; R ₃ and R ₇ are independently selected from hydrogen atoms, CI_ ₇ alkyl, halo-substituted C ^ alkyl- ₇ -aryl, - (CH _{2) m} -aryl, - (CH _{2) m} -Heterocyclo-, - (CH2 ) _m -cycloalkyl radicals, the radicals - (CH ₂ ) _n -O-Ri ₅ , - (CH ₂ J _n -SR ₁₅ , - < ^c Vn- ^N , / ^R 15 / ^R 15 - (CH ₂₎ -S- (CH ₂₎ -0-R _15, - (CH _{2) n} -O- (CH _{2) g} -N ^R 16 - (CH ₂ ) _n -S- (CH ₂ ) _g -N . "(CH ₂ ) _n COR ₁₅ II. " - (CH ₉ ) -CN, - (CH ₂ J _n -NH-CO-lower alkyl, ^ ^R 16 (CH ₂ ) _n -NH-C-lower alkyl ,. - (CH ₂ ) -NH-C - (CH ₂ ) _m " - (CH ₂ ) - NH - C - O - (CH ₂ ) _m - Aryl _ _(CH 2 -Q- (CH ₉ ) - NH-CO- nieaoroalkyl (CH,) - O- (CH ₉ ) - NH-C- lower alkyl * 2'- - (CH ₉ ) -O- (CH ₂ ) _g - NH-C- (CH ₂ ) _m -aryl, Il ) -NH-C-O- (CH ₂ ) _m - ^ y ¹ 0 Il g "" ¹ ^ ⁵ " ⁰ " ⁰ " ^Lower Y ¹ ' - (CH ₉ ) - NH-C-lower alkyl, (CH ₂ ) -S- (CH ₂ ) -NH-C- - (CH ₂ ) -S- (CH ₂ ) -NH-CO- (CH ₂ ) -aryl, , NH ") · - NH-C ^ _nN NH, R _{4 represents} a hydrogen atom or a C 1-6 alkyl radical; R _{9 is} the group -CH ₂ -O-CH ₂ - (O /; R _{10 is} one of the groups or -C-O-CH. or -CH ₉ -OC means; R ₁₅ and R _{16 are} independently selected from hydrogen, C _w -alkyl, - (CH ₂ ) _m -cycloalkyl, - (CH ₂ ) _m -aryl and (CH ₂ ) _m -heterocyclo radicals; G- formula a heterocyclic ring of the general ^(CH 2 ^J a means wherein A represents a -CH ₂ group, an oxygen or sulfur atom or an NR ₁₉ radical, a is an integer from 1 to 4 and b is an integer from 1 to 4, with the proviso that the sum of a and b is an integer of 2 to 5, and those mean heterocyclic rings in which an available carbon atom is substituted with a lower alkyl group; R _{19 is} a hydrogen atom, a lower alkyl, - (CH ₂ ) _n -phenyl or a - (CH ₂ ) _n -cycloalkyl radical means; m is O or an integer from 1 to 5; η is an integer from 1 to 5; g is an integer from 2 to 5; the term "C 1-4 -alkyl" is straight or branched chain radicals having up to 7 carbon atoms means; the term "lower alkyl" means straight or branched chain radicals of up to 4 carbon atoms; the terms "lower alkoxy" and "lower alkylthio" mean the alkyl radicals as defined above which are bonded to an oxygen or sulfur atom; the term "alkenyl" means straight or branched chain radicals of 2 to 7 carbon atoms containing at least one double bond; the term "cycloalkyl" means saturated rings of 4 to 7 carbon atoms; the term "halogen" means chlorine, bromine, fluorine and iodine atoms; the term "halogen-substituted alkyl" means an alkyl group having one or more hydrogen atoms replaced by chlorine, bromine or fluorine atoms; the term "aryl" means phenyl, diphenylmethyl, 1-naphthyl, 2-naphthyl groups, monosubstituted phenyl, diphenylmethyl, 1-naphthyl or 2-naphthyl groups which are substituted with lower alkyl groups having 1 to 4 carbon atoms, lower alkylthio groups with up to 4 carbon atoms, lower alkoxy radicals having 1 to 4 carbon atoms, halogen atoms, hydroxy, amino groups, -NH-alkyl radicals, wherein the alkyl radical has 1 to 4 carbon atoms, or -N (alkyl) ₂ radicals, where the alkyl radical is 1 to 4 Having carbon atoms, di- or trisubstituted phenyl, diphenylmethyl, 1-naphthyl or 2 naphthyl groups which are substituted with methyl, methoxy, methylthio, hydroxy, amino groups and halogen atoms, and the term "heterocyclic" fully saturated, partially saturated or unsaturated monocyclic rings of five or six atoms containing one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, with the proviso that the total number of heteroatoms in the ring 4 or less, bicyclic rings in which the 5- or 6-membered ring containing oxygen, sulfur and nitrogen atoms as described above is fused to a benzene or pyridyl ring, wherein the monocyclic or bicyclic ring is attached to an available carbon atom , and substituted monocyclic and bicyclic rings as described above, refers to groups substituted on an available carbon atom with C ^ alkyl, C ₁ halosubstituted ^ - alkyl, hydroxy, benzyl or cyclohexylmethyl, and if said monocyclic or bicyclic ring has an available nitrogen atom, the nitrogen atom givenf alls is substituted by the groups ^CH 3, oder2,4-nitrophenyl, benzyl, or C ₁ _4 oderBenzhydrylgruppen-lower alkyl means. 15. Compounds of the general formula ^R 7 OH R. Prot-N C - CH - C - Z - NH - E Ö ~ R CH _n where E is one of the radicals - (CH ₂ ) _g -OR ₁₅ , - (CH ₂ ) _g -SR ₁₅ , R ₁₅ (CH ₂ ) _g -N (CH ₂ ) _m -CN 15 - (CH ₂ ) _p -CH-C O rr -CH- (CH ₂ ) _n -N 15 R _f - (CH ₂ J-CH-C-N or 15 16 ^R 2 R ₈ O - R ₂₀ 0 - (CH ₂ J-CH-C-NH-CH-C-OR ₁₅ , R ⁸ ί I ²⁰ l / ^l5 - (CH ₂ ) -CH-C-NH-CH-CN; ^R 16 R _3, R ₇ / R a and R ₂ o are independently selected from hydrogen, C 1-4 -alkyl, halogen-substituted C _1-7 -alkyl, - (CH ₂ ) _m -aryl, - (CH ₂ ) _m -heterocyclo- , - (CH ₂ ) _m -Cycloalkylresten, the radicals 15 16 - (CH ₂ ) _n -O- (CH ₂ ) _g -OR ₁₅ , - (CH ₂ J _n -O- (CH ₂ JN; / ^R 15 16 - _{ CH ₂ ) _n -S- (CH ₂ ) _g -N / ^R 15 / ^R 15 H / 15 -CN . - (CH ₂ ) -NH-CO-lower alkyl, n ν ^{Δ R} 16 (CH ₂ ) _n -NH-C ^ lower alkyl, - (CH ₂ J _n - NH-C-) ₁₇ -NH-CO- (CH ₂ ) _m -aryl, - (CB.) - O- (CH ₀ Jr-NH-CO-lower alkyl, ^v 2'n ^ 9 Il - (CH ₂ JO- (CH ₂ Jg-NH-C-) - (CH ₂ J _n -O- (CH ₂ Jg-NH-C- (CH ₂ J _1n -ArVl, - NH-C-O - (CH ₂ J _1n - aryl ₂ J _1n 0 - s- (CH ₂ ) -NH-CO - lower alkyl Il (CH) -S- (CH-J-NH-C- lower alkyl, ^v 2 η ^ y - (CH ₂ ) - S - (CH ₂ ) _g - NH-C- (CH ₂ ) J _n - - (CH ₂ ) -S- (CH ₂ ) - -NH-CO- (CH ₂ ) _m -aryl, , NH W ₂ Ν ' ^R 10 R _{4 represents} a hydrogen atom or a C _1-7 -alkyl radical; Rq is the group -CH ₂ -O-CH ₂ means; R _{10 is} one of the groups 0 or ~ ^CH 2 ~ \ O / or -CH ₂ -O-CH ₂ - \ U; means; R ₁₅ and R _{16 are} independently selected from hydrogen, C 1-4 alkyl, - (CH ₂ ) _m cycloalkyl, - (CH ₂ ) _m aryl and - (CH ₂ ) _m heterocyclo radicals; m is 0 or an integer from 1 to 5; η is an integer from 1 to 5; ρ is 0 or 1; g is an integer from 2 to 5; the term "C 1 -C 4 -alkyl" denotes straight-chain or branched-chain radicals having up to 7 carbon atoms means; the term "lower alkyl" straight or branched chain radicals having up to 4 carbon atoms means; the terms "lower alkoxy" and "lower alkylthio" mean the above-defined alkyl radicals bonded to an oxygen or sulfur atom; the term "cycloalkyl" means saturated rings of 4 to 7 carbon atoms; the term "halogen" means chlorine, bromine, fluorine and iodine atoms; the term "halogen-substituted alkyl" means an alkyl group in which one or more hydrogen atoms are replaced by chlorine, bromine or fluorine atoms; the term "aryl" means phenyl, diphenylmethyl, 1-naphthyl, 2-naphthyl groups, monosubstituted phenyl, diphenylmethyl, 1-naphthyl or 2-naphthyl groups substituted with lower alkyl groups having 1 to 4 carbon atoms, lower alkylthio groups having 1 to 4 carbon atoms, lower alkoxy radicals having 1 to 4 carbon atoms, halogen atoms, hydroxy, amino groups, -NH-alkyl radicals, wherein the Alkylresti has up to 4 carbon atoms, or -N (alkyl) 2 radicals, wherein the alkyl radical has 1 to 4 carbon atoms represents di- or trisubstituted phenyl, diphenylmethyl, 1-naphthyl or 2-naphthyl groups which are substituted by methyl, methoxy, methylthio, hydroxy, amino groups and halogen atoms, and the term "heterocyclo" fully saturated, partially saturated or unsaturated monocyclic rings of five or six atoms containing one or two oxygen or sulfur atoms and / or one to 4 nitrogen atoms, with the proviso that the total number of heteroatoms in the ring 4 or less, bicyclic rings in which the 5- or 6-membered ring containing oxygen, sulfur and nitrogen atoms as described above is fused to a benzene or pyridyl ring, wherein the monocyclic or bicyclic ring is attached to an available carbon atom , and substituted monocyclic and bicyclic rings, concerns as described above, which are substituted on an available carbon atom with C ^ alkyl, halo-substituted C ₁ ^ - alkyl, hydroxy, benzyl or cyclohexylmethyl, and if said monocyclic or bicyclic Ring has an available nitrogen atom, the nitrogen atom optionally is substituted by the groups -CH ₀ -O-CH ₇ or 2,4-nitrophenyl, benzyl or benzhydryl groups or C 1-6 lower alkyl groups. 16. Compounds of the general formula O OCH, / 3 Prot-N C C N H ₃ C -i O ^CH 3 CH ₃ in which R ₇ and Protdie have the meanings given in claim 14. 17. Medicines for combating high blood pressure and other diseases in which the reduction in the level of circulating angiotensin II has a beneficial effect, the pharmaceutically acceptable carrier and an effective amount of renin inhibiting compounds of any one of claims 1 to 13 or their pharmaceutically acceptable salts includes. 18. Use of the compounds according to any one of claims 1 to 13 in the control of hypertension and other diseases in which the reduction of the level of the circulating angiotensin II is beneficial _t acts. 19. Process for the preparation of compounds of the general formula R ₇ R ₃ R ₁ H ₂ N - CH - CH - CH - C - ZN OH OH R ₄ R ₂ in which R ₁ , R ₂ , R ₃ , R ₄ , R ₇ and Z have the meanings given in claim 14, comprising the removal of the protective groups on the nitrogen atom from the compounds of the general formula R ₇ R ₃ -R ₁ I I / Prot-NH-CH CH-CH - C-Z-N ill \ OH OH R ₄ R ₂ wherein R ₁ , R ₂ , R ₃ , R ₄ , R 7, Z and Prot have the meanings given in claim 14. 20. Process for the preparation of compounds of the general formula R ₇ R ₃ I i H ₂ N-CH - CH - CH - C - Z - NH - E ! I i OH OH R ₄ in which E, R ₃ , R ₄ , R ₇ and Z have the meanings given in claim 15, comprising the removal of the protective group on the nitrogen atom from the compounds of the general formula ι ι Prot-NH-CH-CH-CH-C-Z-NH - E OH OH R ₄ wherein E, R ₃ , R ₄ , R ₇ , Z and Prot have the meanings given in claim 15. 21. A process for the preparation of compounds of the general formula R ₇ ^0R 6 ^R 3 / Κ Ι I! / X-NH-CH-CH-C-C-Z-N ¹ li OH R ₅ R ₄ R ₂ in the X one of the leftovers O O R Ii Ii ι -CR ₁₁ , -C-CH-NW ₁ , ^R 15 OR ₁₃ OR ₁₄ OR Il I II! l | | ¹³ C-CH-NC-CH-NW ₁ , -C-CH-OW ₃ , ^R 15 ^R 16 OR ₁₃ OR ₁₄ 11 i Il -C-CH-NC-CH-CH ₂ -W ₂ , -COR ₁₁ , -C-N means that is the coupling of the acids of the general formula HX, in which X has the above meanings, with the amines of the general formula having in the presence of a coupling agent, wherein R _1, R _2, R3, R4 R5 / R6 R7 / R11 "R13. Ru. R15-R16-Z, W ₁ , W2 and W3 have the meanings given in claim 1. 22. A process for the preparation of compounds of the general formula R ₇ OR ₆ R ₃ R ₁ χ -NH-CH-CH-C-CZ-N ill \ OH R ₅ R ₄ R ₂ in the X the rest ^R 15 SO - N ν or -SO ₂ -R ₁₁ means ^R 16 that is the reaction of sulfonyl chlorides of the general formula (s) ^R _15V N _n _so R ₁₁ - SO ₂ - Cl or y ^R 16 with amines of the general formula R ₇ OR ₆ R ₃ R ₁ H ₂ N-CH - CH - C - C - ZN OH R ₅ R ₄ R ₂ wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₆ , R ₇ , R ₁₁ , Ri ₅ , R ₁₆ and Z have the meanings given in claim 1.
23. A process for the preparation of compound of the general formula R ₇ OR ₆ R ₃ R HC - NH - CH - CH - C C - Z - N R ₂₁ OH R ₅ R ₄ the reaction of ketones of the general formula R ₁ J- C = O. ^R 21
with amines of the general formula R ₇ OR ₆ R ₃ I I