Amidine compound, process for producing same and anti-complement agent comprising same

• US 4,570,006 A
• Filed: 10/24/1984
• Issued: 02/11/1986
• Est. Priority Date: 02/27/1981
• Status: Expired due to Term

• Current Assignee: Torii & Company Limited
• Original Assignee: Torii & Company Limited
• Inventors: Sakurai, Yojiro, Nunomura, Shigeki, Nakayama, Toyoo, Fujii, Setsuro, Okutome, Toshiyuki, Yaegashi, Takashi
• Primary Examiner(s): Shippen, Michael L.
• Application Number:
  US06/664,261
• Time in Patent Office: 475 Days
• Field of Search: 560/1, 560/9, 560/18, 560/16, 560/20, 560/32, 560/34, 560/12, 560/37, 560/48, 560/49, 560/51, 560/55, 560/72, 560/75, 560/81, 560/86, 560/66, 560/104, 560/105, 560/107, 560/109, 560/115, 560/122 , 560/123, 560/124, 560/125, 560/128, 560/140, 560/142, 260/465 D, 424/282, 424/304, 424/305, 424/308, 424/309, 424/310, 424/311, 424/315, 549/436, 549/442, 514/466, 514/488, 514/522, 514/529, 514/530, 514/531, 514/533, 514/534, 514/535, 514/540, 514/541, 514/542, 514/546, 514/549
• US Class Current: 549/442
• CPC Class Codes: C07C 255/00 Carboxylic acid nitriles cyanogen or compounds thereof C01C3/00
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 279/18 having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 335/22 being further substituted by carboxyl groups
• CPC Class Codes: C07C 45/54 of compounds containing doubly bound oxygen atoms, e.g. esters
• CPC Class Codes: C07C 49/83 polycyclic
• CPC Class Codes: C07D 317/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

Amidino compounds represented by the formula ##STR1## and pharmaceutically acceptable acid addition salts thereof are novel compounds and are useful as powerful anti-trypsine, anti-plasmin, anti-kallikrein and anti-thrombin agents. Having strong anti-Cl (Clr, Cls) activities and an anticomplement activity, they are also useful as anticomplement agents. These amidino compounds are prepared by usual esterification of carboxylic acid compounds represented by the formula (II)

R.sub.1 --COOH                                             (II)

with amidinophenol compound (III) and, if necessary, can be transformed into pharmaceutically acceptable acid addition salts thereof. ##STR2##

Claims

1. An amidino compound or a pharmaceutically acceptable acid addition salt thereof, said amidino compound being represented by the formula ##STR74## wherein R₁ represents a straight or branched chain alkyl group of 1 to 6 carbon atoms, a straight or branched chain alkenyl group of 2 to 6 carbon atoms including 1 to 3 double bonds, R₃ --(CH₂)_a --, R₄ --(CH₂)_b --, ##STR75## where R₃ is cycloalkyl group of 3 to 6 carbon atoms or cycloalkenyl group of 3 to 6 carbon atoms including 1 to 2 double bonds;

a is 0, 1, 2 or 3;

R₄ is amino or guanidino group possessing radical protecting group or not;

b is a number of 1 to 5;

R₅ and R₆, which may be the same or different, are each a hydrogen atom, straight or branched alkyl group of 1 to 4 carbon atoms, --OR₇, methylenedioxy group, --SR₇, --COOR₇, --COR₈, --OCOR₉, --NHCOR₉, ##STR76## NO₂, CN, halogen atom, --CF₃, or ##STR77## R₇ is hydrogen atom, straight or branched alkyl group of 1 to 4 carbon atoms or benzyl group;

R₈ is hydrogen atom, straight or branched alkyl group of 1 to 4 carbon atoms;

R₉ is straight or branched alkyl group of 1 to 4 carbon atoms;

R₁₀ and R₁₁, which may be the same or different, are each a hydrogen atom, straight or branched alkyl group of 1 to 4 carbon atoms, or amino radical protecting group;

R₁₂ is O, S, or NH;

R₁₃ is 2'"'"',3'"'"'-dimethyl or 3'"'"'-CF₃ group;

Z is --(CH₂)_d -- (d is 0, 1, 2 or

     3), ##STR78## (e is 0, 1 or

     2) or ##STR79## R₁₄ is straight or branched alkyl group of 1 to 4 carbon atoms;

R₁₅ is hydrogen atom, straight or branched alkyl group of 1 to 4 carbon atoms;

R₂ represents --OR₁₆, --COOR₁₆, halogen atom, --NO₂, ##STR80## wherein R₁₆ is straight or branched alkyl group of 1 to 4 carbon atoms; and

R₁₈ is hydrogen atom or guanidino group;

wherein said protecting group is an amino or guanidino radical protecting group selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, acetyl, benzoyl, tosyl, nitro, benzyl and t-butyl groups.

2. An amidino compound and a pharmaceutically acceptable acid addition salt thereof according to claim 1, wherein R₂ is 2-OCH₃, 2-COOCH₃, 2-chloro, 2-NO₂, ##STR81##

3. An anti-complement agent comprising as an active ingredient an amidino compound, or a pharmaceutically acceptable acid addition salt thereof, represented by the formula ##STR82## wherein R₁ represents a straight or branched chain alkyl group of 1 to 6 carbon atoms, a straight or branched chain alkenyl group of 2 to 6 carbon atoms including 1 to 3 double bonds, R₃ --(CH₂)_a --, R₄ --(CH₂)_b --, ##STR83## where R₃ is cycloalkyl group of 3 to 6 carbon atoms or cycloalkenyl group of 3 to 6 carbon atoms including 1 to 2 double bonds;

a is 0, 1, 2 or 3;

R₄ is amino or guanidino group possessing radical protecting group or not;

b is a number of 1 to 5;

R₅ and R₆, which may be the same or different, are each a hydrogen atom, straight or branched alkyl group of 1 to 4 carbon atoms, --OR₇, methylenedioxy group, --SR₇, --COOR₇, --COR₈, --OCOR₉, --NHCOR₉, ##STR84## NO₂, CN, halogen atom, --CF₃ or ##STR85## R₇ is hydrogen atom, straight or branched alkyl group of 1 to 4 carbon atoms or benzyl group;

R₈ is hydrogen atom, straight or branched alkyl group of 1 to 4 carbon atoms;

R₉ is straight or branched alkyl group of 1 to 4 carbon atoms;

R₁₀ and R₁₁, which may be the same or different, are each a hydrogen atom, straight or branched alkyl group of 1 to 4 carbon atoms, or amino radical protecting group;

R₁₂ is O, S or NH;

R₁₃ is 2'"'"',3'"'"'-dimethyl or 3'"'"'-CF₃ group;

Z is --(CH₂)₃ -- (d is 0, 1, 2 or

     3), ##STR86## (e is 0, 1 or

     2) or ##STR87## R₁₄ is straight or branched alkyl group of 1 to 4 carbon atoms;

R₁₅ is hydrogen atom, straight or branched alkyl group of 1 to 4 carbon atoms;

R₂ represents --OR₁₆, --COOR₁₆, halogen atom, --NO₂, ##STR88## wherein R₁₆ is straight or branched alkyl group of 1 to 4 carbon atoms; and

R₁₈ is hydrogen atom or guanidino group;

wherein said protecting group is an amino or guanidino radical protecting group selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, acetyl, benzoyl, tosyl, nitro, benzyl and t-butyl groups.

4. An anticomplement agent comprising as an active ingredient an amidino compound or a pharmaceutically acceptable acid addition salt thereof according to claim 3, wherein R₂ is 2-OCH₃, 2-COOCH₃, 2-chloro, 2-NO₂, ##STR89##