ZA200305542B

ZA200305542B - Pharmaceutical formulation containing pyrazole [4,3-d]pymidines and antithrombotic agents calcium antagonists prostaglandins or prostaglandin derivatives

Info

Publication number: ZA200305542B
Application number: ZA2003/05542A
Authority: ZA
Inventors: Eggenweiler Hans-Michael; Eiermann Volker
Original assignee: Merck Patent Gmbh
Priority date: 2000-12-19
Filing date: 2003-07-17
Publication date: 2005-01-26

Description

2am ac @

Pharmaceutical formulation comprising pyrazolo[4,3-d]pyrimidines and antithrombotics, calcium antagonists, prostaglandins or prostaglandin derivatives

The invention relates to pharmaceutical formulations comprising at least one phosphodiesterase V inhibitor and/or physiologically acceptable salts and/or solvates thereof and at least one antithrombotic.

The invention relates in particular to pharmaceutical formulations compris- ing at least one compound of the formula - R? i HN Ca

N22 R2

N N\A Me

N X

R4 in which

R' and R? are each, independently of one another, H, A, OH, OA or Hal,

R' and R? together are alternatively alkylene having 3-5 carbon atoms, -O-CH>-CH,-, -CH;-O-CH,-, -O-CH.-O- or -O- a © 25 CH,-CH,-O-,

R®and R* are each, independently of one another, H or A,

X is R®, R® or R”, each of which is monosubstituted by R®,

R® is linear or branched alkylene having 1-10 carbon atoms, in which one or two CH; groups may be replaced by -CH=CH-groups, O, S or SO, : R® is cycloalkyl or cycloalkylalkylene having 5-12 carbon atoms,

R’ is phenyl! or phenylmethyl,

R® is COOH, COOA, CONH,, CONHA, CON(A); or CN,

A is alkyl having from 1 to 6 carbon atoms, and

Hal is F, Cl, Brorl, and/or physiologically acceptable salts and/or solvates thereof and

® a) at least one antithrombotic or b) at least one calcium antagonist or c) at least one prostaglandin or prostaglandin derivative.

The invention furthermore relates to the use of the formulation for the pre- paration of a medicament for the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure (CHF), chronic obstruct- ive pulmonary disease (COPD), cor pulmonale, dextrocardiac insufficien- cy, atherosclerosis, conditions of reduced patency of heart vessels, peri- pheral vascular diseases, strokes, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours,

ER B renal insufficiency, liver cirrhosis and for the treatment of female sexual disorders.

Pharmaceutical formulations consisting of other phosphodiesterase V (PDE V) inhibitors together with a second active ingredient are described in WO 00/15639.

Pyrimidine derivatives are disclosed, for example, in EP 201 188 and

WO 93/06104.

The use of other PDE-V inhibitors is described, for example, in

WO 94/28902. ] Pharmaceutical formulations consisting of other phosphodiesterase V ea 25 (PDE V) inhibitors together with calcium antagonists (= calcium channel! . blockers) are described in WO 00/15639.

Pharmaceutical formulations consisting of other phosphodiesterase V : (PDE V) inhibitors together with a prostaglandin or prostaglandin deriva- tive are described in WO 00/15639 and WO 0015228.

The use of (other) phosphodiesterase IV or V inhibitors in combination with a prostaglandin or prostaglandin derivative for the local treatment of : erectile dysfunction is described in WO 9921558.

® >

R.T. Schermuly et al. in the American Journal of Respiratory and Critical

Care Medicine, 160, 1500-6 (1999), describe the therapeutic potential of prostaglandin I, (PGl,) in aerosol form with systemic PDE inhibitors, pre- ferably duai-selective PDE iii/iV inhibitors, in low doses for acute and chronic pulmonary hypertension.

In Pneumologie (54, Suppl. 1, S42, 2000), R. Schermuly et al. describe the influence of PDE-V inhibition on prostacyclin-induced vasorelaxation in experimental pulmonary hypertonia.

The invention had the object of providing novel medicaments in the form of pharmaceutical preparations which have better properties than known medicaments which can be used for the same purpose.

This object has been achieved by the discovery of the novel preparation.

The compounds of the formula | and their salts have very valuable pharmacological properties and are well tolerated. In particular, they exhibit specific inhibition of cGMP phosphodiesterase (PDE V).

Quinazolines having a cGMP phosphodiesterase-inhibiting activity are described, for example, in J. Med. Chem. 36, 3765 (1993) and ibid. 37, 2106 (1994). a 25 The biological activity of the compounds of the formula | can be deter- mined by methods as described, for example, in WO 93/06104.

The affinity of the compounds according to the invention for cGMP and cAMP phosphodiesterase is determined by measuring their ICs, values (concentration of the inhibitor needed to achieve 50% inhibition of the enzyme activity).

The determinations can be carried out using enzymes isolated by known methods (for example W.J. Thompson et al., Biochem. 1971, 10, 311). The experiment can be carried out using a modified batch method of W.J.

Thompson and M.M. Appleman (Biochem. 1979, 18, 5228).

®

The compounds are therefore suitable for the treatment of illnesses of the cardiovascular system, in particular cardiac insufficiency, and for the treat- ment and/or therapy of impotence (erectile dysfunction).

The use of substituted pyrazolopyrimidinones for the treatment of impotence is described, for example, in WO 94/28902.

The compounds are effective as inhibitors of phenylephrine-induced con- tractions in corpus cavernosum preparations of rabbits. This biological action can be demonstrated, for example, by the method described by

F. Holmquist et al. in J. Urol., 150, 1310-1315 (1993). : The inhibition of the contraction demonstrates the effectiveness of the compounds according to the invention for the therapy and/or treatment of impotence.

The efficacy of the pharmaceutical formulations according to the invention, in particular for the treatment of pulmonary hypertension, can be demon- strated, as described by E. Braunwald in Heart Disease 5™ edition, WB

Saunders Company, 1997, Chapter 6: Cardiac Catheterisation, 177-200.

The compounds of the formula | can be employed as medicament active ingredients in human and veterinary medicine. They can furthermore be employed as intermediates for the preparation of further medicament active ingredients. a 25

The compounds of the formula | according to Claim 1 and their salts are prepared by a process which is characterised in that a) a compound of the formula li

RS

\ L

N~Z>N ’

N NN J

N X

R4

J

° > in which

R® R*and X are as defined above, and L is Cl, Br, OH, SCHs or a reactive esterified OH group, is reacted with a compound of the formula Ill

Ri

CH

Pd 2

H,N a Wi

R2 in which

R' and R? are as defined above, or b) a radical X in a compound of the formula | is converted into another radical X by, for example, hydrolysing an ester group to a COOH group or converting a COOH group into an amide or into a cyano group, and/or in that a compound of the formula | is converted into one of its salts.

A 25

The invention also relates to the use of all optically active forms (stereo- isomers), the enantiomers, the racemates, the diastereomers, and the hydrates and solvates of the compounds.

The term solvates of the compounds of the formula | is taken to mean adductions of inert solvent molecules onto the compounds of the formula which form owing to their mutual attractive force. Solvates are, for example, monohydrates or dihydrates or alkoxides.

Above and below, the radicals R', R%, R?>, R*, R>, R®, R", R®, X and L are as defined under the formulae |, Il and lll, unless expressly stated otherwise.

® vr

A is alkyl having 1-6 carbon atoms.

In the above formulae, alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 carbon atoms and is preferably methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl.

X is an R®, R® or R’ radical which is monosubstituted by R®.

R® is a linear or branched alkylene radical having 1-10 carbon atoms, where the alkylene radical is preferably, for example, methylene, ethylene, ce propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, 1-, 2- or 3-methylbutylene, 1,1-, 1,2- or 2,2-dimethylpropylene, 1-ethyl- propylene, hexylene, 1-, 2-, 3- or 4-methylpentyiene, 1,1-, 1,2-,1,3-, 2,2-, 2,3- or 3,3-dimethylbutylene, 1- or 2-ethylbutylene, 1-ethyl-1-methyl- propylene, 1-ethyl-2-methylpropylene, 1,1,2- or 1,2,2-trimethylpropylene, linear or branched heptylene, octylene, nonylene or decylene.

RS is furthermore, for example, but-2-enylene or hex-3-enylene.

A CH; group in R® may preferably be replaced by oxygen.

Very particular preferance is given to ethylene, propylene, butylene or

CH2-O-CH...

R® is cycloalkylalkylene having 5-12 carbon atoms, preferably, for example, cyclopentyimethylene, cyclohexylmethylene, cyclohexylethylene, aE 25 cyclohexylpropylene or cyclohexylbutylene.

R® is altemnatively cycloalkyl, preferably having 5-7 carbon atoms.

Cycloalkyl is, for example, cyclopentyl, cyclohexyl or cycloheptyl.

Hal is preferably F, Cl or Br, but also |.

The radicals R' and R? may be identical or different and are preferably located in the 3- or 4-position of the phenyl ring. They are, for example, in each case independently of one another, H, alkyl, OH, F, Cl, Bror | or : together are alkylene, such as, for example, propylene, butylene or pentyl- : 35 ene, furthermore ethyleneoxy, methylenedioxy or ethylenedioxy. They are

J

° preferably also in each case alkoxy, such as, for example, methoxy, ethoxy

Or Propoxy.

The radicai R® is preferably, for example, COOH, COOA, such as, for example, COOCH; or COOC,Hs, CONH,, CON(CHs),, CONHCHs or CN, but in particular COOH or COOA.

For the entire invention, all radicals which occur more than once may be identical or different, i.e. are independent of one another.

The term antithrombotics also covers so-called anticoagulants and blood platelet aggregation inhibitors (thrombocyte aggregation inhibitors).

The invention relates in particular to pharmaceutical formulations comprising an antithrombotic, a calcium antagonist or a prostaglandin or prostaglandin derivative and at least one compound of the formula | in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds may be expressed by the following sub-formulae la to If, which conform to the formula | and in which the radicals not designated in greater detail are as defined under the formula I, but in which infa X is R®, phenyl or phenylmethyl, each of which is substituted by COOH, COOA, CONH,, CONA.,

I 25 CONHA or CN; inlb R'andR®> together are alkylene having 3-5 carbon atoms, -O-CH.-CHz-, -O-CH,-0- or -O-CH,-CH,-O-,

X is R®, phenyl or phenylmethyl, each of which is substituted by COOH, COOA, CONH,, CONA,,

CONHA or CN; inlc R'andR?® are each, independently of one another, H, A, OH, :

OA or Hal,

R' and R? together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -O-CH;-O- or -O-CH,-CH,-O-,

° ”

X is R®, phenyl or phenylmethyl, each of which is substituted by COOH, COOA, CONH,, CONA;,

CONHA or CN; inld R'andR? are each, independently of one another, H, A, OH,

OA or Hal,

R'and R® together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -O-CH,-O- or -O-CH>-CH,-O-,

X is alkylene having 2-5 carbon atoms, cyclohexyl, phenyl or phenylmethyl, each of which is mono- substituted by R®, fo R® is alkyl having 1-6 carbon atoms,

R* is alkyl having 1-6 carbon atoms,

R® is COOH or COOA,

A is alkyl having from 1 to 6 carbon atoms,

Hal isF,Cl, Brorl; inle R'andR?® are each, independently of one another, H, A, OH,

OA or Hal,

R'and R? together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -O-CH,-O- or -O-CH,-CH,-O-,

R® is alkyl having 1-6 carbon atoms,

R* is alkyl having 1-6 carbon atoms,

X is -(CH,)2.s-R%, 4-R®-cyclohexyl, 4-R8-phenyl or 4- ee 25 (R®-methyl)pheny!; in if R'and R® are each, independently of one another, H, A, OH,

OA or Hal,

R'and R®> together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -O-CH,-O- or -O-CH,-CH,-O-,

R® is alkyl having 1-6 carbon atoms,

R* is alkyl having 1-6 carbon atoms,

X is -(CH,)2s-R®, in which one CH, group may be replaced by O, or is 4-R®-cyclohexyl, 4-R®-pheny! or 4-(R®-methyl)phenyl,

R® is COOH or COOA.

® ~

The invention preferably relates to a formulation comprising [7-(3-chioro-4- methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-y|- methoxylacetic acid and physiologically acceptable salts and/or solvates

S thereof and an antithrombotic.

Besides the free acid, the ethanolamine salt is preferred.

Preferred antithrombotics are vitamin K antagonists, heparin compounds, thrombocyte aggregation inhibitors, enzymes, factor Xa inhibitors, factor

Va inhibitors and other antithrombotic agents.

Preferred vitamin K antagonists are selected from the group consisting of dicoumarol, phenindione, warfarin, phenprocoumon, acenocoumarol, ethyl biscoumacetate, clorindione, diphenadione and tioclomarol.

Preferred heparin compounds are selected from the group consisting of heparin, antithrombin lll, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, danaparoid, tinzaparin and sulodexide.

Preferred thrombocyte aggregation inhibitors are selected from the group consisting of ditazole, cloricromen, picotamide, clopidogrel, ticlopidine, acetylsalicylic acid, dipyridamole, calcium carbassalate, epoprostenol, indobufen, iloprost, abciximab, tirofiban, aloxiprin and intrifiban. he 25 Preferred enzymes are selected from the group consisting of streptokinase, alteplase, anistreplase, urokinase, fibrinolysin, brinase, reteplase and saruplase.

Preferred antithrombotics are furthermore the blood platelet glycoprotein receptor (llb/llla) antagonists which inhibit blood platelet aggregation.

Preferred compounds are described, for example, in EP 0 623 615 B1 on page 2 or in EP 0 741 133 A2, page 2, line 2, to page 4, line 56.

Preferred factor Xa and Vlla inhibitors are, for example, a) the compounds of the formula

® -10 -

R] Y

NT ORS xX” NS 1

RZ in which

R’ is -C(=NH)-NH,, which may also be monosubstituted by -COA, -CO-[C(R®),]s-Ar, -COOA, -OH or by a conven- tional amino protecting group, or is

San t~¢™o t~Mo

N= N=( 0) CH, :

R? is H, A, OR®, N(R®),, NO,, CN, Hal, NHCOA, NHCOAr,

NHSO-A, NHSO.Ar, COOR®, CON(R®),, CONHAY,

COR?®, COA, S(O).A or S(O).Ar,

R® is A, cycloalkyl, {C(R®)].Ar, {C(R®)2].-O-Ar, [C(R®)z]-Het or -C(R®%):=C(R®),-Ar,

R® is H, A or benzyl,

X is absent or is -CO-, -C(R%)-, -C(R®),-C(R®)z-, -C(R%),-CO-, -C(R®).-C(R®),-CO-, -C(R®)=C(R®)-CO-,

BN NR®CO-, -N{[C(R®),],-COOR"}-CO- or

Te 25 -C(COOR®R®-C(R®),-CO-,

Y is -C(R%),-, -SO,-, -CO-, -COO- or -CONR®-,

A is alkyl having 1-20 carbon atoms, in which one or two

CH, groups may be replaced by O or S atoms or by -CR®=CR®- groups and/or 1-7 H atoms may be replaced by F,

Ar is phenyl or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by A,

Ar, OR®, N(R®),, NO, CN, Hal, NHCOA, NHCOAr',

NHSO.A, NHSO,Ar", COOR®, CON(R®),, CONHAr',

COR® COATr, S(O),A or S(O).Ar, ad

PY -11-

OR®, N(R%),, NO,, CN, Hal, NHCOA, COOR®, CON(R®),,

COR® or S(O)nA,

Het is a monocyclic or bicyclic, saturated or unsaturated heterocyclic ring system which contains one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen and sulfur, and is unsubstituted or monosubstituted or polysubstituted by Hal, A, Ar’,

COOR®, CN, N(R®),, NO,, Ar-CONH-CH, and/or carbonyl oxygen,

Hal is F, Cl, Bror |, n is0, 1 or 2, and salts thereof, which are described in WO 9916751, b) the compounds of the formula r1 ol. : XY “WR 4

R2 lo)

RS” a 25 in which

R' is -C(=NH)-NH,, which may also be monosubstituted by -COA, -CO-C(R®);]m-Ar, -COOA, -OH or by a conven- tional amino-protecting group, or is ~o t~Mo

NE N=( 0) CH,

R? is H, A, OR®, N(R®), NO, CN, Hal, NR°COA, NHCOA,

NHSO,A, NHSO,Ar, COOR®, CON(R®),, CONHA,

COR?®, COA, S(0)nA or S(O)Ar,

PA -12-

R® is R® or {C(R%)2}Jm-COOR®,

Rand X together are alternatively -CO-N-, with formation of a 5-membered ring, where R® is -C=0 and X is N,

R* is A, cycloalkyl, {C(R®)z]mAr, {C(R%):]-Het or -CR’=CR®-Ar,

R® is H, A or benzyl,

X is 0, NR® or CH,

Y is 0, NR®, N[C(R®)2]m-Ar, N[C(R®)2Jm-Het, 5 5 /\

N[C(R’);Jn=-COOR®, —N N—, —/ - ‘Pa RS R®

RS ’ NNN ,

N[C(R®)2lm-CON(R®)2, N[C(R®)2Jn-CONRAr or

N[C(R®)2]m-CONAT,

Ww is a bond, -SO,-, -CO-, -COO- or -CONR’-,

A is alkyl having 1-20 carbon atoms, in which one or two

CH, groups may be replaced by O or S atoms or by -CR=CR®- groups and/or 1-7 H atoms may be replaced by F,

Ar is phenyl or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R', A, oo Ar, OR® N(R®),, NO, CN, Hal, NHCOA, NHCOAY', or 25 NHSO.A, NHSOAr", COOR®, CON(R®),, CONHAr’,

COR®, COAr', S(O)A or S(O)Ar,

Ar is phenyl or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R', A,

OR®, N(R%)2, NO, CN, Hal, NHCOA, COOR®, CON(R®),,

COR® or S(O),A,

Het is a monocyclic or bicyclic, saturated or unsaturated heterocyclic ring system which contains one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen and sulfur, and which is unsubstituted or monosubstituted or polysubstituted by Hal, A, Ar’, a

® -13-

OR®, COOR®, CN, N(R®),, NO,, NHCOA, NHCOAr' and/or carbonyl oxygen,

Hal is F, Cl, Brorl, m is 0, 1, 2, 3 or 4, n is0O,1or2, and salts thereof, which are described in WO 9931092, c) the compounds of the formula

R1 5 a l

RS R% in which

R'andR* are each, independently of one another, -C(=NH)-NH., which may also be monosubstituted by -COA, ~CO{C(R%).].-Ar, -COOA, -OH or by a conventional amino-protecting group, or are NH-C(=NH)-NH_, -CO-N=C(NH),, ad 25 N { No I~¢ 0

In — or Yl , 0) CH, 3 0 R?, = and R® are each, independently of one another, H, A, OR,

N(R®);, NO, CN, Hal, NHCOA, NHCOAr, NHSO:A,

NHSO,Ar, COOR®, CON(R®),, CONHAr, COR®, COA,

S(O)A, S(O)wAr, -O-[C(R®),]m-COOR®, -{C(R%)2];-COOR?®, -O-[C(R®)]m-CON(R®),,

IC(R®),],-CON(R®),, -O-[C(R®),].-CONHAr or {C(R®);],-CONHA,

PY -14 -

X is -[C(R®)2}-, -CR®=CR®-, -[C(R®),}x-O-, -O-[C(R®)zln-, -COO0-, -00C-, -CONR®- or -NR°CO-,

R® is H, A or benzyl,

A is alkyi having 1-20 carbon atoms, in which one or two

CH, groups may be replaced by O or S atoms or by -CR°=CR®- groups and/or 1-7 H atoms may be replaced by F,

Ar, OR®, OA, N(R%),, NO,, CN, Hal, NHCOA,

NHCOAr, NHSOA, NHSO.Ar, COOR®, CON(R®),,

Ln CONHAF, COR®, COAr, S(0).A or S(O).Ar,

Ar' is phenyl or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by A,

OR®, N(R®)2, NO, CN, Hal, NHCOA, COOR®, CON(R®,,

COR® or S(0)aA,

Hal isF, Cl, Brorl, n is0,1or2, m is1or2, p is1or2, and salts thereof, which are described in WO 9957096, d) the compounds of the formula

Tee 25

Rt 304

IAN

R2—xX—Y " °c

ACH),

R3 in which

RandR' are each, independently of one another, H, A, “(CH2)m-R*, -(CHa)m-OA or -(CH2)-Ar,

PS -15-

NH a

R is Ar, or

RS6

NH

LO

{ co

CR is Ar,

R* is CN, COOH, COOA, CONH,, CONHA, CONA; or

C(=NH)-NH_,

R® is -C(=NH)-NH,, -NH-C(=NH)-NH or oo -C(=0)-N=C(NHy,),, each of which is unsubstituted or monosubstituted by -COA, -COOA, -OH or by a conven- : tional amino-protecting group, or is { No { ” Noo

HL oe =

O CH,

R® is H, A or NH,

Ar is phenyl, naphthyl or biphenyl, each of which is unsub- stituted or monosubstituted, disubstituted or trisubstitu- ted by A, cycloalkyl having 3-6 carbon atoms, OH, OA,

Lo Hal, CN, NO,, CF3, NH, NHA, NA, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO,NH,, SO.NHA, SONA, ~(CH2)a-NHz, -(CH2)-NHA, -(CH2)s-NA;, -O-(CH:)n-NH;, -O-(CHa)n-NHA, -O-(CHa)n-NA;, -O~(CH,)m-O- or R®,

A is alkyl having 1-6 carbon atoms,

X is absent or is alkylene having 1-4 carbon atoms or carbonyl,

Y is absent or is NH, O or S,

Hal isF, Cl, Brorl, : m is0, 10r2, n is0,1,2o0r3, and salts thereof, which are described in WO 0012479,

PA -16 - e) the compounds of the formula

R3 3,

RXR

R2 SE (CHp)i—R? 0 in which

R is H, unbranched or branched alkyl having 1-6 carbon atoms or cycloalkyl having 3-6 carbon atoms, - R' is Ar,

R? is Ar’,

R® is H, R, R, Hal, CN, COOH, COOA or CONH;,,

Arand Ar are each, independently of one another, phenyl, naphthyl or biphenyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R,

OH, Hal, CN, NO,, CF3, NH,, NHR, NR;, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO.NH,, SO.NHR, SO,NR;, -CONHR, -CONR;, -(CH2),-NHz, ~(CH2),-NHR, =(CH2)n-NR3, -O~(CH2),-NHa, -O-(CH2),-NHR, -0-(CH,)n-NR;, R* or together by -O-(CHz)m-O-,

R* is <C(=NH)-NH,, -NH-C(=NH)-NH, or -C(=0)-N=C(NH.),, each of which is unsubstituted or wo 25 monosubstituted by -COR, -COOR, -OH or by a conventional amino-protecting group, or is { No { Z 0

In — or 1 » 0) CH,

A is alkyl having 1-4 carbon atoms, :

Hal is F, Cl, Brorl, m is 1 or 2, n is0, 1,2o0r 3, p isOor1, and salts thereof, which are described in WO 0020416,

PY -17 - f) the compounds of the formula

R3

N

XR

LX (CH,).—R!

R2 2/n 0] in which

R is H, unbranched or branched alkyl having 1-6 carbon atoms or cycloalkyl having 3-6 carbon atoms, . R' is Ar,

R? is Ar,

R® is H, R, R*, Hal, CN, COOH, COOA or CONH_, 16 Ar and Ar are each, independently of one another, phenyl, naphthyl or biphenyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R,

OH, Hal, CN, NO, CFs, NH;, NHR, NR;, pyrrolidin-1-yi, piperidin-1-yl, benzyloxy, SO.NH,, SO.NHR, SO:NR;, -CONHR, -CONR;, -(CH3),-NH_, -(CH2),-NHR, -(CH2)n-NR;, -O-(CH2)n-NH;, -O-(CH2)-NHR, -O-(CH,)-NR2, R* or together by -O-(CHy)m-O-, or isoquinolinyl which is substituted by NH,

R* is -C(=NH)-NH,, -NH-C(=NH)-NH, or

Ei 25 -C(=0)-N=C(NH,),, each of which is unsubstituted or monosubstituted by -COR, -COOR, -OH or by a conventional amino-protecting group, or is { Ng { z Neo

In ~ or 1 . 0) CH,

A is alkyl having 1-4 carbon atoms, :

Hal is F, Cl, Brorl, m is 1or2, n isOor1, and salts and solvates thereof,

° A which are described in WO 0040583, g) the compounds of the formula

R4 v~

R? ~ Ae 1

NN x—R®

R? in which ons R'and R®> are each, independently of one another, H, A, cycloalkyl-{C(R'R”)}s- or Ar-{C(R'R”)}x-,

R®*and R* are each, independently of one another, H, Ar, Het or

R® where at least one of the two radicals is R®,

R® is phenyl, naphthyl or biphenyl, each of which is substituted by —C(=NH)-NH., which may aiso be monosubstituted by —COA, Ar-{C(R'R")},-CO-, COOA,

OH or by a conventional amino-protecting group, -NH-C(=NH)-NH., -CO-N=C(NH.).,

N

~~ I~¢ Ne) 0)

HN— or N={ 0) CH, i= 25 and which may optionally additionally be monosubstitu- ted or disubstituted by A, Ar’, Het, OR®, NR°R®, NO,

CN, Hal, NR°COA, NR°COAr', NR°SO,A, NR°SO,Ar,

COOR®, CO-NR°R®, COR’, CO-Ar', SO,NR°R®, S(0)sAr or S(O)A,

R®and R® are each, independently of one another, H, A,

CR'R"-Ar' or CR'R"-Het,

R’ and R” are each, independently of one another, H or A, 5 XandY are each, independently of one another, (CR'R”),, 3 A is alkyl having 1-20 carbon atoms, in which one or two

CH, groups may be replaced by O or S atoms and/or by di

® -19- —CH=CH- groups and/or in addition 1-7 H atoms may be replaced by F,

Ar is phenyl, naphthyl or biphenyl, each of which is unsub- stituted or monosubstituted, disubstituted or trisubstitu- ted by A, Ar', Het, OR®, NR°R®, NO, CN, Hal, NR°COA,

NR®COAr, NR°SO,A, NR®SO,Ar', COOR®, CO-NR°R®,

CON®Ar, COR’, COAr, SO,NR°R®, S(O):Ar or S(O)A,

Ar' is phenyl! or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by A,

OR’, NR’R”, NO,, CN, Hal, NR'COA, NR'SO-A,

COOR’, CO-NR’R”, COR’, SO;NR'R” or S(O)A, ) Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic radical having from 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono- substituted, disubstituted or trisubstituted by A, OR’,

NR'R”, NO,, CN, Hal, NR'COA, NR’SO,A, COOR’,

CO-NR'R”, COR’, SO.NR'R”, S(0).A and/or carbonyl oxygen,

Hal is F, Cl, Brorl, n is 0, 1o0r2, and their pharmaceutically tolerated salts and solvates, which are described in WO 0051989,

N h) compounds of the formula

ES 25 1

SCI nA ~~ N in which

R is -CO-N=C(NH,),, -NH-C(=NH)-NH; or —C(=NH)-NH_, which may also be monosubstituted by OH, -OCOOA, -OCOO(CH.).NAA', -COO(CH.).NAA', -OCOO(CHz)m-Het, -COO(CH;)m-Het, -CO-CAA'-R’, -COO-CAA'-R?, COOA, COSA, COOAr, COOAr or by a conventional amino-protecting group, or is

PS -20- { No { z No

HL oe dy CH,

R is unbranched, branched or cyclic alkyl having 1-20 carbon atoms, in which one or two CH, groups may be replaced by O or S atoms, or is Ar, Ar or X,

R? is phenyl which is monosubstituted by S(O),A,

S(0O).NHA, CF3, COOA, CH:NHA, CN N OA, or {— CH, A 0

R® is -C(Hal)s, -O(C=0)A or 0X ©

OA, NAA’, NO,, CF3, CN, Hal, NHCOA, COOA,

CONAA', S(O),A or S(O),NAA',

Ar is -(CH2)n-Ar,

Aand A are each, independently of one another, H or unbranched, branched or cyclic alkyl having 1-20 carbon atoms,

Het is a monocyclic or bicyclic, saturated, unsaturated or go 25 aromatic heterocyclic radical having from 1 to 4 N, O . and/or S atoms, bonded via N or C, which may be unsubstituted or substituted by A,

X is -(CH2),-Y,

N

= . t N %

Y is COOA or ba N

A

Hal isF, Cl, Brorl, m isOor1, n is1,2, 3,4, 50r6, p is0, 1o0r2, and their pharmaceutically tolerated salts and solvates,

PS -21- i) compounds of the formula o “ 2

I AF

N 0

Sof

R1 in which

R is -CO-N=C(NH,),, -NH-C(=NH)-NH, or —C(=NH)-NH, which may also be monosubstituted by OH, -OCOOA, -OCOO(CH_),NAA', -COO(CH,).NAA', -OCOO(CHy)m-Het, -COO(CHy)m-Het, -CO-CAA-R®, : -COO-CAA'-R?, COOA, COSA, COOAr, COOAr or by a conventional amino-protecting group, or is

N.

HN N= 0) CH,

R’ is unbranched, branched or cyclic alkyl having 1-20 carbon atoms, in which one or two CH. groups may be replaced by O or S atoms, or is Ar, Ar or X, i R? is phenyl which is monosubstituted by S(O),A, wed 25 S(O),NHA, CF;, COOA, CH,NHA, CN or OA,

A

{—CH, A o rR? is -C(Hal)s, -O(C=0)A or 0 i, :

Oo

OA, NAA’, NO,, CF3, CN, Hal, NHCOA, COOA,

CONAA', S(0),A or S(O),NAA,

Ar is -(CH2),-Ar, rl

PS -22-

Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic radical having from 1to4 N, O and/or S atoms, bonded via N or C, which may be unsubstituted or substituted by A,

X is -(CH2).-Y, —N, ¢ —F MN

Y is COOA or ANT

Hal is F, Cl, Bror|, m isOor1, n is1,2,3, 4 50r6, p is0, 1or2, and their pharmaceutically tolerated salts and solvates,

J) compounds of the formula

RS RS

R4

RR. *

NT OUT Tw bo “ 05 pf Le RS" Rs5™

R2 in which

R' is H, Cl, F, OH, OA, O-(CHa)s-Ar, NH,, NHCOA,

NHCOOA, NH-(CHy)s-Ar, CN, CONH,, CSNH,,

C(=NH)SA, C(=NH)NH;, C(=NH-OH)-NH;,

C(=NH-O-COA)-NH,, C(=NH-O-COAr)-NH.,

C(=NH-O-COHet)-NH,, C(=NH)-OA, C(=NH)NHNH.,

C(=NH)NHNHA, C(=NH)NH-COOA, C(=NH)NH-COA,

C(=NH)NH-COO-(CHz)m-Ar,

C(=NH)NH-COO-(CH_)m-Het, NH-C(=NH)NH,

NH-C(=NH)NH-COOA, NHC(=NH)NH-COO-(CH_)m-Ar, ri

Ps -23 - ~Mo | to aN © N =( © ¥

R? R? and R* are each, independently of one another, H, A, CFs, Cl,

F, COA, COOH, COOA, CONH,, CONHA, CONA;,

CH.NH,, CH.NHCOA, CH,NHCOOA, OH, OA, OCF,

NO;, SOA, SO.NH. or SO:NHA,

R®and R* together are (CH.)p, CO(CHa),, COO(CHy)a,

N COOCH(A)-, COOCH(Ar)-, CONH(CH2)n,

CH.CH(OR")~(CHz)a-, CH2-O~(CHa)n, CH2-S~(CH2)n,

CA2-O-(CHa)a, CA2-S-(CHy>),, CHAr-S-(CHz)s, (CH2),NHCH; or (CH,).-N(R®)-CH,,

R® R°, R”,

R¥ and R® are each, independently of one another, (CH,),-COOH, (CH2)a-COO-(CH,),-Ar, Ar, Py or R?,

R® is OH, A or Ar,

R’ is H, A, Ar or Het,

R® is H, (CH2)a-COOH, (CH;)m-COOA, (CH2)m-COO~(CH_2)n-Ar, (CH2)m-COO-(CH;),-Het, (CH2)m-CONH., (CH2)m-CONHA, (CH2)-CONA;, A,

E . 25 COA, SOA or SO3H;

R® is H, A or benzyl,

U is CO or CH,

Vv is NH or CO, w is absent or is CO,

X is CH or N,

Y is absent or is CH,, CO or SO,,

A is unbranched, branched or cyclic alkyl having 1-20 carbon atoms, in which one or two CH, groups may be replaced by O or S atoms, -CH=CH- or -C=C- and/or 1-7 H atoms may be replaced by F,

PY -24 -

CFs, Hal, OH, OA, OCFs, SOA, SO2NH;, SO,NHA,

SO,NA;, NHz, NHA, NA;, NHCHO, NHCOA, NHCOOA,

NACOOA, NHSO.A, NHSOAr, COOH, COOA,

COO-(CHaz)m-Ar’, COO-(CH_)m-Het, CONH,, CONHA,

CONA,, CONHAr', CHO, COA, COAr, CHAT, (CH2)mNH,, (CH2)mNHA, (CHz)mNA;, (CH,)mNHCHO, (CH2)mNHCOA, (CH2),\NHCOOA, (CH2)mNHCOO-(CH,)mAr, (CH2)mNHCOO-(CH2)mHet,

NO;, CN, CSNH,, C(=NH)SA, C(=NH)OA, C(=NH)NHz,

C(=NH)NHOH, C(=NH)NHCOOA or C(=NH)NHCOOATr,

Ar is phenyl or naphthyl, each of which is unsubstituted or

EE monosubstituted, disubstituted or trisubstituted by A,

OR’, N(R%),, NO, CN, Hal, NHCOA, COOR®, CON(R®);,

COR’ or S(0).A,

Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic radical having 1-4 N, O and/or S atoms, bonded via N or C, which is unsubstituted or monosubstituted, disubstituted, trisubstituted or tetra- substituted by A, CF3, Hal, OH, OA, OCF;, SOA,

SO.~(CH2)m-Ar, SO.NH,, SO.NHA, SO:NA;, NH,, NHA,

NA, NHCHO, NHCOA, NHCOOA, NACOOA, NHSO-A,

NHSO.Ar, COOH, COOA, COO-(CH2)m-Ar', CONH_,

CONHA, COA, COAr', CH,NH,, CH,NHA, CH,NHCHO,

CH,NHCOA, CH.NHCOOA, NO, CN, CSNH, ce 25 C(=NH)SA, C(=NH)OA, C(=NH)NH,, C(=NH)NHOH,

C(=NH)NHCOOA, C(=NH)COOAr" and/or carbonyl oxygen,

Py is 2-, 3- or 4-pyridyl, each of which is unsubstituted or monosubstituted or polysubstituted by A, Hal, CN,

CONH,, CONHA, COOH, COOA, CH,;NH,, CHoNHA,

CH.NHCHO, CH.NHCOA, CH.NHCOOA, CH,OH,

CH:0A, CH,0Ar, CH,OCOA, NO, NH, NHA or NA,,

Hal is F, Cl, Brorl, : n is1or2, m is0, 10r2, p is 2, 3 or 4,

® -25- and their pharmaceutically tolerated salts and solvates, k) compounds of the formula I- 5 . RS RS"

R4

RZ Rz

R’ Yo PAV Jog

N uw ™ ag"

X R3 R= R

R2 in which

R' is H, CI, F, OH, OA, O-(CH.)n-Ar, NH, NHCOA,

NHCOOA, NH-(CH2),-Ar, CN, CONH;, CSNH,

C(=NH)SA, C(=NH)NH,, C(=NH-OH)-NH,,

C(=NH-0O-COA)-NH;, C(=NH-O-COAr)-NH.,

C(=NH-O-COHet)-NH,, C(=NH)-OA, C(=NH)NHNH_,

C(=NH)NHNHA, C(=NH)NH-COOA, C(=NH)NH-COA,

C(=NH)NH-COO-(CH2)m-Ar,

C(=NH)NH-COO-(CH,)n-Het, NH-C(=NH)NH,

NH-C(=NH)NH-COOA, NHC(=NH)NH-COO-(CH,)m-Ar,

N_ { N.

I N=(

Ci 25 0) RS

R? R? and R* are each, independently of one another, H, A, CF;, Cl,

F, COA, COOH, COOA, CONH,, CONHA, CONA;,

CH:NH,, CH,NHCOA, CH.NHCOOA, OH, OA, OCF3,

NO,, SOA, SO.NH,, SO;NHA or SO.NA;,

R® is A, (CH2)-Ar or (CH,),-Het,

R* is A,

R®>and R* together are alternatively (CH.),, (CH2)n-N(R®)-(CHy)2, + 35 (CH2)2-CH(NH,)-(CH2)2-, (CH2)2-CH(NH-COOA)-(CH_)2-, (CH2)-CH(NH-CH,-COOA)-(CH3)2-,

PS -26- : (CH;)2-CH[NH-CH(A)-COOA]-(CHz)z-, (CHz)2-O-(CH:)z, (CH.)2-S(O)m~(CH2)2 or

R7 R7 % or

R”

CH.-

R7™

R® R°, R%,

R% and Rare each, independently of one another, (CH,),-COOH, (CH2)a-COOA, (CH2),-COO-(CH2)m-Ar, = (CH2)n-COO~(CH2)m-Het, Ar, Py or R?,

R® is OH, A or Ar, :

R,R",R” and R” are each, independently of one another, H, Hal, OH,

OA, COOH, COOA, COO(CH:)mAr, CONH,, CONHA or

CONA;,

R® is H, A, COA, COOA, (CH2),-COOH, (CH2)m-COOA,

COO-(CHy)-Ar, COO-(CHy)m-Het, (CH2)n-COO-(CHz)m-Ar, (CH2),-COO-(CH2)m-Het, (CH2)m-CONHg,, (CH2)m-CONHA, (CH2)n-CONA;, SOA or SOsH,

R® is H, A or benzyl, uU is CO or CHa, a 25 \ is NH or CO,

Ww is absent or is CO,

X is CH or N,

Y is absent or is CH,, CO or SO,

CF3, Hal, OH, OA, OCF;, SOA, SO:NH,, SO;NHA,

SONA; NH2, NHA, NA;, NHCHO, NHCOA, NHCOOA,

NACOOA, NHSO,A, NHSO,Ar, COOH, COOA,

PS -27 -

COO-(CH2)m-Ar', COO-(CH;)m-Het, CONH,, CONHA, : CONA;, CONHAr', CHO, COA, COAr, CHAI, (CH2)mNH2, (CH2)wNHA, (CH2)mNAz, (CH2) \NHCHO, (CH2)mNHCOA, (CH2)NHCOOA, (CH2)mNHCOO-(CH,)Ar, (CH2)m NHCOO-(CHa)mHet,

NO,, CN, CSNH,, C(=NH)SA, C(=NH)OA, C(=NH)NH.,

C(=NH)NHOH, C(=NH)NHCOOA or C(=NH)NHCOOAr',

Ar is phenyl! or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by A,

OR® N(R®)., NO, CN, Hal, NHCOA, COOR®, CON(R®),,

COR® or S(0):A,

Het is @ monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic radical having 1-4 N, O and/or S atoms, bonded via N or C, which is unsubstituted or 16 monosubstituted, disubstituted, trisubstituted or tetra- substituted by A, CF3, Hal, OH, OA, OCF3;, SOA,

SO2-(CH2)m-Ar, SO2NH,, SO.NHA, SONA, NH;, NHA,

NA;, NHCHO, NHCOA, NHCOOA, NACOOA, NHSO:A,

NHSO.Ar, COOH, COOA, COO-(CH;)x-Ar', CONH,,

CONHA, COA, COAr', CH,NH,, CH,NHA, CH.NHCHO,

CH,NHCOA, CH,NHCOOA, NO,, CN, CSNH,,

C(=NH)SA, C(=NH)OA, C(=NH)NH,, C(=NH)NHOH,

C(=NH)NHCOOA, C(=NH)COOAr" and/or carbonyl oxygen,

Hr 25 Py is 2-, 3- or 4-pyridyl, each of which is unsubstituted or monosubstituted or polysubstituted by A, Hal, CN,

CONH,, CONHA, COOH, COOA, CH2NH,, CH,NHA,

CH,NHCHO, CH,NHCOA, CH,NHCOOA, CH.OH,

CH,0A, CH,0Ar, CH,OCOA, NO2, NH, NHA or NA,

Hal is F, Cl, Brorl, n is 1 or2, m is0, 1o0r2 p is2,3,4o0rb5, and their pharmaceutically tolerated salts and solvates,

I) compounds of the formula

® -28- xX PN = )

H

R Pp lL in which

R is CN, CHuNH,, -NH-C(=NH)-NH,, -CO-N=C(NH), ~C(=NH)-NH., which may also be monosubstituted by

Ar’, OH, O-COA, O-COAr, OCOQA, OCOO(CH:2)nN(A)2, . -COO(CH_2)nNA,, OCOO(CH;)mHet, COO-(CH2)m-Het,

CO-C(A)-R®, COOA, COSA, COSAr, COOAr, COOAr, :

COA, COAr, COAT or by a conventional amino-protecting group, or is ~"o t~™o

N= N= 0) CH,

R' is R* Ar, Ar or X,

R? is phenyl which monosubstituted by SA, SOA, SOA,

SONHA, SO.NHA, CF; COOA, CH.NHA, CN or OA,

HH ®

FEY: Aq

R® is CHals, OCOA or { 0 ~ oO

R* is alkyl having 1-20 carbon atoms, in which one or two

CH, groups may be replaced by O or S atoms and/or by ~CH=CH- groups and/or in addition 1-7 H atoms may be replaced by F,

A is H or alkyl having 1-20 carbon atoms,

A is alkyl having 1-10 carbon atoms,

Ar is phenyl or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by A’,

OH, OA’, NH, NHA', NA';, NO,, CF3, CN, Hal, NHCOA, of

® -29- : COOA, CONH,;, CONHA', CONA';, SA, SOA, SOA,

SO;NH,;, SO,NHA' or SO,NA',,

Ar is (CH2)n-Ar,

Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic radical having from 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono- substituted, disubstituted or trisubstituted by A’, OA,

NH., NHA', NA';, NO,, CN, Hal, NHCOA', NHSOZA',

COOA, CONH,, CONHA', CONA',, COA, SO.NH, SA,

SOA, SOA’ and/or carbonyl oxygen,

X is (CH2)nY, : . NN {—

Y is COOA or N- N

A

Hal isF, Cl, Brorl, n is1,2, 3,4, 50r6, m isOor1, and their pharmaceutically tolerated salts and solvates, m) compounds of the formula 1

R2 i 25 < OB

R1 in which

R is CH2NH,, -CO-N=C(NH.)2, -NH-C(=NH)-NH, or —C(=NH)-NH,, which may also be monosubstituted by

OH, -OCOO0A, -OCOO(CH2).NAA’, -COO(CH_).NAA', -OCOO(CH,)m-Het, -COO(CH,)m-Het, -CO-CAA'-R’, -COO-CAA'-R®, COOA, COSA, COOAr, COOAr or by a conventional amino-protecting group, or is

Fi

PY -30-

SN N= 0) CH, ° R is unbranched, branched or cyclic alkyl having 1-20 carbon atoms, in which one or two CH; groups may be replaced by O or S atoms, or is Ar, Ar' or X,

R? is phenyl which is monosubstituted by S(O),A,

S(0),NHA, CFs, COOA, CH:NHA, CN N OA, oe {— CH, A 0)

R® is -C(Hal)s, -O(C=0)A or o<{ 0]

OA, NAA’, NO,, CF3, CN, Hal, NHCOA, COOA,

CONAA', S(O),A or S(O),NAA/,

Ar is -(CHa)q-Ar,

A is H or unbranched, branched or cyclic alkyl having 1-20 carbon atoms,

A is unbranched, branched or cyclic alkyl having 1-10 carbon atoms,

Het is a monocyclic or bicyclic, saturated, unsaturated or

Gh 25 aromatic heterocyclic radical having from 1to 4 N, O : and/or S atoms, bonded via N or C, which may be unsubstituted or substituted by A,

X is -(CH2)»-Y,

NN

3 —

Y is COOA or N —N

A

Hal is F, Cl, Brorl, m is 0Oor1, n is1,2, 3,4 50r6, p isQ, 1o0r2,

® or and their pharmaceutically tolerated salts and solvates, n) compounds of the formula 2 0 N AR o=

R1-W-X-V R4

R3 o , \ AR o="> ” x

I

R1—W—X—V R, in which:

R' is phenyl or naphthyl, each of which is substituted by -C(=NH)NH., which may also be monosubstituted by -COA, -CO-[C(R®),-Ar’, -COOA, -OH or by a conventional

Cd 25 amino-protecting group, -NHC(=NH)-NH,,

N NH

\

ROSE lo}

N

{ N- t~¢ No) 0 ~~ _ iN N={ 0) CH, and which may optionally be substituted by -A, -OR®, -N(R®),, -NO., -CN, -Hal, -NR’COA, -NR°COAr’", -NR° SOA, -NR°SO,Ar’, -COOR?®, -CON(R®),, -CONR°Ar’, -COR®, -COAr’ or S(O)nA;

R? is -N(R®),, -NR°COA, -NR*COAr or -NR’COOR®; yr

PS -32-

R® and

R*, independently of one another, are -H, -A, -OR®, -N(R%),, -NO,, -CN, -Hal, -NR’COA, -NR’COAr, -NR°SOA, -NR°SO.Ar", -COOR®, -CON(R®),, -CONR’Ar’, -COR®, -COAr’, -S(O)Ar’ or S(O)A;

R°- is H,-A, -C(R°R")Ar or -C(R°R")Het;

R® and

R’, independently of one another, are -H, -A or -(CH,)-Ar’;

R® is Hor A;

X is -O-, -NR°-, -CONR’-, -N(SO.Ar)- or -N(SO;Het)-;

Ww is {CR°R")n-, -OCR®R’-, 1,3-phenylene, 1,3-phenylene- : -C(R%)-, 1,4-phenylene or 1,4-phenylene-C(R®),-; \ is -(C(R®)2)m~;

A is alkyl having from 1 to 20 carbon atoms, in which one or two CH, groups may be replaced by O or S atoms or by -CH=CH- groups and in addition by from 1 to 7 H atoms may be replaced by F;

Ar is phenyl or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by -A, -Ar’,

Het, -OR®, -N(R®%),, -NO,, -CN, -Hal, -NR’COA, -NR°COAr, -NR’SO,A, -NR*SO.Ar", -COOR®, -CON(R®),, -CONR®Ar, -COR®, -COAr or -S(0)A,

Ar is phenyl or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by -A, -OR®, # 25 -N(R®),, -NO,, -CN, -Hal, -NR®COA, -NR°SO,A, -COOR®, -CON(R®),,-COR®, -SO,NR°® or -S(O)aA,

Het is @ monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic radical having from 1 to 4 N, O and/or

S atoms, bonded via N or C, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by -A, -OR®,

N(R®)2, -NO,, -CN, -Hal, -NR°COA, -NR®SO,A, -COOR®, -CON(R®),, -COR®, -SO,NRS, -S(0)A and/or carbonyl oxygen;

Hal is -F, -Cl, -Br or -I; | is0,1,2,3,40r5; m isOor1; ud

PY -33- n is0,1or2, and their pharmaceutically tolerated salts and solvates, 0) compounds of the formuia i

R?

R'-W

R3 in which

R' is phenyl or naphthyl, each of which is substituted by -C(=NH)NH,, which may also be monosubstituted by -COA, -CO-[C(R");].-Ar’, -COOA, -OH or by a conventional amino-protecting group, -NHC(=NH)-NH;, -CON=C(NH)-, hp NH

CH or | 'o)

N~g ° a and which may optionally be substituted by -A, -OR>, -N(R%)., : -NO;, -CN, -Hal, -NR°COA, -NR°COAr", -NR°SO,A, fh og -NR®SO.Ar, -COOR®, -CON(R®),, -COR’, -COAr" or S(O)nA;

R? is -S(O)A, -CF3, -COOR’ or -OA;

R® and

R* independently of one another, are -H, -A, -OR®, -N(R>),, -NO;, -CN, -Hal, -NR’COA, -NR°COAr’, -NR°SO,A, -NR°SOQ,Ar", -COOR®, -CON(R®),, -CONRAr’, -COR’, -COAr’ or -S(O)nA,

R® and

R®, independently of one another, are -H, -A, -[C(R'R®)J.Ar’ or [C(R'R®)]Het;

R” and

R®, independently of one another, are -H or -A;

Pp

® -34-

WwW is -[C(R°R®)].CONR’[C(R°R%)}- or -OC(R°R®)CONR’[C(R’R%)}r-;

A is alkyl having from 1 to 20 carbon atoms, in which one or two CH, groups may be repiaced by O or S atoms or by -CH=CH- groups and in addition from 1 to 7 H atoms may be replaced by -F;

Het, -OR®, -N(R®),, -NO,, -CN, -Hal, -NR’COA, -NR°COA, -NR’SO,A, -NR*SO,Ar", -COOR®, -CON(R®),, -CONR’Ar’, -COR’, -COAr", -SO,NR?, -S(O),Ar” or -S(O)nA; oo Ar is phenyl or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by -A, -OR’,

N(R"), -NO, -CN, -Hal, -NR'COA, -NR'SO,A, -COOR’, -CON(R),,-COR’, -SO.NR” or -S(0)sA;

Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic radical having from 1 to 4 N, O and/or

S atoms, bonded via N or C, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by -A, -OR’,

N(R")z, -NO2, -CN, -Hal, -NR'COA, -NR’SO,A, -COOR’, -CON(R"),, -COR’, -SO,NR’, -S(0).A and/or carbonyl oxygen, : :

Hal is -F, -Cl, -Br or -I; : isOor1; “25 m is 1 or 2; n is0, 1or2; and their pharmaceutically tolerated salts and solvates, p) compounds of the formula 4 1 1 Je

R xr uw N—OQ

ROR I SE

Rr N l r

PN -35- in which

R' is H, Cl, F, OH, OA, O-(CH,).-Ar, NH, NHCOA, NHCOOA,

NH-(CHz).-Ar, CN, CONH,, CSNH,, C[NH]SA, C[NH]NH,

C[NHIJNHA, C[NHJNOH, C[NHJNOA, C[NH]JNOCOA,

C[NHJNOCOAr, C[NH]JOA, C[NH]JNHNH_, C[NH]NHNHA,

C[NH]JNHCOOA, C[NHINHCOA C[NHINHCOO-(CHz)m-Ar,

CINH]NHCOO-(CH,)m-Het, NHC[NH]NH., NHC[NH]NHCOOA,

NHC[NHIJNHCOO-(CH.)m-Ar or Q1,

R? is H or one or more A, CF3, Br, Cl, F, COA, COOH,

COOA, CONH;, CONHA, CONA;, CH,NH,, CH.NHCOA,

CH.NHCOOA, NHSO2A, OH, OA, OCF3, NO, SOA,

Se SO,NH, or SO.NHA,

R® is H, COH, COA, COCF;, COOA or SOA

R* is H, A, -(CH,)n-Ar, ~(CH,)s-Het, -(CH2)m-COOR, : 16 ~(CH2)m-CONHRY, (CHz)n -S(O)mA, -(CH2)e-NH;, -(CH,).-NHCOOA, -(CH.),-NHCOA, -(CH:).-NHAr, -(CH;)e-NHC[NH]NH;, -(CH2)c-(C[AJOH)-A, -(CH2).-OH, -(CHa)o-OA, -(CH,).-OAr, -(CH_),-OHet, -(CH2).-OCOOA, -(CH2)o-OCOA, -(CH).-OCOAr, Ar or Het,

R® is (CH2)a-COOH, -(CH2)s-COOA, -(CH,),-COO(CHz)nAr,

Ar, Py or R?,

R® is OH, A or Ar,

R’ is H, A, Ar or Het,

U is CO or CH, oh 25 \Y; is NH, CO or O,

WwW is a bond or CO,

X is CHor N,

Y is a bond or CH,, CO or SO,, n is1or2, m is0,1o0r2, lo] is1,2 3, 40r5, p is2, 3o0r4,

A is alkyl having 1 - 20 carbon atoms (linear, branched or : cyclic), in which one or two CH, groups may be replaced by O or S atoms or by -CH=CH- or -C=C- groups and in addition 1 — 7 H atoms may be replaced by F, i

PY - 36 -

CFs, Hal, OA, OCF3, SOA, SO.NH,, SO:NHA, SO.NA;,

NH, NHA, NA, NHCHO, NHCOA, NHCOOA,

NACOOA, NHSO,A, NHSO,Ar, COOH, COOA,

COO-(CHy)m-Ar, COO-(CH,)n-Het CONHz, CONHA,

CONA., CONHAr, COA, COAr, CHAr, -(CH2)m-NHa, ~(CH2)m-NHA, «(CH2)m-NA;, ~(CH2)m-NHCHO, -(CH2)m-NHCOA, -(CH2)»-NHCOOA -(CH2)m-NHCOO-(CH:)Ar, -(CH;)m-NHCOO-(CH2)m-Het, -(CHz)m-Hal, -(CHz)m-Het,

NO,, CN, CSNH,, C[NH]SA, C[NH]OA, C[NH]NH.,

C[NH]NHOH, C[NH]NHCOOA or C[NHJNHCOOAr,

Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic radical having from 1to 4 N, O and/or S atoms, bonded via N or C, which may be un- substituted or monosubstituted, disubstituted, trisubsti- tuted or tetrasubstituted by A, CFs, Hal, OH, OA, SOA,

SO-(CHz)m-Ar, SO.NH,, SO:NHA, SO:NA;, NH, NHA,

NA, NHCHO, NHCOA, NHCOOA, NHSO-A, NHSO-Ar,

COOH, COOA, COO-[CH;]m-Ar, CONH,, CONHA, COA,

COAT, CH,NH,;, CHoNHA, CH,NHCHO, CHNHCOA,

CH,NHCOOA, NO, CN, CSNH,, C[NH]SA, C[NH]OA,

C[NH]NH_, C[NHINHOH, C[NHINHCOOA, oe 25 C[NH]NHCOOAr and/or carbonyl oxygen,

Py is 2-, 3- and/or 4-pyridyl, unsubstituted or monosubstitu- ted or polysubstituted by A, Hal, CN, CONH,, CONHA,

COOH, COOA, CH;NH,, CH.NHA, CH.NHCHO,

CH;NHCOA, CH,NHCOOA, CH,OH, CH,0A, CH,OAr,

CH,OCOA, NO, NH;, NHA or NA,

Hal is F, Cl, Brorl, and their pharmaceutically tolerated salts and solvates, gq) compounds of the formula :

PS -37 - (F)

Re it jar a Vd NN

RJ | 4 = R H in which

R' is -(CH2)a-NH2, -CON=C(NH,),, -NHC(=NH)-NH, or -C(=NH)-NH,, which may also be monosubstituted by -OH, -OCOOA, -OCOO(CH.).N(A),, -OCOO(CH:)m-Het, -CO-C(A)-R®, -COOA, -COSA, COOAY, -COOAF or

N N

~~ SMe o ~ NO b N—O N—O y ’

R® is H or COOA,

R® is unbranched, branched or cyclic alkyl having 1-20 carbon atoms, in which one or two CH, groups may be replaced by O or S atoms, or is Ar, Ar, X or Hal,

R* is phenyl which is monosubstituted by S(O)A, S(O)NHA,

CF3, COOA, CH2NHA, CN or OA, . H A ae, ~ o—4 2% R® is -CHals, -O(C=O)A or o

Ar is phenyl or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by A, OH,

OA, NH,, NHA, NA, NO,, CF3, CN, Hal, NHCOA, COOA,

CONH,;, CONHA, CONA;, S(O)nA, S(O)nNH;, S(O),NHA or

S(O)NA,

Ar is -(CH2)n-Ar,

S atoms, bonded via N or C, which may be unsubstituted or substituted by A,

® or

A is H or unbranched, branched or cyclic alkyl having 1-20 carbon atoms,

X is -(CH2)n-Y,

A N “N

Jn

N—N /

Y iscooa, A

Hal isF, Cl Brorl, n is1,2, 3,4 50r6, m isOor1, . k is0,1or2, ha | is0, 1, 2, 3or4, and their pharmaceutically tolerated salts and solvates, r) compounds of the formula

R3 _E

D 5 4 S

R' R? R in which = 28 -D=E- is -N=C(NHy)- or -C(NH,)=N-,

R'and R?, independently of one another, are H, A, OR®, N(R®).,

NO., CN, Hal, NR°COA, NR°COAr’", NR°SO-A,

NR®SO.Ar’, COOR®, CON(R®),, CONR®Ar‘, COR’,

COAr or S(0)nA,

R® is SOz(NR®),, S(O)nA, CFs, COOR®, OA or CN,

R*and R®, independently of one another, are H, A, OR®, N(R®),,

NO,, CN, Hal, NR® COA, NR°COAr’, NR°SO.A,

NR®SO.Ar’, COOR®, CON(R®),, CONR®Ar', COR’,

COA or S(O)A,

R® is H, A, [C(R)2]nAr or [C(R7);]Het, ~ Fl

® >

R’ isH or A,

W is CONR®C(R®),CONR®[C(R®).}-, -NR°C(R®),CONR® [C(R%)2}-, {C(R®)2JmCONR[C(R®).}- or | -OC(R®),CONR®[C(R®).}-,

A is alkyl having 1 - 20 carbon atoms, in which one or two CH, groups may be replaced by O or S atoms or by -CH=CH- groups and in addition 1 — 7 H atoms may be replaced by F,

Ar is phenyl or naphthyl, each of which is unsubstituted or monosubstituted, disubstituted or trisubstituted by

A, Ar, Het, OR®, N(R®),, NO, CN, Hal, NR°COA,

NR®COAr’, NR®SO,A, NR®SO-Ar’, COOR®,

CON(R®),, CONR®Ar, COR’, COAr, SO,NR®

S(O)Ar or S(O)nA,

A, OR’, N(R);, NO, CN, Hal, NR'"COA, NR’SO:A,

COOR’, CON(R"),, COR’, SO,NR’ or S(O),A,

Het is @ monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic radical having from 1to 4 N, O and/or S atoms, bonded via N or C, which may be unsubstituted or monosubstituted, disubstituted or <1 og trisubstituted by A, OR’, N(R"), NO, CN, Hal, ) NR’COA, NR’SO,A, COOR’, CON(R"),, COR’,

SO.NR’, S(0).A and/or carbonyl oxygen,

Hal is F, Cl, Brorl, n is0, 1o0r2, m is 1o0r2, isOorf, and their pharmaceutically tolerated salts and solvates, : s) compounds of the formula

PS -40- o KX

D_ J] AA

N" Xx (CHp)y—E —W 0) in which

D is phenyl or pyridyl, each of which is unsubstituted or monosubstituted or polysubstituted by Hal, A, OR? N(R?) NO,, CN, COOR? or CON(R?),

R' is H, Ar, Het, cycloalkyl or A, which may be substituted by

OR?, SR? N(R?),, Ar, Het, cycloalkyl, CN, COOR? or

CON(R?),,

R® is Hor A,

E is phenylene, which may be monosubstituted or poly- substituted by Hal, A, OR? N(R®),, NO,, CN, COOR? or

CON(R?),, or is piperidine-1,4-diyl,

Ww is Ar, Het or N(R?), and, if E = piperidine-1,4-diyl, is alternatively R? or cycloalkyl,

X is NH or O,

A is unbranched or branched alkyl having 1-10 carbon atoms, in which one or two CH, groups may be replaced by O or S atoms and/or by —-CH=CH- groups and/or in addition 1-7 H atoms may be replaced by F,

N Ar is phenyl which is unsubstituted or monosubstituted, disubsti- e258 tuted or trisubstituted by Hal, A, OR?, N(R?),, NO, CN,

COOR?, CON(R?),, NR’COA, NR’SO,A, COR? SO:NR?,

SOsH or S(O)mA,

S atoms, which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A, OR? N(R?),, NO,

CN, COOR?, CON(R?),, NR?COA, NR’SO,A, COR?, SO.NR?, ~~ 8SOsH or S(O)wA and/or carbonyl oxygen,

Hal isF, Cl, Brorl, n isO or, m is0, 1or2, py

° and their pharmaceutically tolerated salts and solvates.

Other preferred factor Xa inhibitors are, for example, the compounds described in the foliowing documents: a) in WO 97/30971, page 4, line 5, to page 13, line 19; b) inEP 0921116 A1, page 2, line 1, to line 51; c) in EP 0540 051 B1, page 2, line 41, to page 3, line 14, d) in EP 0798 295 A1, page 68, line 10, to page 71, page 53,

Other preferred compounds are selected from the group consisting of defibrotide, desirudin and lepirudin.

The invention preferably relates to a formulation comprising [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]- pyrimidin-5-ylmethoxy)acetic acid and physiologically acceptable salts and/or solvates thereof and a calcium antagonist.

Besides the free acid, the ethanolamine salt is preferred.

Preference is given to calcium antagonists selected from the group con- sisting of selective and non-selective calcium antagonists.

Preference is given to selective calcium antagonists selected from the group consisting of dihydropyridine derivatives, phenylalkylamine } derivatives, benzothiazepine derivatives and other selective calcium

SL 25 antagonists.

Dihydropyridine derivatives are preferably selected from the group con- sisting of amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine and lercanidipine.

The phenylalkylamine derivatives are preferably selected from the group consisting of verapamil and gallopamil. :

The benzothiazepine derivatives are preferably diltiazem. .

PS -42 -

The other selective calcium antagonists are preferably mibefradil.

The non-selective calcium antagonists are preferably selected from the group consisting of fendiline, bepridil, lidoflazine and perhexiline.

The invention preferably relates to a formulation comprising [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyi-1H-pyrazoio[4,3-d]- pyrimidin-5-ylimethoxyJacetic acid and physiologically acceptable salts and/or solvates thereof and a prostaglandin or prostaglandin derivative.

Besides the free acid, the ethanolamine salt is preferred. ne Preference is given to prostaglandins or prostaglandin derivatives selected from the group consisting of PGE,, PGA, PGB,, PGF, PGA2, PGB;, 19- hydroxy-PGA;, 19-hydroxy-PGB,, 19-hydroxy-PGA;, 19-hydroxy-PGB,,

PGEs;, PGFs, alprostadil (PGE), dinoprost (PGF), dinoprostone (PGE), epoprostenol sodium (PGI; prostacyclin sodium), gemeprost, iloprost, latanoprost, misoprostol, sulprostone, carboprost thromethamin, dinoprost thromethamin, lipoprost, metenoprost and tiaprost.

Particular preference is given to prostaglandins or prostaglandin deriva- tives selected from the group consisting of alprostadil (PGE,), dinoprost (PGF.), dinoprostone (PGE), epoprostenol sodium (PGl,; prostacyclin sodium), gemeprost, iloprost, latanoprost, misoprostol, sulprostone,

N carboprost thromethamin, dinoprost thromethamin, lipoprost, metenoprost

Le 25 and tiaprost.

Particular preference is given to PGE, or prostacyclin, especially preferably prostacyclin.

The compounds of the formula | and also the starting materials for their preparation are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as

Houben-Weyl, Methoden der organischen Chemie [Methods of Organic :

Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use can

® also be made here of variants which are known per se, but are not mentioned here in greater detail. in the compounds of the formula ii or Ill, R}, R?, R®, R* and X have the

S meanings indicated, in particular the preferred meanings indicated.

If L is a reactive esterified OH group, this is preferably alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy) or arylsulfonyioxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy, further- more also 2-naphthalenesulfonyloxy). a The compounds of the formula | can preferably be obtained by reacting compounds of the formula Il with compounds of the formula Ill.

If desired, the starting materials can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the formula |.

On the other hand, it is possible to carry out the reaction stepwise.

The starting compounds of the formulae Il and lll are generally known. If they are not known, they can be prepared by methods known per se.

Compounds of the formula ll can be prepared by methods known from the literature, for example from 4-amino-3-alkoxycarbonylpyrazoles by cyclisation using nitriles and subsequent reaction of the cyclisation

Fo 25 products with phosphorus oxychloride (analogously to Houben Weyl

E9b/2).

In detail, the reaction of the compounds of the formula Il with the com- pounds of the formula Ill is carried out in the presence or absence of an inert solvent at temperatures between about -20 and about 150°, prefer- ably between 20 and 100°,

The addition of an acid-binding agent, for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably of potassium, sodium or calcium, or the addition of an organic base, such as triethylamine,

® -44 - dimethylamine, pyridine or quinoline or of an excess of the amine component, may be favourable.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloro- form or dichloromethane; alcohols, such as methanol, ethanol, isopropan- ol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, di- isopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.

It is furthermore possible to convert a radical X in a compound of the formula | into another radical X, for example by hydrolysing an ester or a cyano group to give a COOH group.

Ester groups can be saponified, for example, using NaOH or KOH in water, water/THF or water/dioxane at temperatures between 0 and 100°.

Carboxylic acids can be converted into the corresponding carboxylic acid chlorides, for example using thionyl chloride, and these can be converted into carboxamides. Elimination of water therefrom in a known manner or 25 gives carbonitriles.

An acid of the formula 1 can be converted into the associated acid-addition salt using a base, for example by reaction of equivalent amounts of the acid and the base in an inert solvent, such as ethanol, followed by evapo- ration. Suitable bases for this reaction are, in particular, those which give physiologically acceptable salts.

Thus, the acid of the formula | can be converted into the corresponding metal salt, in particular alkali metal or alkaline earth metal salt, or into the corresponding ammonium salt using a base (for example sodium hydrox- ide, potassium hydroxide, sodium carbonate or potassium carbonate).

PS -45 -

Also suitable for this reaction are, in particular, organic bases which give physiologically acceptable salts, such as, for example, ethanolamine.

On the other hand, a base of the formula | can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable acids. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phos- phoric acids, such as orthophosphoric acid, or sulfamic acid, furthermore so organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethyl- acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, or laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and/or purification of the compounds of the formula |. ) The invention furthermore relates to pharmaceutical formulations compris- = 25 ing at least one compound of the formula | and/or one of its physiologically acceptable salts and at least one antithrombotic, a calcium antagonist or at least one prostaglandin or prostaglandin derivative, and comprising one or more excipients and/or assistants.

The pharmaceutical preparations are prepared, in particular, by non- chemical methods. The active ingredients are converted into a suitable dosage form here together with at least one solid, liquid and/or semi-liquid excipient or assistant.

These preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administra-

® -46 - tion and do no react with the novel compounds, for example water, vege- table oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearates, taic or vaseline. Suitable for oral administration are, in particu- lar, tablets, pills, coated tablets, capsules, powders, granules, Syrups, juices or drops, suitable for rectal administration are suppositories, suit- able for parenteral administration are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical application are ointments, creams or powders. The novel compounds may also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations. The prepa- i rations indicated may be sterilised and/or comprise assistants, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, colorants and flavours and/or a plurality of further active ingredients, for example one or more vitamins. They can furthermore be administered as nasal sprays.

In general, the substances are preferably administered in doses of be- tween about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dose is preferably between about 0.02 and 10 mg/kg of body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of = health, sex, on the diet, on the time and method of administration, on the ~ - 25 excretion rate, medicament combination and severity of the particular illness to which the therapy applies. Oral administration is preferred.

The invention therefore also relates to the use of the pharmaceutical pre- parations described for the preparation of a medicament for the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor : pulmonale, dextrocardiac insufficiency, atherosclerosis, conditions of reduced patency of heart vessels, peripheral vascular diseases, strokes, : bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal insufficiency, liver cirrhosis and for the treatment of female sexual disorders.

Claims

PA - 66 - Patent Claims

1. Pharmaceutical formulation comprising at least one phospho- diesterase V inhibitor and/or physiologically acceptable salts and/or solvates thereof and at least one antithrombotic.

2. Pharmaceutical formulation comprising at least one compound of the formula R? ? HN a W - ~ I - \ Sy J x R4 in which R'andR® are each, independently of one another, H, A, OH, OA or Hal, : R'and R® together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -CH,-O-CH,-, -O-CH,-O- or -O-CH,-CH,-O-, : 25 R’andR* are each, independently of one another, H or A, - X is R®, R® or R” which is monosubstituted by R®, R® is linear or branched alkylene having 1-10 carbon atoms, in which one or two CH, groups may be replaced by -CH=CH- groups, O, S or SO, R® is cycloalkyl or cycloalkylaikylene having 5-12 carbon atoms, R’ is phenyl or phenylmethyl, R® is COOH, COOA, CONH,, CONHA, CON(A); or CN, A is alkyl having from 1 to 6 carbon atoms, and Hal isF, Cl, Brorl, and/or physiologically acceptable salts and/or solvates thereof and a) at least one antithrombotic or

® -67 - b) at least one calcium antagonist or c) at least one prostaglandin or prostaglandin derivative.

3. Pharmaceutical formulation according to Claim 2, comprising at least one compound of the formula R1 R HN LW Ne 2 R? AVENE = N X : R4 in which R'and R? are each, independently of one another, H, A, OH, OA or Hal, R'and R* together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -CH,-O-CH5-, -O-CH,-O- or -O-CH,-CH-O-, : R*and R* are each, independently of one another, H or A, X is R®, R® or R” which is monosubstituted by R®, R® is linear or branched alkylene having 1-10 carbon ST 25 atoms, in which one or two CH, groups may be replaced by -CH=CH- groups, O, S or SO, R® is cycloalkyl or cycloalkylalkylene having 5-12 carbon atoms, RY is phenyl! or phenyimethyl, R® is COOH, COOA, CONH,, CONHA, CON(A), or CN, A is alkyl having from 1 to 6 carbon atoms, and Hal is F, Cl, Brorl, and/or physiologically acceptable salts and/or solvates thereof and at least one antithrombotic.

4. Pharmaceutical formulation according to Claim 3, comprising at least one compound of the formula | according to Claim 3 in which

PY - 68 - X is R®, phenyl or phenylmethyl, each of which is substituted by COOH, COOA, CONH;, CONA;, CONHA or CN; and/or physiologically acceptable salts and/or solvates thereof and at least one antithrombotic.

5. Pharmaceutical formulation according to Claim 3, comprising at least one compound of the formula | according to Claim 3 in which R'and R? together are alkylene having 3-5 carbon atoms, -0-CH;-CH_-, -O-CH;-O- or -O-CH2-CH,-O-, X is R®, phenyl! or phenylmethyl, each of which is : substituted by COOH, COOA, CONH_, CONA,;, CONHA or CN; and/or physiologically acceptable salts and/or solvates thereof and at least one antithrombotic.

6. Pharmaceutical formulation according to Claim 3, comprising at least one compound of the formula | according to Claim 3 in which R'and R? are each, independently of one another, H, A, OH, OA or Hal, R'and R® together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -O-CH,-O- or -O-CH,-CH,-O-, X is R®, phenyl! or phenylmethyl, each of which is substituted by COOH, COOA, CONH,, CONA;, CONHA “ 25 or CN; and/or physiologically acceptable salts and/or solvates thereof and at least one antithrombotic.

7. Pharmaceutical formulation according to Claim 3, comprising at least one compound of the formula | according to Claim 3 in which R'andR?® are each, independently of one another, H, A, OH, OA or Hal, R' and R? together are alternatively alkylene having 3-5 carbon : atoms, -O-CH,-CH,-, -O-CH,-O- or -O-CH,-CH,-0O-,

PS -69 - X is alkylene having 2-5 carbon atoms, cyclohexyl, phenyl or phenylmethyl, each of which is monosubstituted by R® R® is alkyl having 1-6 carbon atoms, R* is alkyl having 1-6 carbon atoms, R® is COOH or COOA, A is alkyl having from 1 to 6 carbon atoms, Hal isF,Cl, Brorl; and/or physiologically acceptable salts and/or solvates thereof and at least one antithrombotic.

8. Pharmaceutical formulation according to Claim 3, comprising at least one compound of the formula | according to Claim 3 in which R'and R> are each, independently of one another, H, A, OH, OA or Hal, R'and R® together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -O-CH,-O- or -O-CH,-CH,-0O-, R® is alkyl having 1-6 carbon atoms, R* is alkyl having 1-6 carbon atoms, X is ~(CH2)2.5-R®, in which one CH, group may be replaced by O, or is 4-R®<cyclohexyl, 4-R®-phenyl or 4- (R®-methyl)phenyl, R® is COOH or COOA; and/or physiologically acceptable salts and/or solvates thereof and at EE 25 least one antithrombotic.

9. Pharmaceutical formulation according to Claim 3, comprising at least one compound of the formula | according to Claim 3 selected from the group consisting of (a) 5-7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-yl}pentanoic acid; (b) 4{7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-yl]benzoic acid; : (c) 4{7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyi-1H- pyrazolo[4,3-d]pyrimidin-5-yl]butyric acid;

® -70- (d) 5-[7-(benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]- pyrimidin-5-yl]pentanoic acid; (e) [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- pyrazoio[4, 3-d]pyrimidin-5-yimethoxy]acetic acid and/or physiologically acceptable salts and/or solvates thereof and at least one antithrombotic.

10. Pharmaceutical formulation according to Claim 9, comprising at least [7-(3-chioro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo- [4,3-d]pyrimidin-5-yImethoxy]acetic acid, ethanolamine salt, and at least one antithrombotic. :

11. Pharmaceutical formulation according to Claims 1 to 10, in which the antithrombotic is selected from the group consisting of vitamin K 16 antagonists, heparin compounds, thrombocyte aggregation inhibitors, enzymes, factor Xa inhibitors, factor Vila inhibitors and other anti- thrombotic agents.

12. Pharmaceutical formulation according to Claim 11, where the vitamin K antagonists are selected from the group consisting of dicoumarol, phenindione, warfarin, phenprocoumon, acenocoumarol, ethyl biscoumacetate, clorindione, diphenadione and tioclomarol.

13. Pharmaceutical formulation according to Claim 11, where the heparin - 25 compounds are selected from the group consisting of heparin, antithrombin lll, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, danaparoid, tinzaparin and sulodexide.

14. Pharmaceutical formulation according to Claim 11, where the throm- bocyte aggregation inhibitors are selected from the group consisting of ditazole, cloricromen, picotamide, clopidogrel, ticlopidine, acetyl- salicylic acid, dipyridamole, calcium carbassalate, epoprostenol, indobufen, iloprost, abciximab, tirofiban, aloxiprin and intrifiban. :

156. Pharmaceutical formulation according to Claim 11, where the enzymes are selected from the group consisting of streptokinase,

° Th alteplase, anistreplase, urokinase, fibrinolysin, brinase, reteplase and saruplase.

16. Pharmaceutical formulation according to Claim 11, where other antithrombotic agents are selected from the group consisting of defibrotide, desirudin and lepirudin.

17. Pharmaceutical formulation according to Claims 1-10, where the antithrombotic is selected from the group consisting of blood platelet glycoprotein receptor (lib/llla) antagonists. Co - 18. Pharmaceutical formulation according to Claim 2, comprising at least one compound of the formula R’ CH a HN ~~ R2 SG N\A N X . R4 in which ot 25 R'andR?* are each, independently of one another, H, A, OH, OA or Hal, R'and R? together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH;-, -CH;-O-CH,-, -O-CH.-O- or -O-CH2-CH»>-O-, R>and R* are each, independently of one another, H or A, X is R>, R® or R’, each of which is monosubstituted by R®, R® is linear or branched alkylene having 1-10 carbon atoms, in which one or two CH, groups may be replaced by -CH=CH- groups, O, S or SO, R® is cycloalkyl or cycloalkylalkylene having 5-12 carbon atoms, R’ is phenyl or phenylmethy!,

PS -72- R® is COOH, COOA, CONH,, CONHA, CON(A), or CN, A is alkyl having from 1 to 6 carbon atoms, and Hal isF, Cl, Brorl, and/or physiologically acceptable salts and/or solvates thereof and at least one calcium antagonist.

19. Pharmaceutical formulation according to Claim 18, comprising at least one compound of the formula | according to Claim 18 in which X is R®, phenyl or phenylmethyl, each of which is substituted by COOH, COOA, CONH,, CONA,, CONHA or CN; and/or physiologically acceptable salts and/or solvates thereof and at least one calcium antagonist.

20. Pharmaceutical formulation according to Claim 18, comprising at least one compound of the formula | according to Claim 18 in which R'and R® together are alkylene having 3-5 carbon atoms, -0-CH,-CH,-, -O-CH,-O- or -O-CH>-CH,-0O-, X is R®, phenyl or phenylmethyl, each of which is substituted by COOH, COOA, CONH;, CONA,, CONHA or CN; and/or physiologically acceptable salts and/or solvates thereof and at least one calcium antagonist. a 25 © 21. Pharmaceutical formulation according to Claim 18, comprising at least one compound of the formula | according to Claim 18 in which R'and R? are each, independently of one another, H, A, OH, OA or Hal, R'and R> together are alternatively alkylene having 3-5 carbon : atoms, -O-CH,-CH,-, -O-CH,-O- or -O-CH,-CH»-0-, X is R®, phenyl or phenylmethyl, each of which is substituted by COOH, COOA, CONH,, CONA;, CONHA or CN; : and/or physiologically acceptable salts and/or solvates thereof and at least one calcium antagonist.

PY -73-

22. Pharmaceutical formulation according to Claim 18, comprising at least one compound of the formula | according to Claim 18 in which R'and R? are each, independently of one another, H, A, OH, OA or Hal, R'and R® together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -O-CH,-0- or -O-CH,-CH,-O-, X is alkylene having 2-5 carbon atoms, cyclohexyl, phenyl or phenylmethyl, each of which is monosubstituted by R®, R® is alkyl having 1-6 carbon atoms, R* is alky! having 1-6 carbon atoms, = R® is COOH or COOA, . A is alkyl having from 1 to 6 carbon atoms, Hal isF, Cl, Brorl; and/or physiologically acceptable salts and/or solvates thereof and at least one calcium antagonist.

23. Pharmaceutical formulation according to Claim 18, comprising at least one compound of the formula | according to Claim 18 in which R'and R® are each, independently of one another, H, A, OH, OA or Hal, R'and R? together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -O-CH2-O- or -O-CH,-CH,-0O-, R® is alkyl having 1-6 carbon atoms, > 25 R* is alkyl having 1-6 carbon atoms, X is -(CH.).s-R®, in which one CH, group may be replaced by O, or is 4-R®-cyclohexyl, 4-R®-phenyl or 4- (R®-methyl)phenyl, R® is COOH or COOA,; and/or physiologically acceptable salts and/or solvates thereof and at least one calcium antagonist.

24. Pharmaceutical formulation according to Claim 18, comprising at least one compound of the formula | according to Claim 18 selected from the group consisting of

PY -74- } (a) 5-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-yl]pentanoic acid; (b) 4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-yl]benzoic acid, (c) 4-[7-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-yl]butyric acid; (d) 5-7-(benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d}- pyrimidin-5-yl]pentanoic acid; (e) [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-yimethoxyjacetic acid and/or physiologically acceptable salts and/or solvates thereof and at least one calcium antagonist.

25. Pharmaceutical formulation according to Claim 24, comprising at least [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- ~ pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetic acid, ethanolamine salt, and at least one calcium antagonist.

26. Pharmaceutical formulation according to Claims 2 and 18 to 25, in which the calcium antagonist is selected from the group consisting of selective and non-selective calcium antagonists.

27. Pharmaceutical formulation according to Claim 26, in which the selective calcium antagonists are selected from the group consisting oo 25 of dihydropyridine derivatives, phenylalkylamine derivatives, benzo- thiazepine derivatives and other selective calcium antagonists.

28. Pharmaceutical formulation according to Claim 27, in which the dihydropyridine derivatives are selected from the group consisting of amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, : nisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine and lercanidipine.

29. Pharmaceutical formulation according to Claim 27, in which the phenylalkylamine derivatives are selected from the group consisting of verapamil and gallopamil.

] °

30. Pharmaceutical formulation according to Claim 27, in which the benzothiazepine derivative is diltiazem.

31. Pharmaceutical formulation according to Claim 27, in which the other selective calcium antagonist is mibefradil.

32. Pharmaceutical formulation according to Claim 26, in which the non- selective calcium antagonists are selected from the group consisting of fendiline, bepridil, lidoflazine and perhexiline.

33. Pharmaceutical formulation according to Claim 2, comprising at least one compound of the formula R CH ? HN ~~ R2 N\A N X R4 in which nL 25 R'and R® are each, independently of one another, H, A, OH, OA or Hal, R'and R? together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -CH,-O-CH,-, -O-CH,-O- or -0O-CHz-CH,-O-, R*and R* are each, independently of one another, H or A, X is R®, R® or R’, each of which is monosubstituted by R®, R® is linear or branched alkylene having 1-10 carbon atoms, in which one or two CH, groups may be replaced by -CH=CH- groups, O, S or SO, R® is cycloalkyl or cycloalkylalkylene having 5-12 carbon atoms, R’ is phenyl! or phenyimethyl,

® -76- R® is COOH, COOA, CONH,, CONHA, CON(A), or CN, A is alkyl having from 1 to 6 carbon atoms, and Hal isF, Cl Brorl, and/or physiologically acceptable salts and/or solvates thereof and at least one prostaglandin or prostaglandin derivative.

34. Pharmaceutical formulation according to Claim 33, comprising at least one compound of the formula | according to Claim 33 in which X is R®, phenyl or phenylmethyl, each of which is substituted by COOH, COOA, CONH,, CONA;, CONHA or CN; and/or physiologically acceptable salts and/or solvates thereof and at least one prostaglandin or prostaglandin derivative.

35. Pharmaceutical formulation according to Claim 33, comprising at least one compound of the formula | according to Claim 33 in which R'and R® together are alkylene having 3-5 carbon atoms, -O-CH,-CH;-, -O-CH,-O- or -O-CH,-CH>-O-, X is R®, phenyl or phenylmethyl, each of which is substituted by COOH, COOA, CONH,, CONA;, CONHA or CN; and/or physiologically acceptable salts and/or solvates thereof and at least one prostaglandin or prostaglandin derivative. oo 25 36. Pharmaceutical formulation according to Claim 33, comprising at least one compound of the formula I according to Claim 33 in which R'and R® are each, independently of one another, H, A, OH, OA or Hal, R'and R? together are alternatively alkylene having 3-5 carbon atoms, -O-CH>-CH,-, -O-CH;-O- or -O-CH,-CH,-O-, X is R®, phenyl or phenylmethyl, each of which is substituted by COOH, COOA, CONH_, CONA;, CONHA or CN; and/or physiologically acceptable salts and/or solvates thereof and at least one prostaglandin or prostaglandin derivative.

® -77 -

37. Pharmaceutical formulation according to Claim 33, comprising at least one compound of the formula | according to Claim 33 in which R'and R® are each, independently of one another, H, A, OH, OA or Hai, R'and R* together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -O-CH,-O- or -O-CH2-CH,-O-, X is alkylene having 2-5 carbon atoms, cyclohexyl, phenyl or phenylmethyl, each of which is monosubstituted by

R® . R® is alkyl having 1-6 carbon atoms, R* is alkyl having 1-6 carbon atoms, R® is COOH or COOA, A is alkyl having from 1 to 6 carbon atoms, Hal isF, Cl, Brorl and/or physiologically acceptable salts and/or solvates thereof and at least one prostaglandin or prostaglandin derivative.

38. Pharmaceutical formulation according to Claim 33, comprising at least one compound of the formula | according to Claim 33 in which R'and R® are each, independently of one another, H, A, OH, OA or Hal, R'and R? together are alternatively alkylene having 3-5 carbon atoms, -O-CH,-CH,-, -O-CH,-O- or -O-CH2-CH,-O-, R® is alkyl having 1-6 carbon atoms, SE 25 R* is alkyl having 1-6 carbon atoms, X is -(CH.)2.5-R®, in which one CH, group may be replaced by O, or is 4-R®-cyclohexyl, 4-R®-pheny! or 4- (R®-methyl)pheny!, R® is COOH or COOA,; and/or physiologically acceptable salts and/or solvates thereof and at least one prostaglandin or prostaglandin derivative.

39. Pharmaceutical formulation according to Claim 33, comprising at : least one compound of the formula | according to Claim 33 selected from the group consisting of

® -78- (a) 5-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-yl]pentanoic acid; (b) 4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-yl]benzoic acid, S (¢) 447-(3,4-methylenedioxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d)pyrimidin-5-yl]butyric acid; (d) 5-[7-(benzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]- pyrimidin-5-ylJpentanoic acid; (e) [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetic acid and/or physiologically acceptable salts and/or solvates thereof and at least one prostaglandin or prostaglandin derivative.

40. Pharmaceutical formulation according to Claim 39, comprising at least [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetic acid, ethanolamine salt, and at least one prostaglandin or prostaglandin derivative.

41. Pharmaceutical formulation according to Claims 2 and 33 to 40, in which the prostaglandin or prostaglandin derivative is selected from the group consisting of alprostadil (PGE,), dinoprost (PGF), dinoprostone (PGE,), epoprostenol sodium (PGl,; prostacyclin sodium), gemeprost, iloprost, latanoprost, misoprostol, sulprostone, carboprost, thromethamin, dinoprost thromethamin, lipoprost, a 25 metenoprost and tiaprost.

42. Pharmaceutical formulation according to Claim 41, in which the prostaglandin is PGE, or prostacyclin. :

43. Pharmaceutical formulation according to Claim 41, in which the prostaglandin is prostacyclin.

44. Pharmaceutical formation according to one of the preceding claims, comprising one or more excipients and/or assistants.

: ® -79-

45. Use of a pharmaceutical preparation according to one of Claims 1 to 44 for the preparation of a medicament for the treatment of angina, high blood pressure, pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale, dextrocardiac insufficiency, atherosclerosis, conditions of reduced patency of heart vessels, peripheral vascular diseases, strokes, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, irritable bowel syndrome, tumours, renal insufficiency, liver cirrhosis and for the treatment of female sexual disorders.

46. Use according to Claim 45 for the preparation of a medicament for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale and/or dextrocardiac insufficiency.

47. Set (kit) consisting of separate packs of (a) an effective amount [7-(3-chloro-4-methoxybenzylamino)-1- methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yimethoxyJacetic acid, ethanolamine salt, and (b) an effective amount of an antithrombotic.

48. Use of [7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H- pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]acetic acid, ethanolamine salt, i 25 for the preparation of a medicament for the treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale and/or dextrocardiac insufficiency.

49. Set (kit) consisting of separate packs of ] (a) an effective amount of [7-(3-chloro-4-methoxybenzylamino)- 1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yimethoxy]acetic acid, ethanolamine salt, and (b) an effective amount of a calcium antagonist.

° or

50. Set (kit) consisting of separate packs of : (a) an effective amount of [7-(3-chloro-4-methoxybenzylamino)- 1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-ylmethoxylacetic acid, ethanolamine salt, and (b) an effective amount of a prostaglandin or prostaglandin derivative.

51. Use of a pharmaceutical preparation comprising at least one phosphodiesterase V inhibitor and at least one prostaglandin or prostaglandin derivative for the preparation of a medicament for the : oral treatment of pulmonary hypertension, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), cor pulmonale and/or dextrocardiac insufficiency.