DE19841985A1 - New heterocyclic alkanesulfonic and alkane carboxylic acid derivatives are VEGF receptor blockers useful in treatment of e.g. psoriasis, rheumatoid arthritis, stroke, tumors and endometriosis - Google Patents

Abstract

Heterocyclic alkanesulfonic and alkanecarboxylic acid derivatives are new. The heterocyclic alkanesulfonic and alkanecarboxylic acid derivatives have formula (I): A and B = group of formula (i)-(iv): R<1> = H; 1-4C alkyl, 1-4C alkoxy, 2-4C alkenyl or 2-4C alkynyl; thien-3-yl; pyrid-4-yl; or a group of formula (v); R<2> = 1-4C alkanesulfonic acid or 1-4C alkanecarboxylic acid; R<3> and R<4> = H; halo; 1-4C alkoxy or phenyl; R<5> and R<6> = H; halo; 1-4C alkyl; or 1-4C alkoxy; Z' = N; O; S; =C(R<7>)(R<8>); or =N-R<9>; R<7> and R<8> = H; halo; 1-4C alkyl; or 1-4C alkoxy; R<9> = 1-4C alkyl; m and n = 0-6; bonds a-d are single or double (double bonds present can be isolated or conjugated); compounds are excluded when m = n = 0 and R<1> = H.

Description

The invention relates to dialkyl sulfonic acid and dialkyl carboxylic acid substituted Alkenes with VEGF receptor blocker properties and their use for Manufacture of medicines for the treatment of various Diseases.

Persistent angiogenesis can cause various diseases such as Psoriasis, rheumatoid arthritis, hemangioma, angiofribroma, diabetic Retinopathy and neovascular glaucoma or worsening of these diseases. An inhibitor with VEGF receptor blocker properties can be used for treatment such diseases and other VEGF-induced pathological Angiogenesis and vascular permeable conditions, such as tumor Vascularization.

It is known that by soluble receptors and antibodies against VEGF that Growth of tumors can be inhibited.

In WO 94/21679 vascular endothelial cell growth factor (VEGF) are Described inhibitors that are of natural origin or recombinant represent soluble forms produced. It is also described that the soluble forms of the receptor to the growth factor with high affinity bind and do not lead to signal transduction. Such soluble forms of Receptor bind VEGF and inhibit its function.

A disadvantage of the known inhibitors is that they consist of high molecular weight Peptides exist, their isolation or production, characterization and Cleaning involves a lot of work. Furthermore, Such high molecular weight compounds are usually not without problems Formulate medication and then apply it as a medication. Furthermore, the shelf life of such preparations is less than that of low molecular weight compounds.  

From DE 29 09 190 monomethine cyanines are known as find photographic recording material. Over a The use of such compounds in medicine is not described.

Japanese Patent Application JP 97227378 discloses compounds known to be used as a means of treating cancer and tumors can be. Nothing is known about their effect as VEGF receptor blockers described.

It would therefore be desirable to have new and effective compounds VEGF receptor blocker properties that are used to treat the diseases mentioned above can be used.

It has now been found that dialkylsulfonic acid and dialkylcarboxylic acid substituted alkenes of the general formula I

in the
A and B simultaneously or independently of one another each of the groups

R ^{1 is} hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or the group

R ^{2 is} C ₁ -C ₆ alkyl sulfonic acid or C ₁ -C ₆ alkyl carboxylic acid,
R ³ and R ⁴ independently of one another are hydrogen, halogen, C ₁ -C ₆ alkoxy or phenyl,
R ⁵ and R ⁶ independently of one another are hydrogen, C ₁ -C ₆ alkyl, halogen or C ₁ -C ₆ alkoxy,
Z = N, O, S or the group

R ⁷ and R ^{8 are} hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halogen,
R ⁹ C ₁ -C ₆ alkyl,
represents a single or double bond, which can be isolated or conjugated
and
n and m independently of one another represent 0, 1, 2, 3, 4, 5 or 6, with the exception of the compounds in which n and m = 0 and represent hydrogen,
mean have a VEGF receptor blocker property.

The term "alkyl" means that the carbon chain is straight or can be branched.

The term "alkenyl" means that the carbon chain is one or more times can be interrupted by double bonds.  

The term "alkynyl" means that the carbon chain is one or more times can be interrupted by triple bonds.

Instead of the free bases, their hydrogen salts can also be used inorganic or organic acids such as e.g. B. hydrohalides, Use hydrogen sulfates, p-toluenesulfonates, perfluorobutyrates etc. Instead of The free sulfonic acids can also be their alkali or alkaline earth metal salts, such as Li, Na, K, Rb, Cs, Ca and Mg or ammonium salts, including primary and use secondary organic bases.

Instead of the free carboxylic acids, halogens such as F ^- , Cl ^- , Br ^- and J ^- can also be used.

Preferred cations are e.g. B. Na ⁺ , K ⁺ , HN ⁺ (C ₂ H ₅ ) ₃ , N ⁺ (C ₂ H ₅ ) ₄ ,

The term halogen stands for fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

Preferred compounds of the general formula I are those in which A and B simultaneously or independently of one another each of the groups

R ^{1 is} hydrogen, C ₁ -C ₄ alkyl or the group

R ^{2 is} C ₁ -C ₄ alkylsulfonic acid or C ₁ -C ₄ alkylcarboxylic acid,
R ³ and R ⁴ independently of one another are hydrogen, chlorine, methoxy or phenyl,
R ⁵ and R ^{6 are} independently hydrogen, bromine, C ₁ -C ₄ alkyl or methoxy
Z = N, O, S or the group

R ⁷ , R ⁸ and methyl or ethyl,
represents a single or double bond, which can be isolated or conjugated
and
n and m independently of one another represent 0, 1, 2, 3 or 4, with the exception of the compounds in which n and m = 0 and represent hydrogen.

The invention further relates to the use of the compounds of the general formula I in which R ¹ -R ⁹ , A, B, Z and the meanings given in general formula I and n and m independently of one another for 0 1, 2, 3, 4, 5 or 6 and stand for hydrogen, as an active pharmaceutical ingredient.

The compounds according to the invention come as active pharmaceutical ingredients for use and can be used alone or in the form of a pharmaceutical Composition containing one or more compounds of general Formula I contains, together with pharmaceutically suitable solutions and Carriers are applied.

The compounds of the invention can be used alone, as a mixture or as Composition together with pharmaceutically suitable solutions and Carriers enterally, parenterally, intravenously, subcutaneously, orally or transdermally be applied.

The compounds according to the invention and their compositions and Mixtures can be used to make a drug for the treatment of Diseases such as psoriasis, rheumatoid arthritis, hemangioma, Angiofibroma, diabetic retinopathy and neovascular glaucoma and other VEGF-induced pathological angiogenesis, VEGF-related Vascular permeabilization, edema, stroke and vascular permeable Conditions such as tumor vascularization can be used.

In particular, the compounds according to the invention can be used for the preparation a drug to inhibit the growth of tumors and Metastases are used.  

The compounds according to the invention, their compositions and Mixtures can also be used to manufacture a drug for treatment diseases with an angiogenic background such as endometriosis, Adenomyosis, dysfunctional uterine bleeding, choriocarcinoma, ectopic Pregnancy and diseases of the ovary can be used.

The active pharmaceutical ingredients in their composition or Mixtures and their uses are also part of the present invention.

Suitable compositions may be prepared by processes known per se, all solutions used for formulation of the compounds of general formula I in the pharmaceutical carriers and additives can be used (Remington's Pharmaceutical Science, 15 ^th Ed. Mack Publishing Company, East Pennsylvania , 1980).

Different doses of come for therapeutic use Compounds according to the invention in question. So the applicable dose depends of the respective connection, the individual, the type of application (enteral, parenteral, intravenous, subcutaneous, oral, transdermal) and the severity of the treating disease.  

The following example explains the preparation of the invention Connections without restricting them to this example.

example 1

750 mg of 2-methyl-1- (3-sulfopropyl) naphtho (1,2-D) thiazolium betaine are mixed with 0.93 ml of triethoxyorthopropionate in 5 ml of pA pyridine. This reaction mixture is kept at 135 ° C. oil bath temperature with stirring for 4 hours. After cooling, the precipitated dark green crystals are filtered off and washed with a little pyridine. After recrystallization from methanol, 33.8% is obtained.
2,2'-di (3-sulfopropyl) -8-ethyl-3,4,3 ', 4'-dibenzothiacarbocyanin-ethyl-pyridinium salt.
Melting point: 201-202 ° C.

In analogue and according to literature (Brooker and White, JACS 57, 547, (1935 and 57, 2480 (19935)) The following compounds are also prepared.  

The following examples show the application of the Connections without restricting them to the examples.

Application example 1 Inhibition of ¹²⁵ VEGF binding to sVEGFR II Coating the microtiter plates

Microtiter plates are shaken with 50 µl of a VEGFR II solution (0.4 µg / ml) obtained by infection with baculoviruses from supernatants of SF-9 cells were. Then another 30 min by adding 4% BSA solution in PBS buffer blocked. The solution is removed and the cavities are removed Washed 0.1% BSA in PBS buffer.

displacement

10 ul of the compounds of the invention or unlabeled VEGF in PBS / 0.1% BSA and then 40 µl 125l VEGF in PBS / BSA (approx. 15000 cpm or 300-600 pM) are placed on the microtiter plates. Incubate at Room temperature with shaking for 60 min. removes the radioactivity, washes within 10 seconds 3 times with 0.1% BSA in PBS buffer, adds 100 µl 0.5% Add SDS solution and shake for 30 min. 80 µl of the solution are in the γ counter measured.

The results are shown in Table I.  

Example of use 2 Receptor autophosphorylation (VEGFR II ELISA)

1 × 10 ⁵ PAEC-VEGFr-II / well were cultured in 6-well plates for 72 hours without changing the medium to grow together. After 1 hour at 4 ° C, the cells were stimulated for a further hour with and without recombinant VEGF ₁₆₅ (50 ng / ml) at 4 ° C, washed with PBS buffer containing 0.1 mM Na ortho vanadate and then lysed in 300 µl / well lysis buffer. After centrifugation at 13,000 rpm for 15 minutes at 4 ° C., the clear supernatant was transferred to 96-well fluorine plates coated with MAb 2-10-1 (500 ng / well). After incubation at room temperature for 1 hour, the plates were washed and bound tyrosine-phosphorylated VEGFr-II was measured with biotinylated anti-phosphotyrosine MAb (PY-20, Transduction Labs) in combination with peroxidase-streptavidin and BM chemiluminescent substrate.

The results are shown in Table I.  

The results of the tests are shown in Table I below. In Table I µM stands for the substrate concentrations that the 125l VEGF 50% inhibit binding to the receptor.

Table I

Claims (10)

1. Compounds of the general formula I
in the
A and B simultaneously or independently of each other the group
R ^{1 is} hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or the group
R ^{2 is} C ₁ -C ₄ alkylsulfonic acid or C ₁ -C ₄ alkylcarboxylic acid,
R ³ and R ⁴ independently of one another are hydrogen, halogen, C ₁ -C ₄ alkoxy or phenyl,
R5 and R6 independently of one another are hydrogen, C ₁ -C ₄ -alkyl, halogen or C ₁ -C ₄ -alkoxy,
Z = N, O, S or the group
R ⁷ and R ^{8 are} hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen,
R ⁹ C ₁ -C ₄ alkyl,
represents a single or double bond, which can be isolated or conjugated
and
n and m independently of one another represent 0, 1, 2, 3, 4, 5 or 6, with the exception of the compounds in which n and m = 0 and represent hydrogen,
mean. 2. Compounds of general formula I, according to claim 1, in which A and B simultaneously or independently of one another the group
R ^{1 is} hydrogen, C ₁ -C ₄ alkyl or the group
R ^{2 is} C ₁ -C ₄ alkylsulfonic acid or C ₁ -C ₄ alkylcarboxylic acid,
R ³ and R ⁴ independently of one another are hydrogen, chlorine, methoxy or phenyl,
R ⁵ and R ^{6 are} independently hydrogen, bromine, C ₁ -C ₄ alkyl or methoxy
Z = N, O, S or the group
R ⁷ , R ⁸ and R ^{9 are} methyl or ethyl,
represents a single or double bond, which can be isolated or conjugated
and
n and m independently of one another represent 0, 1, 2, 3, 4, 5 or 6, with the exception of the compounds in which n and m = 0 and R1 represents hydrogen,
mean. 3. Compounds of general formula I, according to one of claims 1 and 2, as an active pharmaceutical ingredient. 4. Compounds of the general formula I in which
R ¹ -R ⁹ , A, B, Z and have the meanings given in the general formula I and
n and m independently of one another represent 0, 1, 2, 3, 4, 5 or 6 and represent hydrogen, as an active pharmaceutical ingredient. 5. A pharmaceutical composition containing one or more Compounds of general formula I, according to claims 1-4, together with pharmaceutically suitable solutions, carriers and Contains additives. 6. An enteral, parenteral, intravenous, subcutaneous, oral, or transdermal Applicable composition containing one or more compounds of the general formula I, according to claims 1-4, together with pharmaceutically suitable solutions, carriers and additives contains. 7. Use of the compounds according to claims 1-4 and their Compositions according to claims 5 and 6 or their Mixtures for the manufacture of a medicament for the treatment of Psoriasis, rheumatoid arthritis, hemangioma, angiofibroma, Diabetic retinopathy and neovascular glaucoma. 8. Use of the compounds according to claims 1-4 and their Compositions according to claims 5 and 6 or their Mixtures for the manufacture of a medicament for the treatment of VEGF-induced pathological angiogenesis, VEGF-related Vascular permeabilization, edema and stroke. 9. Use of the compounds according to claims 1-4 and their Compositions according to claims 5 and 6 or their  Mixtures for the manufacture of a medicament for inhibiting the Growth of tumors and metastases. 10. Use of the compounds according to claims 1-4 and their Compositions according to claims 5 and 6 or their Mixtures for the manufacture of a medicament for the treatment of Diseases with an angiogenic background such as endometriosis, Adenomyosis, dysfunctional bleeding of the uterus, choriocarcinoma, Ectopic pregnancy and diseases of the ovary.