Provided herein are sulfonamides of general formula (A); a conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient or a diagnostic compound; a process for preparing a conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient; a pharmaceutical composition comprising the conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient or a diagnostic compound; and to the use of the conjugate as a medicament.

The release of insulin by the pancreas is strictly coupled to the concentration of the blood glucose. Elevated blood glucose levels, such as occur after meals, are rapidly compensated by a corresponding increase in insulin (a blood glucose lowering hormone) secretion. In the fasting state, the plasma insulin level falls to a basal value which is adequate to guarantee a continuous supply of insulin-sensitive organs and tissue with glucose and to keep hepatic glucose production low in the night. Diabetes mellitus is a metabolic disorder in which this tight regulation of blood glucose is disturbed.

Diabetes mellitus is characterized by either a reduced/missing production of insulin by the pancreas and/or the incapability to use insulin. As a consequence, blood glucose levels are inadequately controlled and therefore elevated. Blood glucose levels which are increased for years without initial symptoms are a considerable health risk. The large-scale DCCT study in the USA (The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med. 329, 977-986) demonstrated clearly that chronically elevated blood glucose levels are essentially responsible for the development of diabetic late complications, such as microvascular and macrovascular damage which is manifested, under certain circumstances, as retinopathy, nephropathy or neuropathy and leads to loss of sight, kidney failure and the loss of extremities. Moreover diabetes is accompanied by an increased risk of cardiovascular diseases.

Worldwide, in 2016, approximately 422 million people suffer from type 1 and type 2 diabetes mellitus. Diabetes mellitus is classified in type 1 and type 2 diabetes. In type 1 diabetes patients, no insulin produced by the body itself is available. Therefore, since no cure is available, for type 1 diabetics the substitution of the lacking endocrine insulin secretion is the only currently possible therapy. The affected persons are dependent lifelong on insulin injections, as a rule a number of times daily. In contrast to type 1 diabetes, there is not basically a deficiency of insulin in type 2 diabetes, but in a large number of cases, especially in the advanced stage, treatment with insulin, optionally in combination with an oral antidiabetic, is regarded as the most favourable form of therapy.

The goal of current diabetes mellitus therapy is primarily to keep the blood glucose as closely as possible in the physiological range. Current therapy recommendations include treatment with oral anti-diabetic drugs, GLP-1 receptor agonists and finally treatment with insulin.

Human insulin is a polypeptide of 51 amino acids, which is comprised of 2 amino acid chains: the A chain having 21 amino acids and the B chain having 30 amino acids. The chains are connected to one another by means of 2 disulfide bridges

(interchenar disulfide brigdes are between Cys(A7) and Cys(B7) and between Cys(A20) and (Cys(B19)). Additonally, an intrachenar disulfide bridge is present between Cys(A6) and Cys(A11 ). Insulin preparations have been employed for diabetes mellitus therapy for many years. Not only human insulins are used here, but recently also insulin derivatives and analogs.

In view of the problems and discomforts associated with a daily or repeated daily injection(s), there are ongoing efforts to find insulin preparations with a prolonged profile of action - the aim is a once weekly dosage regimen.

Provided herein are sulfonamides of formula (A)

As used herein, the terms’’analog of insulin” and“insulin analog” refer to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring insulin, for example that of human insulin, by deleting and/or exchanging at least one amino acid residue occurring in the naturally occurring insulin and/or adding at least one amino acid residue. The added and/or exchanged amino acid residue can either be codable amino acid residues or other naturally occurring residues or purely synthetic amino acid residues. Examples of analogs of insulin include, but are not limited to, the following:

(i). 'Insulin aspart' is human insulin where the amino acid B28 (i.e. the amino acid no. 28 in the B chain of human insulin), which is proline, is replaced by aspartic acid. Insulin aspart is a short-acting insulin.

(ii). 'Insulin lispro' is human insulin where the penultimate lysine and proline residues on the C-terminal end of the B-chain of are reversed (human insulin: ProB28LysB29; insulin lispro: LysB28ProB29). Insulin lispro is a short-acting insulin.

(iii). 'Insulin glulisine' differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid. Insulin glulisine is a short-acting insulin.

(iv). “Insulin glargine” differs from human insulin in that the asparagine at position

A21 is replaced by glycine and the B chain is extended at the carboxy terminal by two arginines. Insulin glargine a long-acting insulin.

As used herein, the term“insulin conjugate” is synonymous with ..derivative of insulin” and “insulin derivative” - the term refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring insulin, for example that of human insulin, in which one or more organic substituents (e.g. a fatty acid) is bound to one or more of the amino acids. The one or more organic substituents are designed to interact with serum proteins like albumin and are called herein “binder(s)” or “binder molecule(s)”. Optionally, one or more amino acids occurring in the naturally occurring insulin may have been deleted and/or replaced by other amino acids, including non-codeable amino acids, or amino acids, including non-codable, have been added to the naturally occurring insulin. Examples of conjugates of insulin include, but are not limited to, the following:

(i). 'Insulin detemir' which differs from human insulin in that amino acid threonine at position B30 is deleted and a fatty acid residue (myristic acid) is attached to the epsilon-amino function of the lysine in position B29. Insulin detemir is a long-acting insulin.

(ii). 'Insulin degludec' which differs from human insulin in that the amino acid threonine at position B30 is deleted and that a hexadecanedioic acid is conjugated to the amino acid lysine B29 via a gamma-L-glutamyl-linker. Insulin degludec is a long-acting insulin.

As used herein, the term“fast acting insulin” refers to insulin analogs and/or insulin derivatives, wherein the insulin-mediated effect begins within 5 to 15 minutes and continues to be active for 3 to 4 hours. Examples of fast acting insulins include, but are not limited to, the following: (i). insulin aspart; (ii). insulin lispro and (iii). insulin glulisine.

As used herein, the term“long acting insulin” refers to insulin analogs and/or insulin derivatives, wherein the insulin-mediated effect begins within 0.5 to 2 hours and continues to be active, for about or more than 24 hours. Examples of fast acting insulins include, but are not limited to, the following: (i). insulin glargin; (ii). insuline detemir and (iii). insulin degludec.

Provided herein are serum albumin binding moieties, which when coupled to a peptide lead to improved pharmacodynamics and/or pharmacokinetic properties of the peptide for example, an extended pharmacokinetic half life in blood and/or blood plasma and/or a prolonged profile of action, i.e. a prolonged reduction of blood glucose level.

Surprisingly, it was found that such peptide conjugates can be provided using specific sulfonamides, which can be used for peptide conjugates. The resulting peptide conjugates exhibit favorable half-life in blood and/or blood plasma and a prolonged profile of action. It could be shown that the resulting peptide conjugates have an increased pharmacokinetic half-life (t-1/2) and also an increased Mean

Residence Time (MRT) compared to the unconjugated peptides. Moreover, the

peptide conjugates have a significant prolongation of the duration of action in vivo in relation to the unconjugated peptides.

Thus, provided herein are sulfonamides of formula (A)

wherein:

A is selected from the group consisting of oxygen atom, -CH2CH2- group, -OCH2- group and -CH2O- group;

E represents a -C6H3R- group with R being a hydrogen atom or a halogen atom, wherein the halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atom;

X represents a nitrogen atom or a -CH- group;

m is an integer in the range from 5 to 17;

n is zero or an integer in the range from 1 to 3;

p is zero or 1 ;

q is zero or 1 ;

r is an integer in the range from 1 to 6;

s is zero or 1 ;

t is zero or 1 ;

R1 represents at least one residue selected from the group of hydrogen atom, halogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group;

R2 represents at least one residue selected from the group of hydrogen atom, halogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group:

Rx represents a hydrogen atom or an activation group, optionally an activation group selected from the group consisting of 7-azabenzotriazole (optionally derived from HATU [1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- bjpyridinium 3-oxide hexafluorophosphate] or HBTU [3-[bis- (dimethylamino)methyliumyl]-3H-benzotriazol-1 -oxide hexafluorophosphate]),

4-nitro benzene and N-succinim idyl-group, wherein Rx is optionally a N- succinimidyl -group.

In some embodiments, the combination of s being 1 , p being zero, n being zero, A being an oxygen atom and t being 1 is excluded. In some embodiments, s is zero, wherein the remaining residues and indices have the meaning as indicated above for formula (A).

For example, the halogenated C1 to C3 alkyl group of R1 and/or the halogenated C1 to C3 alkyl group of R2 is/are partially halogenated or per halogenated. In some embodiments, the halogenated C1 to C3 alkyl group of R1 and/or the halogenated C1 to C3 alkyl group of R2 is/are per halogenated.

As used herein, the term“sulfonamides of formula (A)” comprises the sulfonamides of formula (A), pharmaceutically acceptable salts thereof and all pharmaceutically acceptable isotopically-labeled sulfonamides of formula (A), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. The same applies to all subtypes of the sulfonamides of formula (A), i.e. to the sulfonamides of formula (A-1 ) to (A-5) as detailed below and also to their substructures respetively, for example, the sulfonamides of formula (A-1 -1 ). That is, the term“sulfonamides of formula (A-... )”, wherein (A-... ) represents the number of the sulfonamides of formula (A-1 ) to (A-5) as detailed below and also their

substructures, comprises the compounds themselves, pharmaceutically acceptable salts and all pharmaceutically acceptable isotopically-labeled compounds thereof.

Pharmaceutically acceptable salts of the sulfonamides of formula (A) are base salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, bis(2-hydroxyethyl)amine (diolamine), glycine, lysine, magnesium, meglumine, 2-aminoethanol (olamine), potassium, sodium, 2-amino-2-(hydroxymethyl)propane-1 ,3-diol (tris or tromethamine) and zinc salts. For a review on suitable salts, see

Flandbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

The sulfonamides of formula (A), and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the sulfonamides of formula (A), or a

pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

Examples of isotopes suitable for inclusion in the sulfonamides of formula (A) include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, and sulfur, such as 35S.

Certain isotopically-labelled sulfonamides of formula (A), for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled sulfonamides of formula (A) can generally be prepared by conventional techniques known to those skilled in the art.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, de acetone, d6-DMSO.

In order to identify suitable binder molecules, which when bound to a peptide, such as an insulin, are able to improve the half-life in plasma and to prolong the profile of action, a system was established based on affinity chromatography with serum albumin columns, i.e. columns with immobilized serum albumin.

The net retention time of the binders (samples) was calculated according to the following formula:

Net retention time = RetTime sample - RetTime to marker

Sulfonamides of formula (A) have a net retention in the range of from 9 to 19, for example in the range of from 9.5 to18, and were consequently considered to be useful binders for peptide conjugates, such as insulin conjugates.

According to one embodiment, the sulfonamide has the formula (A-1 )

wherein:

E represents a -C6H3R- group with R being a hydrogen atom or a halogen atom, wherein the halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atom and is for example a fluorine atom;

X represents a nitrogen atom or a -CH- group;

p is zero or 1 ;

q is zero or 1 ;

r is an integer in the range from 1 to 6;

R1 represents at least one residue selected from the group of hydrogen atom and halogen atom, wherein the halogen atom is for example a fluorine or chlorine atom;

R2 represents at least one residue selected from the group of hydrogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group, wherein the C1 to C3 alkyl group is for example a methyl group and the halogenated C1 to C3 alkyl group is for example perhalogenated such as a trifluoromethyl group;

Rx represents a hydrogen atom or an activation group, optionally an activation group selected from the group consisting of 7-azabenzotriazole (optionally derived from HATU or HBTU), 4-nitro benzene and N-succinimidyl-group, wherein Rx is optionally a N-succinimidyl-group;

with m being an integer in the range from 5 to 15 if p is zero, or m being an integer in the range from 7 to 15 if p is 1 .

In one embodiment of the sulfonamide, R1 and R2 are hydrogen atoms.

In one embodiment of the sulfonamide, X represents a nitrogen atom.

According to another embodiment of the sulfonamide, the H00C-(CH2)m-(0)s-(E)P-(CH2)n-(A)t- group of formula (A) or the H00C-(CH2)m-(E)P-0- group of formula (A-1 ) is situated in meta or para position on phenyl ring Ph with respect to the -S(0)2- group.

According to another embodiment of the sulfonamide, if p is 1 , the H00C-(CH2)m-(0)s-group and the -(CH2)n-(A)t- group are situated in meta or para position on (E)P of formula (A) or the HOOC-(CH2)m- group and the -0- are situated in meta or para position on (E)P of formula (A-1 ).

According to another embodiment of the sulfonamide, q is zero.

According to another embodiment, the sulfonamide has the formula (A-1 -1 )

wherein X is a nitrogen atom or a -CH- group, for example a nitrogen atom; m is an integer in the range from 7 to 15; r is an integer in the range from 1 to 6; q is zero or 1 , for example zero; Hal is a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine atom, for example a fluorine atom; Rx is a hydrogen atom or an activation group, optionally an activation group selected from the group consisting of 7-azabenzotriazole (optionally derived from HATU or HBTU), 4-nitro benzene and N-succinimidyl-group, wherein Rx is optionally a N-succinimidyl-group;

and the H00C-(CH2)m-C6H3Hal-0- group is situated in meta or para position on phenyl ring Ph with respect to the -S(0)2- group.

According to one embodiment, the sulfonamide has the formula (A-1 -1 a)

According to another embodiment, the sulfonamide has the formula (A-1 -2)

wherein X is a nitrogen atom or a -CH- group, for example a nitrogen atom; m is an integer in the range from 5 to 15; r is an integer in the range from 1 to 6; q is zero or 1 , for example zero; Rx is a hydrogen atom or an activation group, optionally an activation group selected from the group consisting of 7-azabenzotriazole (optionally derived from HATU or HBTU), 4-nitro benzene and N-succinimidyl-group, wherein Rx is optionally a N-succinimidyl-group;and the H00C-(CH2)m-0- group is situated in meta or para position on phenyl ring Ph with respect to the -S(0)2- group.

According to one embodiment, the sulfonamide has the formula (A-1 -2a)

or the formula (A-1 -2c)

According to another embodiment, the sulfonamide has the formula (A-2)

wherein

X represents a nitrogen atom or a -CH- group;

Rx represents a hydrogen atom or an activation group, optionally an activation group selected from the group consisting of 7-azabenzotriazole (optionally derived from HATU or HBTU), 4-nitro benzene and N-succinimidyl-group, wherein Rx is optionally a N-succinimidyl-group; and

m is an integer in the range from 5 to 17, for example in the range from 11 to 17.

According to one embodiment of the sulfonamide of formula (A-2), the HOOC-(CH2)m-group is s situated in meta or para position on phenyl ring Ph with respect to the -S(0)2-group.

According to another embodiment, the sulfonamide has the formula (A-3)

wherein

E represents a -C6H3R- group with R being a hydrogen atom or a halogen atom, wherein the halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atom;

X represents a nitrogen atom or a -CH- group;

Rx represents a hydrogen atom or an activation group, optionally an activation group selected from the group consisting of 7-azabenzotriazole (optionally derived from HATU or HBTU), 4-nitro benzene and N-succinimidyl-group, wherein Rx is optionally a N-succinimidyl-group; and

m is an integer in the range from 5 to 17, for example 11.

According to one embodiment of the sulfonamide of formula (A-3), the HOOC-(CH2)m-0- group and the -(CH2)2- group are situated in para position on (E) of formula (A-3) and the H00C-(CH2)m-0-(E)-(CH2)2- group is situated in para position on phenyl ring Ph with respect to the -S(0)2- group.

According to another embodiment, the sulfonamide has the formula (A-4)

wherein

A is a -OCH2- group or a -CH2O- group;

E represents a -C6H3R- group with R being a hydrogen atom or a halogen atom, wherein the halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atom;

X represents a nitrogen atom or a -CH- group;

Rx represents a hydrogen atom or an activation group, optionally an activation group selected from the group consisting of 7-azabenzotriazole (optionally derived from HATU or HBTU), 4-nitro benzene and N-succinimidyl-group, wherein Rx is optionally a N-succinimidyl-group; and

m is an integer in the range of from 5 to 17, for example in the range of from 9 to 13.

According to one embodiment of the sulfonamide of formula (A-4), the HOOC-(CH2)m-group and the -A- group are situated in para position on (E) of formula (A-4) and the -A- group is situated in para position on phenyl ring Ph with respect to the -S(0)2- group.

According to another embodiment, the sulfonamide has the formula (A-5)

wherein

E represents a -C6H3R- group with R being a hydrogen atom or a halogen atom, wherein the halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atom;

X represents a nitrogen atom or a -CH- group;

Rx represents a hydrogen atom or an activation group, optionally an activation group selected from the group consisting of 7-azabenzotriazole (optionally derived from HATU or HBTU), 4-nitro benzene and N-succinimidyl-group, wherein Rx is optionally a N-succinimidyl-group; and

m is an integer in the range of from 5 to 17, for example in the range of from 7 to 9.

According to one embodiment of the sulfonamide of formula (A-5), the HOOC-(CH2)m-group and the -(CH2)2- group are situated in para position on (E) of formula (A-5) and the H00C-(CH2)mE)-(CH2)2-0-- group is situated in para position on phenyl ring Ph with respect to the -S(0)2- group.

Conjugate

Provided herein are conjugates comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient or a diagnostic compound

wherein in the sulfonamide of formula (I):

A is selected from the group consisting of oxygen atom, -CH2CH2- group, -OCH2- group and -CH2O- group;

E represents a -C6H3R- group with R being a hydrogen atom or a halogen atom, wherein the halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atom;

X represents a nitrogen atom or a -CH- group;

m is an integer in the range from 5 to 17;

n is zero or an integer in the range from 1 to 3;

p is zero or 1 ;

q is zero or 1 ;

r is an integer in the range from 1 to 6;

s is zero or 1 ;

t is zero or 1 ;

R1 represents at least one residue selected from the group of hydrogen atom, halogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group;

R2 represents at least one residue selected from the group of hydrogen atom, halogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group; wherein the sulfonamide of formula (I) is covalently bound to the active pharmaceutical ingredient or the diagnostic compound in that the terminal carboxy group“a” of the sulfonamide of formula (I) is covalently bound to a suitable functional group of the active pharmaceutical ingredient or of the diagnostic compound, for example to an amino group or a hydroxyl group of the active pharmaceutical ingredient or of the diagnostic compound.

For example, the active pharmaceutical ingredient is a peptide, wherein the peptide and the sulfonamide of formula (I) are for example connected by an amide bond, for example formed between the terminal carboxy group“a” of the sulfonamide of formula (I) and an amino group of the peptide. It goes without saying that in case of an amide bond, the carboxyl group“a” is present in the conjugate as carbonyl group -C(=0)- , as shown below, wherein all residues E, A, R1, R2, X, as well as the indizes m, s, p, n, t, r and q have the meaning as indicated above for formula (I) and the NH— group is already the part remaining from the peptide’s amino group :

In some embodiments, the combination of s being 1 , p being zero, n being zero, A being an oxygen atom and t being 1 is excluded for the sulfonamide of formula (I). In some embodiments, s is zero, wherein the remaining residues and indices have the meaning as indicated above for formula (I).

Claims

1. A sulfonamide of formula (A)

wherein:

A is selected from the group consisting of oxygen atom, -CH2CH2- group, - OCH2- group and -CH2O- group;

E represents a -C6H3R- group with R being a hydrogen atom or a halogen atom, wherein the halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atom;

X represents a nitrogen atom or a -CH- group;

m is an integer in the range from 5 to 17;

n is zero or an integer in the range from 1 to 3;

p is zero or 1 ;

q is zero or 1 ;

r is an integer in the range from 1 to 6;

s is zero or 1 ;

t is zero or 1 ;

R1 represents at least one residue selected from the group of hydrogen atom, halogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group; R2 represents at least one residue selected from the group of hydrogen atom, halogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group; Rx represents a hydrogen atom or an activation group.

2. The sulfonamide according to claim 1 having the formula (A-1 )

wherein:

E represents a -C6H3R- group with R being a hydrogen atom or a halogen atom, wherein the halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atom;

X represents a nitrogen atom or a -CH- group;

p is zero or 1 ;

q is zero or 1 ;

r is an integer in the range from 1 to 6;

R1 represents at least one residue selected from the group of hydrogen atom and halogen atom;

R2 represents at least one residue selected from the group of hydrogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group;

Rx represents a hydrogen atom or an activation group; and

with m being an integer in the range from 5 to 15 if p is zero, or m being an integer in the range from7 to 15 if p is 1.

3. The sulfonamide according to claim 1 or 2, wherein the sulfonamide has the formula (A-1 -1 )

wherein X is a nitrogen atom or a -CH- group; m is an integer in the range from 7 to 15; r is an integer in the range from 1 to 6; q is zero or 1 ; Hal is a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine atom; Rx represents a hydrogen atom or an activation group; and the HOOC-(CH2)m- C6H3Hal-0- group is situated in meta or para position on phenyl ring Ph with respect to the -S(0)2- group.

4. The sulfonamide according to any of claims 1 to 3, wherein the sulfonamide has the formula (A-1-1 a)

5. The sulfonamide according to claim 1 or 2, wherein the sulfonamide has the formula (A-1 -2)

wherein X is a nitrogen atom or a -CH- group; m is an integer in the range from 5 to 15; r is an integer in the range from 1 to 6; q is zero or 1 ; and the HOOC-(CH2)m- 0- group is situated in meta or para position on phenyl ring Ph with respect to the -S(0)2- group.

6. The sulfonamide according to any of claims 1 to 2 or 5, wherein the sulfonamide has the formula (A-1 -2a)

the formula (A-1 -2c)

7. A conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient

wherein in the sulfonamide of formula (I):

A is selected from the group consisting of oxygen atom, -CH2CH2- group, - OChte-group and -CH2O- group;

E represents a -C6H3R- group with R being a hydrogen atom or a halogen atom, wherein the halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atom;

X represents a nitrogen atom or a -CH- group;

m is an integer in the range from 5 to 17;

n is zero or an integer in the range from 1 to 3;

p is zero or 1 ;

q is zero or 1 ;

r is an integer in the range from 1 to 6;

s is zero or 1 ;

t is zero or 1 ;

R1 represents at least one residue selected from the group of hydrogen atom, halogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group; R2 represents at least one residue selected from the group of hydrogen atom, halogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group; wherein the sulfonamide of formula (I) is covalently bound to the active pharmaceutical ingredient in that the terminal carboxy group“a” of the sulfonamide of formula (I) is covalently bound to an amino group of the pharmaceutically active agent.

8. The conjugate according to claim 7, wherein the active pharmaceutical ingredient is selected from the group consisting of insulin, insulin analog, GLP-1 , and GLP-1 analog.

9. The conjugate according to claim 7 or 8, wherein the active pharmaceutical ingredient is insulin or an insulin analog, wherein the amino group of the peptide, to which the sulfonamide of formula (I) is covalently bound, is an epsilon amino group of a lysine present in the insulin or insulin analog or is the N-terminal amino group of the B chain of the insulin or insulin analog.

10. A process for preparing a conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient

wherein in the sulfonamide of formula (I):

A is selected from the group consisting of oxygen atom, -CH2CH2- group, - OCH2- group and -CH2O- group;

E represents a -C6H3R- group with R being a hydrogen atom or a halogen atom, wherein the halogen atom is selected from the group consisting of fluorine, chlorine, bromine and iodine atom;

X represents a nitrogen atom or a -CH- group;

m is an integer in the range from 5 to 17;

n is zero or an integer in the range from 1 to 3;

p is zero or 1 ;

q is zero or 1 ;

r is an integer in the range from 1 to 6;

s is zero or 1 ;

t is zero or 1 ;

R1 represents at least one residue selected from the group of hydrogen atom, halogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group; R2 represents at least one residue selected from the group of hydrogen atom, halogen atom, C1 to C3 alkyl group and halogenated C1 to C3 alkyl group; wherein the sulfonamide of formula (I) is covalently bound to the active pharmaceutical ingredient in that the terminal carboxy group“a” of the sulfonamide of formula (I) is covalently bound to an amino group of the active pharmaceutical ingredient;

comprising:

(a) providing a sulfonamide of formula (Aa)

wherein X, Y, A, E, R1, R2 and the indices m, n, p, q, r, s, t have the meaning as defined in claim 1 , Rx is a hydrogen atom or an activation group; and R3 is a protective group or a hydrogen atom,; and a active pharmaceutical ingredient having a protected or unprotected C terminus;

(b) reacting the sulfonamide of formula (Aa) and the active pharmaceutical ingredient having a protected or unprotected C terminus under conditions suitable to form an amide bond between the free or activated carboxy group “a” of the sulfonamide of formula (Aa) and an amino group of the active pharmaceutical ingredient having a protected or unprotected C terminus;

(c) optionally removing one or both protection groups.

11. A conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient obtained or obtainable from the process according to claim 10.

12. Pharmaceutical composition comprising in a pharmaceutically effective amount the conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient according to any of claims 7 to 9 or according to claim 11.

13. The conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient according to any of claims 7 to 9 or according to claim 11 for use as a medicament.

14. The conjugate comprising a sulfonamide of formula (I) and an active pharmaceutical ingredient according to any of claims 7 to 9 or according to claim 11 for use as a medicament for treatment of a disease selected from the group

consisting of gestational diabetes, diabetes mellitus type 1 , diabetes mellitus type 2 and hyperglycemia and/or for lowering blood glucose levels.